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Hagerty BL, Sato T, Wu R, Ishikawa T, Takabe K. Mesothelin (MSLN) is Highly Expressed in Triple Negative Breast Cancer and is Associated with Enhanced Cell Proliferation and Proinflammatory Tumor Microenvironment. Ann Surg Oncol 2025:10.1245/s10434-025-17117-y. [PMID: 40080368 DOI: 10.1245/s10434-025-17117-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Accepted: 02/18/2025] [Indexed: 03/15/2025]
Abstract
BACKGROUND Mesothelin (MSLN), a cell surface glycoprotein, is commonly expressed in several cancers, including 40% of triple negative breast cancer (TNBC) cases. Although its cellular or physiologic functions remain unclear, MSLN has been leveraged as a target for molecular therapies. This study investigates MSLN's potential role in TNBC, the breast cancer (BC) subtype with poorest outcomes. PATIENTS AND METHODS The breast cancer (BC) cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 313), The Cancer Genome Atlas (TCGA, n = 160), and SCAN-B (n = 155) were used to obtain biological variables and gene expression data. RESULTS High MSLN expression was primarily observed in epithelial cells, and its expression was associated with reduced stromal adipocytes in the tumor microenvironment (TME), supporting its role as a TNBC surface marker. MSLN expression was also associated with the TNBC subtype and advanced N stages in BC. However, MSLN expression did not correlate with long-term survival outcomes, including overall survival (OS), disease-specific survival (DSS), or disease-free survival (DFS); nevertheless, it was still associated with favorable response to neoadjuvant chemotherapy (NAC). Indeed, MSLN-high tumors exhibited a proinflammatory microenvironment, higher cancer-testis antigen (CTA) scores, and increased immune cell activity, notably immature dendritic cells (iDCs) and M1 macrophages. Biologically, MSLN expression was linked to increased cellular proliferation, with gene set enrichment analysis (GSEA) showing enrichment in pathways related to rapid proliferation, such as G2M checkpoint and E2F targets. CONCLUSIONS MSLN-high TNBC is characterized by increased tumor grade, enhanced cell proliferation, and a proinflammatory microenvironment, showing better response to neoadjuvant chemotherapy without significant impact on long-term survival outcomes.
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Affiliation(s)
- Brendan L Hagerty
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Takumi Sato
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan.
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA.
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
- Department of Gastroenterological Surgery, Yokohama City University School of Medicine, Yokohama, Kanagawa, Japan.
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan.
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Yee G, Wu R, Oshi M, Endo I, Ishikawa T, Takabe K. Activity-Regulated Cytoskeleton-Associated Protein Gene Expression Is Associated With High Infiltration of Stromal Cells and Immune Cells, but With Less Cancer Cell Proliferation and Better Overall Survival in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancers. World J Oncol 2025; 16:16-29. [PMID: 39850523 PMCID: PMC11750752 DOI: 10.14740/wjon1936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Accepted: 01/03/2025] [Indexed: 01/25/2025] Open
Abstract
Background Peritumoral lidocaine infiltration prior to excision is associated with better survival in breast cancer (BC), which led us to hypothesize that innervation to the tumor affects its biology and patient survival. Activity-regulated cytoskeleton-associated protein (ARC) gene expression is known to be regulated by neuronal activity. Therefore, we studied the clinical relevance of ARC gene expression as a surrogate of neuronal activity in BC. Methods Sweden Cancerome Analysis Network - Breast (SCAN-B (GSE96058), n = 3,273) cohort and The Cancer Genome Atlas (TCGA, n = 1,069) were analyzed. Results High ARC expression was significantly associated with smaller tumor size, without lymph node metastasis, and less stage IV disease in one cohort, but not validated by the other. Estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) and luminal A expressed significantly higher ARC compared to the other subtypes in both cohorts (P < 0.005). High ARC BC was significantly associated with lower Nottingham histological grade and lower Ki67 gene expression consistently in ER+/HER2- but not triple negative breast cancer (TNBC) in both cohorts (P < 0.001). Cell proliferation-related gene sets in the Hallmark collection (E2F targets, G2M checkpoint, and mitotic spindle) were significantly enriched to low ARC BC in ER+/HER2- but not TNBC in TCGA. The stromal cells (fibroblasts, vascular endothelial cells, and adipocytes) were all significantly infiltrated in high ARC ER+/HER2-, but not in TNBC, except for neurons. Homologous recombination deficiency, intratumor heterogeneity, fraction altered, silent or non-silent mutation rate were all significantly lower in high ARC ER+/HER2- but not TNBC. Although there was no difference in single nucleotide variant or indel neoantigens, tumor infiltrating lymphocytes, and cytolytic activity by ARC expression regardless of subtype, multiple immune cells were significantly infiltrated in high ARC ER+/HER2-, including CD8, CD4 memory cells, helper type II T cells, regulatory T cells, M2 macrophages, and B cells (all P < 0.03 in both cohorts), but not in TNBC. Disease-specific and overall survival were significantly improved in high ARC ER+/HER2- consistently in both cohorts (all P < 0.05), but this was not the case in TNBC. Conclusion ARC gene expression was associated with less cancer cell proliferation, high infiltration of stromal cells and immune cells, and better survival in the ER+/HER2- but not TNBC subtype.
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Affiliation(s)
- Gabrielle Yee
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA
- These authors equally contributed to this manuscript
| | - Rongrong Wu
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- These authors equally contributed to this manuscript
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Kisar Tunca S, Unal R. Adipocyte-derived fatty acid uptake induces obesity-related breast cancer progression: a review. Mol Biol Rep 2024; 52:39. [PMID: 39644365 DOI: 10.1007/s11033-024-10139-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 11/25/2024] [Indexed: 12/09/2024]
Abstract
Obesity is a metabolic disorder that occurs when excess energy taken into the body is stored as fat. It is known that this metabolic imbalance affects the development of other diseases such as cancer, cardiovascular diseases, insulin resistance, and diabetes. The main cellular component of adipose tissue is adipocytes, and the environmental interactions of adipocytes are important to study the mechanism of disorder formation. Breast tissue is rich in adipose tissue and obesity is known to be an important risk factor in the development of breast cancer. Altered adipogenesis and lipogenesis processes in adipocytes in breast tissue support tumor development through the transfer of fatty acids released from adipocytes. We believe that blending adipocyte biology with breast cancer development is important for investigating the mechanisms that regulate breast tumor malignant behavior and providing new targets for treatment. Fatty acids, which are an energy source for breast cancer cells, are discussed from molecular perspectives in this review.
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Affiliation(s)
- Selin Kisar Tunca
- Faculty of Science, Department of Molecular Biology and Genetics, Mugla Sitki Kocman University, Mugla, Turkey
| | - Resat Unal
- Faculty of Science, Department of Molecular Biology and Genetics, Mugla Sitki Kocman University, Mugla, Turkey.
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Chida K, Wu R, Roy AM, Ishikawa T, Hakamada K, Takabe K. DEPTH2 score was associated with cell proliferation and immune cell infiltrations but not with systemic treatment response in breast cancer. RESEARCH SQUARE 2024:rs.3.rs-5260856. [PMID: 39606492 PMCID: PMC11601872 DOI: 10.21203/rs.3.rs-5260856/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Intratumoral genomic heterogeneity (ITGH), the existence of genotypic and phenotypic variation within an individual tumor, is known to be a key mechanism in treatment resistance. Deviating gene Expression Profiling Tumor Heterogeneity 2 (DEPTH2) algorithm was developed to estimate ITGH using solely RNA expression data unlike the others that require both DNA- and RNA-expression data. Total of 6,500 breast cancer patients from multiple independent cohorts were analyzed using DEPTH2. High DEPTH2 score patients were associated with worse overall survival consistently across all subtypes in METABRIC, but not in TCGA and SCAN-B cohort. Higher DEPTH2 score was linked to increased cell proliferation, as evidenced by elevated Nottingham histological grades and Ki67 gene expression, as well as enrichment of the cell proliferation-related gene sets, and immune cell infiltrations. DEPTH2 score was significantly higher in triple negative breast cancer among the subtypes but did not reflect with lymph node and distal metastasis. DEPTH2 scores decreased in two but showed no change in another two cohorts after neoadjuvant chemotherapy (NAC). DEPTH2 score was not associated with pathologic complete response after NAC in any subtypes across 3 cohorts. DEPTH2 score may not capture the entire biological aspects of ITGH in breast cancer patients.
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Sato T, Oshi M, Huang JL, Chida K, Roy AM, Endo I, Takabe K. CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer. Breast Cancer Res Treat 2024; 208:415-427. [PMID: 39017815 PMCID: PMC11849687 DOI: 10.1007/s10549-024-07434-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 07/09/2024] [Indexed: 07/18/2024]
Abstract
PURPOSE CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown. METHODS The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data. RESULTS Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/β-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts. CONCLUSION CD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.
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Affiliation(s)
- Takumi Sato
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA
- University of Tokyo Hospital, Tokyo, 113-8655, Japan
- National Hospital Organization Disaster Medical Center, Tokyo, 190-0014, Japan
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Jing Li Huang
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA
| | - Kohei Chida
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, 036-8562, Japan
| | - Arya Mariam Roy
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm & Carlton Streets, Buffalo, NY, 14263, USA.
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY, 14263, USA.
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8520, Japan.
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, 160-8402, Japan.
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Oshi M, Wu R, Khoury T, Gandhi S, Yan L, Yamada A, Ishikawa T, Endo I, Takabe K. Infiltration of Common Myeloid Progenitor (CMP) Cells is Associated With Less Aggressive Tumor Biology, Lower Risk of Brain Metastasis, Better Response to Immunotherapy, and Higher Patient Survival in Breast Cancer. Ann Surg 2024; 280:557-569. [PMID: 38946549 PMCID: PMC11797412 DOI: 10.1097/sla.0000000000006428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
OBJECTIVE To investigate the clinical relevance of common myeloid progenitor (CMP) cells in breast tumor microenvironment (TME). BACKGROUND The role of rare cells in TME is less studied. In Silico transcriptomic analyses of real-world data enable us to detect and quantify rare cells, including CMP cells. METHODS A total of 5176 breast cancer (BC) patients from SCAN-B, METABRIC, and 5 single-cell sequence cohorts were analyzed using the xCell algorithm. The high group was defined as more than two-thirds of the CMP scores in each cohort. RESULTS CMP cells consist of 0.07% to 0.25% of bulk breast tumor cells, more in estrogen receptor-positive (ER+) compared with triple-negative (TN) subtype (0.1% to 0.75%, 0.18% to 0.33% of immune cells, respectively). CMP cells did not correlate with any of the myeloid lineages or stem cells in TME. CMP infiltration was higher in smaller tumors, with lower Nottingham grade, and in ER+/HER2- than in TNBC consistently in both SCAN-B and METABRIC cohorts. High CMP was significantly associated with a lower risk of brain metastasis and with better survival, particularly in ER+/HER2-. High CMP enriched epithelial-to-mesenchymal transition and angiogenesis pathways, and less cell proliferation and DNA repair gene sets. High CMP ER+/HER2- was associated with less immune cell infiltration and cytolytic activity ( P <0.001). CMP infiltration correlated with neoadjuvant chemoimmunotherapy response for both ER+/HER2- and TNBC in the ISPY-2 cohort (AUC=0.69 and 0.74, respectively). CONCLUSIONS CMP in BC is inversely associated with cell proliferation and brain metastasis, better response to immunotherapy, and survival. This is the first to report the clinical relevance of CMP infiltration in BC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Thaer Khoury
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Akimitsu Yamada
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
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Shang JR, Zhu J, Bai L, Kulabiek D, Zhai XX, Zheng X, Qian J. Adipocytes impact on gastric cancer progression: Prognostic insights and molecular features. World J Gastrointest Oncol 2024; 16:3011-3031. [PMID: 39072151 PMCID: PMC11271780 DOI: 10.4251/wjgo.v16.i7.3011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 03/17/2024] [Accepted: 05/28/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Adipocytes, especially adipocytes within tumor tissue known as cancer-associated adipocytes, have been increasingly recognized for their pivotal role in the tumor microenvironment of gastric cancer (GC). Their influence on tumor progression and patient prognosis has sparked significant interest in recent research. The main objectives of this study were to investigate adipocyte infiltration, assess its correlation with clinical pathological features, develop a prognostic prediction model based on independent prognostic factors, evaluate the impact of adipocytes on immune cell infiltration and tumor invasiveness in GC, and identify and validate genes associated with high adipocyte expression, exploring their potential diagnostic and prognostic value. AIM To explore the relationship between increased adipocytes within tumor tissue and prognosis in GC patients as well as the associated mechanisms and potential biomarkers, using public databases and clinical data. METHODS Using mRNA microarray datasets from the Gene Expression Omnibus database and clinical samples from Jiangsu Provincial Hospital, survival and regression analyses were conducted to determine the relevant prognostic factors in GC. Feature gene selection was performed using least absolute shrinkage and selection operator and support vector machine recursive feature elimination algorithms, followed by differential gene expression analysis, gene ontology, pathway analysis, and Gene Set Enrichment Analysis. Immune cell infiltration was analyzed using the CIBERSORT algorithm. RESULTS Tumor adipocyte infiltration correlated with poor prognosis in GC, leading to the development of a highly accurate and discriminative prognostic prediction model. Key genes, ADH1B, SFRP1, PLAC9, and FABP4, were identified as associated with high adipocyte expression in GC. The diagnostic and prognostic potential of these identified genes was validated using independent datasets. Downregulation of immune cells was observed in GC with high adipocyte expression. CONCLUSION GC with high intratumoral adipocyte expression demonstrated aggressive tumor biology and a poorer prognosis. The genes ADH1B, SFRP1, PLAC9, and FABP4 have been identified as holding diagnostic and prognostic significance in GC. These findings strongly support the use of adipocyte expression as a valuable indicator of tumor invasiveness and anticipated patient outcomes in GC.
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Affiliation(s)
- Jia-Rong Shang
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Jin Zhu
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Lu Bai
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Delida Kulabiek
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Xiao-Xue Zhai
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Xia Zheng
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
| | - Jun Qian
- Department of Oncology, Jiangsu Province Hospital of Chinese Medicine, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
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Takabe YJ, Allen E, Allen L, McCarthy R, Varma A, Bace M, Sharma P, Porter C, Yan L, Wu R, Bouchard RJ, Yendamuri S. Rothia in Nonsmall Cell Lung Cancer is Associated With Worse Survival. J Surg Res 2024; 296:106-114. [PMID: 38271794 DOI: 10.1016/j.jss.2023.12.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 11/29/2023] [Accepted: 12/27/2023] [Indexed: 01/27/2024]
Abstract
INTRODUCTION The microbiome is known to play a significant role in cancer biology; however, few studies have elucidated its relationship with Nonsmall Cell Lung Cancer (NSCLC) patient outcomes. We hypothesized that there are specific microorganisms that are closely related with NSCLC patient survival. METHODS Total of 647 NSCLC (Adenocarcinoma and Squamous Cell Carcinoma combined) patients in The Cancer Genome Atlas (TCGA) were analyzed using the R software. RESULTS A Volcano Plot was analyzed with the patients divided into Short and Long Survivors by overall survival of 0.9 years, and we found that a bacterium Rothia was significantly abundant in Short Survivors, and Blastococcus, Leptospira, and Haematobacter in Long Survivors, but presence of Rothia alone was associated with overall survival. The age, race, subtype, and sex were not significantly different by the presence of Rothia in NSCLC. Unexpectedly, Rothia-positive NSCLC was associated with less cell proliferation by gene set enrichment analysis, Mki67 expression, proliferation score, with less fraction altered and homologous recombination deficiency, and with high infiltration of stromal cells, indicating favorable oncological characteristics. Further, Rothia-positive tumors were associated with significantly higher infiltration of CD8 T cells, CD4 T cells, Monocytes, and NK cells, and high interferon-gamma response, T-cell receptor richness, cytolytic activity, indicating favorable tumor immune microenvironment. CONCLUSIONS NSCLC with Rothia was associated with worse survival but also with favorable oncological characteristics such as less cell proliferation and favorable tumor immune microenvironment. We cannot help but speculate that Rothia in NSCLC is associated with mortality unrelated to oncological characteristics.
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Affiliation(s)
- Yamato J Takabe
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York; Nichols High School, Buffalo, New York; Yale University, New Haven, Connecticut
| | | | | | | | | | | | | | | | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | | | - Sai Yendamuri
- Department of Thoracic Surgery, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Sato T, Oshi M, Huang JL, Chida K, Roy AM, Endo I, Takabe K. CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer. RESEARCH SQUARE 2024:rs.3.rs-4148608. [PMID: 38585981 PMCID: PMC10996805 DOI: 10.21203/rs.3.rs-4148608/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Purpose CD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER+/HER2-) BC, the most abundant subtype, remains unknown. Methods The BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data. Results Epithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER+/HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/β-Catenin, Hedgehog, and Notchsignaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts. Conclusion CD133-high ER+/HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.
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Affiliation(s)
| | - Masanori Oshi
- Yokohama City University Graduate School of Medicine
| | | | | | | | - Itaru Endo
- Yokohama City University Graduate School of Medicine
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Chida K, Oshi M, An N, Kanazawa H, Roy AM, Mann GK, Yan L, Endo I, Hakamada K, Takabe K. Gastric cancer with enhanced myogenesis is associated with less cell proliferation, enriched epithelial-to-mesenchymal transition and angiogenesis, and poor clinical outcomes. Am J Cancer Res 2024; 14:355-367. [PMID: 38323295 PMCID: PMC10839307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 01/12/2024] [Indexed: 02/08/2024] Open
Abstract
Gastric cancer (GC) remains a lethal disease, with over 26,000 new cases and more than 11,000 deaths annually in the US. Thus, a deeper understanding of GC biology is critical to improve survival. Myogenesis is the formation of muscle fibers, which is a mesodermal tissue. In cancer, epithelial-to-mesenchymal transition (EMT) is a known phenomenon that promotes metastasis and poor survival. Given that myogenesis produces mesenchymal cells, we hypothesized that GC with increased myogenesis is linked to aggressive tumor behaviors and less favorable outcomes. In this study, three GC patient cohorts: TCGA (n=375), GSE26253 (n=432), and GSE84437 (n=482), were analyzed. The "MYOGENESIS" set in the Hallmark collection which comprises 200 myogenesis-related genes was analyzed to perform gene set variation analysis to create a score to quantify the myogenesis activity. Our results showed that T category of AJCC cancer staging that reflects the tumor invasion to stomach wall consistently correlated with myogenesis activity in two GC cohorts. High myogenesis GC was associated with lower cell proliferation, evidenced by reduced proliferation scores, decreased Ki67 gene expression, and less enrichment of E2F Targets, G2M checkpoint, MYC Targets V1, and V2 gene sets. High myogenesis tumors showed increased stromal cells (fibroblasts and adipocytes) infiltration within the tumor microenvironment, as well as less silent and non-silent mutation rates and copy number alterations. Higher lymphocyte infiltration, leukocyte fraction, T-cell receptor richness, and B-cell receptor richness were associated with high myogenesis GC. However, infiltration of CD4 cells, T helper type 1 and 2 cells, Natural Killer cells, regulatory T cells, and plasma cells was lower, with increased infiltration of dendritic cells in high myogenesis GC. High myogenesis GC enriched EMT, Hedgehog, TGF-β, and KRAS gene sets. Furthermore, it was associated with enhanced angiogenesis, evidenced by enrichment of Angiogenesis, Coagulation, and Hypoxia gene sets, and increased infiltration of microvascular and lymphatic endothelial cells and pericytes. High myogenesis GC consistently correlated with worse overall survival in all three cohorts, and worse disease-specific and progression-free survival in the TCGA cohort. Hence, our findings suggest that GC with enhanced myogenesis is associated with decreased cell proliferation, increased EMT and angiogenesis, and worse prognosis.
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Affiliation(s)
- Kohei Chida
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of MedicineHirosaki 036-8562, Japan
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa 236-0004, Japan
| | - Nan An
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Hirofumi Kanazawa
- The University of Texas Health Science Center at Tyler School of MedicineTyler, TX 11937, USA
| | - Arya M Roy
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Gabriella K Mann
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa 236-0004, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of MedicineHirosaki 036-8562, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa 236-0004, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New YorkBuffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8510, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
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11
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Wu R, Oshi M, Asaoka M, Yan L, Benesch MG, Khoury T, Nagahashi M, Miyoshi Y, Endo I, Ishikawa T, Takabe K. Intratumoral Tumor Infiltrating Lymphocytes (TILs) are Associated With Cell Proliferation and Better Survival But Not Always With Chemotherapy Response in Breast Cancer. Ann Surg 2023; 278:587-597. [PMID: 37318852 PMCID: PMC10481934 DOI: 10.1097/sla.0000000000005954] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
OBJECTIVE To investigate the clinical relevance of intratumoral tumor infiltrating lymphocytes (TILs) in breast cancer as measured by computational deconvolution of bulk tumor transcriptomes. SUMMARY BACKGROUND DATA Commonly assessed TILs, located in tumor stroma without direct contact with cancer cells (stromal TILs), correlate with breast cancer treatment response and survival. The clinical relevance of intratumoral TILs has been less studied partly due to their rarity; however, they may have nonnegligible effects given their direct contact with cancer cells. METHODS In all, 5870 breast cancer patients from TCGA, METABRIC, GSE96058, GSE25066, GSE163882, GSE123845, and GSE20271 cohorts were analyzed and validated. RESULTS The intratumoral TIL score was established by the sum of all types of lymphocytes using the xCell algorithm. This score was the highest in triple-negative breast cancer (TNBC) and the lowest in the ER-positive/HER2-negative subtype. It correlated with cytolytic activity and infiltrations of dendritic cells, macrophages, and monocytes, and uniformly enriched immune-related gene sets regardless of subtype. Intratumoral TIL-high tumors correlated with higher mutation rates and significant cell proliferation on biological, pathological, and molecular analyses only in the ER-positive/HER2-negative subtype. It was significantly associated with pathological complete response after anthracycline- and taxane-based neoadjuvant chemotherapy in about half of the cohorts, regardless of the subtype. Intratumoral TIL-high tumors correlated with better overall survival in HER2-positive and TNBC subtypes consistently in 3 cohorts. CONCLUSIONS Intratumoral TILs estimated by transcriptome computation were associated with increased immune response and cell proliferation in ER-positive/HER2-negative and better survival in HER2-positive and TNBC subtypes, but not always with pathological complete response after neoadjuvant chemotherapy.
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Affiliation(s)
- Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Mariko Asaoka
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Matthew G.K. Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Thaer Khoury
- Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Masayuki Nagahashi
- Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo Medical University School of Medicine, Nishinomiya, Hyogo, Japan
| | - Yasuo Miyoshi
- Division of Breast and Endocrine Surgery, Department of Surgery, Hyogo Medical University School of Medicine, Nishinomiya, Hyogo, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima, Japan
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12
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Mavatkar AD, Naidu CM, Prabhu JS, Nair MG. The dynamic tumor-stromal crosstalk: implications of 'stromal-hot' tumors in the process of epithelial-mesenchymal transition in breast cancer. Mol Biol Rep 2023; 50:5379-5393. [PMID: 37046108 DOI: 10.1007/s11033-023-08422-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 04/01/2023] [Indexed: 04/14/2023]
Abstract
BACKGROUND Breast cancer metastatic programming involves an intricate process by which the tumor cell coevolves with the surrounding extracellular niche. The supporting cells from the local host stroma get transformed into cancer-associated stromal cells. This complex crosstalk leads to extracellular matrix remodeling, invasion, and eventually distant metastasis. METHODS In this review, we examine the protein-miRNA secretome that is crucial for this crosstalk. We also provide evidence from the literature for the pivotal role played by the various stromal cells like fibroblasts, adipocytes, and immune cells in promoting the process of EMT in breast cancer. Through in-silico analysis, we have also attempted to establish that stromal presence is integral to the process of EMT. RESULTS AND CONCLUSION The in-silico analysis delineates the persuasive role of the stroma in mediating epithelial-to-mesenchymal transition. This review elucidates the importance of examining the role of the stromal niche that can yield promising diagnostic markers and pave avenues for formulating tailored anti-cancer therapy. Process of EMT as driven by 'stroma-hot' tumors: The process of EMT is driven by the stromal cells. The stromal cells in the form of fibroblasts, adipocytes, endothelial cells, mesenchymal stromal cells and tissue associated macrophages secrete the miRNA-protein secretome that modulates the stromal niche and the tumor cells to be become 'tumor associated'. This drives tumor progression and invasion. The 'stromal-hot' tumors eventually get the benefit of the surplus nurturing from the stroma that facilitates EMT leading to distant organ seeding and metastasis.
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Affiliation(s)
- Apoorva D Mavatkar
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, Karnataka, India
| | - Chandrakala M Naidu
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, Karnataka, India
| | - Jyothi S Prabhu
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, Karnataka, India
| | - Madhumathy G Nair
- Division of Molecular Medicine, St. John's Research Institute, St. John's Medical College, Bangalore, Karnataka, India.
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13
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Yu I, Wu R, Tokumaru Y, Terracina KP, Takabe K. The Role of the Microbiome on the Pathogenesis and Treatment of Colorectal Cancer. Cancers (Basel) 2022; 14:5685. [PMID: 36428777 PMCID: PMC9688177 DOI: 10.3390/cancers14225685] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 11/13/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
The gut microbiome has long been known to play a role in various aspects of health modulation, including the pathogenesis of colorectal cancer (CRC). With immunotherapy recently emerging as a successful treatment in microsatellite instability high (MSI-high) CRC, and with a newly demonstrated involvement of the gut microbiome in the modulation of therapeutic responses, there has been an explosion of research into the mechanisms of microbial effects on CRC. Harnessing and reprogramming the microbiome may allow for the expansion of these successes to broader categories of CRC, the prevention of CRC in high-risk patients, and the enhancement of standard treatments. In this review, we pull together both well-documented phenomena and recent discoveries that pertain to the microbiome and CRC. We explore the microbial mechanisms associated with CRC pathogenesis and progression, recent advancements in CRC systemic therapy, potential options for diagnosis and prevention, as well as directions for future research.
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Affiliation(s)
- Irene Yu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | | | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
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14
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Oshi M, Tokumaru Y, Benesch MGK, Sugito N, Wu R, Yan L, Yamada A, Chishima T, Ishikawa T, Endo I, Takabe K. High miR-99b expression is associated with cell proliferation and worse patient outcomes in breast cancer. Am J Cancer Res 2022; 12:4840-4852. [PMID: 36381329 PMCID: PMC9641402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 10/12/2022] [Indexed: 06/16/2023] Open
Abstract
Although miR-99b is a known suppressive microRNA (miRNA) in several cancers, its role in breast cancer has not been elucidated. In this study, we examined the clinical relevance of miR-99b expression in breast cancer. We analyzed miRNA and mRNA expression and their relationships with clinical parameters in 1,961 breast cancer samples from two independent large cohorts, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA). Several algorithms, including gene set enrichment analysis (GSEA) and xCell, have been used to investigate biological functions and the tumor microenvironment. High miR-99b expression significantly enriched the mTORC1 signaling gene set in breast cancer (NES = 1.63, FDR = 0.03, and NES = 1.58, FDR = 0.10, in METABRIC and TCGA, respectively). No other mechanisms, including the epithelial mesenchymal transition, NFκB, and TGF-β signaling, were consistently enriched in both cohorts. MiR-99b-high breast cancer was associated with high homologous recombination deficiencies, intratumor heterogeneity, and high rates of mutation and neoantigens. In agreement, miR-99b-high breast cancer was associated with increased cell proliferation, correlating with Nottingham histological grade, and significant enrichment of E2F targets, G2/M checkpoint, and mitotic spindle gene sets consistently in both cohorts (P = 0.01, P < 0.001). High miR-99b levels were also associated with low stromal cell fractions in the tumor microenvironment, including adipocytes, keratinocytes, and lymphatic endothelial cells (P < 0.001). However, in both cohorts, miR-99b expression was not associated with significant infiltration of immune cells, except dendritic cells (P = 0.006, 0.020). Finally, in both cohorts, breast cancer with high miR-99b expression was significantly associated with worse disease-free survival (DSS) and overall survival (OS), particularly in estrogen receptor (ER)-positive/human epidermal growth factor (HER)2-negative breast cancer (DSS hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10-1.51, P < 0.001 in the METABRIC cohort and HR 1.82, 95% CI 1.12-2.98, P = 0.017 in the TCGA cohort). In conclusion, breast cancer with high miR-99b expression was significantly associated with mTORC1 signaling, cell proliferation, and decreased patient survival, particularly in the ER-positive/HER2-negative subtype.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, New York, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, New York, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Matthew GK Benesch
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, New York, USA
| | - Nobuhiko Sugito
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, New York, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo 14263, New York, USA
| | - Akimitsu Yamada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Takashi Chishima
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo 14263, New York, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo 14263, New York, USA
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15
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Mukhopadhyay S, Tokumaru Y, Oshi M, Endo I, Yoshida K, Takabe K. Low adipocyte hepatocellular carcinoma is associated with aggressive cancer biology and with worse survival. Am J Cancer Res 2022; 12:4028-4039. [PMID: 36119828 PMCID: PMC9442007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 08/10/2022] [Indexed: 06/15/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide, and non-alcoholic fatty liver disease is strongly associated with its development. To explore the role of adipocytes in HCC, we investigated intratumoral adipocytes, also known as cancer-associated adipocytes (CAA). Based on our prior breast cancer findings, we hypothesized that low intratumoral adipocytes would be associated with aggressive cancer biology, worse tumor microenvironment (TME), and clinical outcomes. The Cancer Genome Atlas (TCGA) was used and validated by the Gene Expression Omnibus (GEO) cohort. xCell algorithm was used to quantify intratumoral adipocytes and top 90% were defined as adipocyte high (AH) and bottom 10% as adipocyte low (AL). We found that AL-HCC was significantly associated with worse disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). AL-HCC were higher-grade, had high MKI67 expression, enriched cell proliferation-related gene sets, and had increased altered fraction, aneuploidy, and homologous recombination defects. Also, anti-cancer immune cells, CD8, Th1, and M1 cells, as well as pro-cancer Th2 cells were increased in AL-HCC. Micro-RNAs miR-122 (associated with cholesterol metabolism) and miR-885 (associated with liver pathologies) were significantly increased in the AL TME. In conclusion, we found that AL-HCC has worse patient outcomes and is biologically more aggressive with enhanced cell proliferation. Our findings take initial steps to clarify the role of adipocytes in HCC.
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Affiliation(s)
- Swagoto Mukhopadhyay
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Surgical Oncology, Gifu University Graduate School of Medicine1-1 Yanagido, Gifu 501-1194, Japan
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University Graduate School of Medicine1-1 Yanagido, Gifu 501-1194, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New YorkBuffalo, New York 14263, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
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16
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Cherkassky L, Oshi M, Abdelfatah E, Wu R, Takabe Y, Yan L, Endo I, Takabe K. An immune-inflamed tumor microenvironment as defined by CD8 score is associated with favorable oncologic outcomes in hepatocellular carcinoma independent of measures of tumor mutational burden. Am J Cancer Res 2022; 12:3099-3110. [PMID: 35968349 PMCID: PMC9360211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 06/13/2022] [Indexed: 06/15/2023] Open
Abstract
Despite low mutational burden, immune checkpoint inhibitors have demonstrated promising results in a significant minority of hepatocellular carcinoma (HCC) patients with advanced disease. We hypothesized that HCC patients with higher levels of CD8+ T cell infiltration reflect an immune-inflamed cohort which has improved oncologic outcomes. 355 HCC patients with clinical and transcriptome data in the Cancer Genome Atlas (TCGA) and 151 HCC patients from cohort GSE7624 were analyzed. xCell computational algorithm was used to analyze immune cell infiltration in these patients. Each cohort was divided into high and low expression by the highest 2 terciles value. Gene Set Enrichment Analysis was performed to identify enriched gene sets. High CD8 score associated with improved overall survival in both cohorts (both P < 0.05). High score correlates with early BCLC stage (P = 0.035) but not AJCC stage. High CD8 also correlated with increased IFN-γ response (p = 0.038), lymphocyte infiltration (P < 0.001), and leukocyte fraction (P < 0.001). It was associated with increased polyclonality of T cell (P < 0.001) and B cell response (P = 0.017). High CD8 score correlated with increased cytolytic activity score (P < 0.001) and expression of multiple immune checkpoints including PD-1, PD-L1, CTLA-4 and Lag3 (all P < 0.001). There was no correlation to tumor mutational burden and neoantigens. GSEA demonstrated upregulation of several gene sets involved in inflammatory response and IFN-γ response. In conclusion, HCC patients with high CD8 score demonstrated favorable oncologic outcomes, which may be due to immune-mediated tumor cell attack. Furthermore, CD8 score may be a potentially useful biomarker to select patients for immune checkpoint inhibition.
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Affiliation(s)
- Leonid Cherkassky
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City UniversityYokohama 236-0004, Japan
| | - Eihab Abdelfatah
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
| | - Rongrong Wu
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
| | - Yamato Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City UniversityYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14203, USA
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City UniversityYokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
- Department of Digestive and General Surgery, Graduate School of Medicine and Dental Sciences, Niigata UniversityNiigata 951-8520, Japan
- Department of Breast Surgery, School of Medicine, Fukushima Medical UniversityFukushima 960-1295, Japan
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17
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Oshi M, Roy AM, Gandhi S, Tokumaru Y, Yan L, Yamada A, Endo I, Takabe K. The clinical relevance of unfolded protein response signaling in breast cancer. Am J Cancer Res 2022; 12:2627-2640. [PMID: 35812054 PMCID: PMC9251678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/19/2022] [Indexed: 06/15/2023] Open
Abstract
Protein homeostasis regulated by the Endoplasmic Reticulum (ER) is a recognized process involved in cancer progression. ER stress activates the Unfolded Protein Response (UPR) and has been implicated in a variety of cancers. Given the role of the UPR activation in carcinogenesis, we hypothesized that UPR activation could be associated with pathological progression, higher clinical stage, and worse survival in breast cancer. A total of 4,416 breast cancer patients from multiple independent cohorts were analyzed. We defined the UPR pathway score by the degree of enrichment by Gene Set Variant Analysis and median was used to divide high vs. low score groups in each cohort. High UPR breast cancer significantly enriched not only cell proliferation-related but also other pro-cancerous gene sets consistently in both METABIC and GSE96058 cohort. Majority of UPR pathway score high cells in the bulk tumor were tumor cells compared to other cells, including stromal, T-, B-, and myeloid-cells (P<0.001). UPR score was significantly associated with advanced stage, high grade, and triple negative breast cancer (TNBC) (all P<0.001). High UPR breast cancer was associated with worse patient survival in both cohorts (all P<0.001). Among breast cancer subtype, ER-positive/HER2-negative breast cancer with high UPR was significantly associated with worse survival, but neither HER-positive nor TNBC. High UPR ER-positive/HER2-negative breast cancer was infiltrated with high level of Th1 and Th2 cells, M1 macrophage, and plasma cells. On the other hand, they were significantly infiltrated with high level of several types of stromal cells in tumor microenvironment (all P<0.001). Finally, high UPR metastatic breast cancer was also associated with worse patient survival (P=0.041). UPR signaling is associated with cancer aggressiveness, and worse survival, especially ER-positive/HER2-negative breast cancer subtype.
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Affiliation(s)
- Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Arya Mariam Roy
- Department of Medical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Akimitsu Yamada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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18
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Tan K, Naylor MJ. Tumour Microenvironment-Immune Cell Interactions Influencing Breast Cancer Heterogeneity and Disease Progression. Front Oncol 2022; 12:876451. [PMID: 35646658 PMCID: PMC9138702 DOI: 10.3389/fonc.2022.876451] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/18/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is a complex, dynamic disease that acquires heterogeneity through various mechanisms, allowing cancer cells to proliferate, survive and metastasise. Heterogeneity is introduced early, through the accumulation of germline and somatic mutations which initiate cancer formation. Following initiation, heterogeneity is driven by the complex interaction between intrinsic cellular factors and the extrinsic tumour microenvironment (TME). The TME consists of tumour cells and the subsequently recruited immune cells, endothelial cells, fibroblasts, adipocytes and non-cellular components of the extracellular matrix. Current research demonstrates that stromal-immune cell interactions mediated by various TME components release environmental cues, in mechanical and chemical forms, to communicate with surrounding and distant cells. These interactions are critical in facilitating the metastatic process at both the primary and secondary site, as well as introducing greater intratumoral heterogeneity and disease complexity by exerting selective pressures on cancer cells. This can result in the adaptation of cells and a feedback loop to the cancer genome, which can promote therapeutic resistance. Thus, targeting TME and immune-stromal cell interactions has been suggested as a potential therapeutic avenue given that aspects of this process are somewhat conserved between breast cancer subtypes. This mini review will discuss emerging ideas on how the interaction of various aspects of the TME contribute to increased heterogeneity and disease progression, and the therapeutic potential of targeting the TME.
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Wu R, Oshi M, Asaoka M, Huyser MR, Tokumaru Y, Yamada A, Yan L, Endo I, Ishikawa T, Takabe K. APOBEC3F expression in triple-negative breast cancer is associated with tumor microenvironment infiltration and activation of cancer immunity and improved survival. Am J Cancer Res 2022; 12:744-762. [PMID: 35261799 PMCID: PMC8899983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/16/2021] [Indexed: 06/14/2023] Open
Abstract
The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) causes a point mutation from cytidine to uracil in DNA and/or RNA. The role of APOBEC3A and APOBEC3B in breast cancer has been well described, whereas that of APOBEC3F remains unknown. To investigate the clinical relevance of APOBEC3F expression, we analyzed a total of 3000 breast cancer cases from multiple independent large patient cohorts including METABRIC, TCGA, GSE75688, and GSE114725. High expression of APOBEC3F was associated with improved disease-specific and overall survival in triple negative breast cancer (TNBC). APOBEC3F is not usually a reflection of cancer cell biology in TNBC or luminal breast cancer, except for homologous recombination deficiency in TNBC. In the TNBC homologous recombination deficiency group, APOBEC3F expression was not consistently associated with intratumor heterogeneity, mutation rates, or neoantigens. APOBEC3F expression did not correlate with response to any of the drugs tested in breast cancer cell lines in vitro. However, high APOBEC3F expression was associated with enrichment of several immune-related gene sets and immune activity. High APOBEC3F expression also accompanied higher infiltration of anti-cancer immune cell infiltration in TNBC. However, in luminal breast cancer, high APOBEC3F tumor significantly enriched not only immune-related gene sets, but also cell proliferation-, metastasis-, and apoptosis-related gene sets. Analysis of single-cell transcriptomes showed APOBEC3F exclusively expressed in immune cells and significantly associated with cytolytic activity of the immune cells, immune response, and immune cell proliferation. Expression of immune checkpoint genes was uniformly elevated in APOBEC3F-high tumors. We conclude that APOBEC3F is exclusively expressed in immune cells and this expression is associated with enhanced anti-cancer immune response as well as improved survival in TNBC.
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Affiliation(s)
- Rongrong Wu
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Mariko Asaoka
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Michelle R Huyser
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu UniversityGifu, Japan
| | - Akimitsu Yamada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata, Japan
- Department of Breast Surgery, Fukushima Medical UniversityFukushima, Japan
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20
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Wu R, Sarkar J, Tokumaru Y, Takabe Y, Oshi M, Asaoka M, Yan L, Ishikawa T, Takabe K. Intratumoral lymphatic endothelial cell infiltration reflecting lymphangiogenesis is counterbalanced by immune responses and better cancer biology in the breast cancer tumor microenvironment. Am J Cancer Res 2022; 12:504-520. [PMID: 35261783 PMCID: PMC8899974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 11/08/2021] [Indexed: 06/14/2023] Open
Abstract
Lymphangiogenesis, the generation of new lymphatic vessels from existing ones, results from the dynamic interactions of lymphatic endothelial cells and the tumor microenvironment (TME). It is well known that lymphangiogenesis occurs during the initial stage of metastasis in various types of malignant tumors. However, it is currently not used as a biomarker partially because gold standard method to quantify it is labor and cost intensive. We hypothesized that the quantity of intratumoral lymphatic endothelial cells (iLECs) in the TME is an indicator of lymphangiogenesis and a predictor of metastatic potential and overall survival in breast cancer. We analyzed a total of 4145 breast cancer patients from the Cancer Genome Atlas (TCGA) and GSE96058 by quantifying their iLECs using the xCell algorithm, and correlated these scores with patient survival, tumor grade, and cancer stage. We also assessed various pro- and anti-cancer gene sets for each tumor to characterize tumor behavior and aggressiveness. As we expected, high-iLEC breast cancer demonstrated enriched lymphoangiogenesis and angiogenesis gene sets and was associated with increased expressions of related genes. Also enriched were inflammatory response and immune response-related gene sets; IL2/STAT5 pathway, IL6/JAK/STAT3 pathway, TNFα pathway, allograft rejection, and complement as well as cancer stemness related gene sets like Notch signaling, Hedgehog signaling, epithelial mesenchymal transition, and Wnt beta-catenin signaling. Tumors with high-iLEC showed higher proportions of stromal cells and fewer anti-cancer immune cells. On the other hand, iLEC score did not correlate with patient survival or lymph node metastasis. Surprisingly, breast cancers with fewer iLECs demonstrated enriched E2F Targets, G2M Checkpoint, MYC Targets v1, and MTORC1 signaling which are cancer cell proliferation-related gene sets and exhibited an abundance of pro-cancer immune cells. The amount of iLEC correlated inversely with Ki67 expression and histological grade, which is in agreement that low-iLEC breast cancer was associated with enhanced cancer cell proliferation. In conclusion, while iLECs can be used as a surrogate for lymphangiogenesis in breast cancer, low-iLEC tumors also exhibit features which correspond to aggressive tumor biology, which may explain why the amount of iLECs was not associated with patient survival in our cohorts.
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Affiliation(s)
- Rongrong Wu
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Joy Sarkar
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu UniversityGifu, Japan
| | - Yamato Takabe
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Mariko Asaoka
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer InstituteBuffalo, NY, USA
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Cancer InstituteBuffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata, Japan
- Department of Breast Surgery, Fukushima Medical UniversityFukushima, Japan
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21
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Angarita FA, Oshi M, Yamada A, Yan L, Matsuyama R, Edge SB, Endo I, Takabe K. Low RUFY3 expression level is associated with lymph node metastasis in older women with invasive breast cancer. Breast Cancer Res Treat 2022; 192:19-32. [PMID: 35018543 PMCID: PMC8844209 DOI: 10.1007/s10549-021-06482-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 12/03/2021] [Indexed: 02/03/2023]
Abstract
PURPOSE Sentinel lymph node biopsy is omitted in older women (≥ 70 years old) with clinical lymph node (LN)-negative hormone receptor-positive breast cancer as it does not influence adjuvant treatment decision-making. However, older women are heterogeneous in frailty while the chance of recurrence increase with improving longevity. Therefore, a biomarker that identifies LN metastasis may facilitate treatment decision-making. RUFY3 is associated with cancer progression. We evaluated RUFY3 expression level as a biomarker for LN-positive breast cancer in older women. METHODS Clinical and transcriptomic data of breast cancer patients were obtained from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1903) and The Cancer Genome Atlas (TCGA, n = 1046) Pan-cancer study cohorts. RESULTS A total of 510 (METABRIC) and 211 (TCGA) older women were identified. LN-positive breast cancer, which represented 51.4% (METABRIC) and 48.4% (TCGA), demonstrated worse disease-free, disease-specific, and overall survival. RUFY3 levels were significantly lower in LN-positive tumors regardless of age. The area under the curve for the receiver operator characteristic (AUC-ROC) curves showed RUFY3-predicted LN metastasis. Low RUFY3 enriched oxidative phosphorylation, DNA repair, MYC targets, unfolded protein response, and mtorc1 signaling gene sets, was associated with T helper type 1 cell infiltration, and with intratumor heterogeneity and fraction altered. Low RUFY3 expression was associated with LN-positive breast cancer and with worse disease-specific survival among older women. CONCLUSION Older women with breast cancers who had low expression level of RUFY3 were more frequently diagnosed with LN-positive tumors, which translated into worse prognosis.
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Affiliation(s)
- Fernando A. Angarita
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA;,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Akimitsu Yamada
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Stephen B. Edge
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA;,Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA;,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan;,Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA;,Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan;,Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
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22
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Futamura M, Tokumaru Y, Takabe K, Arakawa H, Asano Y, Mori R, Mase J, Nakakami A, Yoshida K. MIEAP, a p53-downstream gene, is associated with suppression of breast cancer cell proliferation and better survival. Am J Cancer Res 2021; 11:6060-6073. [PMID: 35018242 PMCID: PMC8727819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/19/2021] [Indexed: 06/14/2023] Open
Abstract
Mitochondria-eating protein (MIEAP; also known as SPATA18), a p53-downstream gene, is involved in mitochondrial quality control (MQC). Enforced MIEAP expression induces caspase-dependent cell death in vitro, and impairment of the p53/MIEAP-regulated MQC pathway is frequently observed in breast cancer (BC), resulting in poor disease-free survival (DFS). To investigate the clinical significance of MIEAP in BC, we identified 2,980 patients from two global, large-scale primary BC cohorts: the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; n=1,904) and the Cancer Genome Atlas (TCGA; n=1,076). We divided patients in each cohort into high and low groups based on median gene expression levels and analyzed the association between MIEAP expression and clinical outcomes. Compared with normal tumors, MIEAP expression was significantly downregulated in all patients with p53-mutant BC regardless of subtype. MIEAP expression was negatively correlated with KI67 expression. Gene set enrichment analysis demonstrated that cell cycle- and proliferation-associated gene sets were significantly enriched in MIEAP-low tumors compared to MIEAP-high tumors. Patients with MIEAP-high luminal subtype were associated with significantly longer DFS than those with MIEAP-low luminal tumors in both cohorts, whereas significantly longer overall survival was observed only in the METABRIC cohort, which has roughly double the number of samples. These results indicated that the mechanistic role of MIEAP is clinically relevant in the two independent cohorts. This is the first study to use large cohorts to demonstrate the association between MIEAP expression and survival in patients with luminal subtype BC.
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Affiliation(s)
- Manabu Futamura
- Breast Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Hirofumi Arakawa
- Division of Cancer Biology, National Cancer Center Research Institute5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Yoshimi Asano
- Breast Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Ryutaro Mori
- Breast Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Junichi Mase
- Breast Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Akira Nakakami
- Breast Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Kazuhiro Yoshida
- Gastroenterological Surgery, Department of Surgery, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
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23
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Huang JL, Oshi M, Endo I, Takabe K. Clinical relevance of stem cell surface markers CD133, CD24, and CD44 in colorectal cancer. Am J Cancer Res 2021; 11:5141-5154. [PMID: 34765317 PMCID: PMC8569346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 06/13/2023] Open
Abstract
Colon cancer stem cells (CSC) identified by cell surface markers CD133, CD24, and CD44, have been shown to be involved with tumor formation, chemotherapy resistance, and the progression of metastatic disease. Using an in silico translational approach, we hypothesize that a combination of these CSC markers has prognostic value in a large cohort of patients with colorectal cancer. Clinicopathologic and RNA expression data from a total of 594 colorectal cancer (CRC) patients from TCGA were analyzed. The expression of CD133, CD24, and CD44 was individually defined as "high" or "low" based on the median expression. Disease specific survival (DSS) and overall survival (OS) were not associated with tumors that are CD133-high or CD44-high alone. Patients with CD24-high tumors have significantly better DSS (P<0.001) and OS (P = 0.043). CD24-high, CD44-high and CD133-high tumors were associated with significantly greater EGFR, KRAS and Ki67 expression (all P<0.001). CD133, CD24 and CD44-high tumors were independently enriched for conventional stemness-related signaling pathways such as Wnt/β-catenin and Hedgehog signaling pathways. There was no survival difference linked to CD133-high/CD44-low patients, but CD44-high/CD24-low patients have worse DSS (P = 0.005) compared with CD44-low/CD24-high patients. CD133-high/CD24-low tumors show significant negative enrichment of MYC targets, E2F targets, G2M checkpoint and mitotic spindle gene sets, suggesting less cell proliferation in these tumors. Patients with CD133-high/CD24-low tumors have worse DSS (P = 0.004) and OS (P = 0.044), and are more likely to have early and late recurrences. In conclusion, we demonstrated that CD133-high/CD24-low tumors may predict colorectal cancer prognosis.
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Affiliation(s)
- Jing Li Huang
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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24
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Satyananda V, Oshi M, Tokumaru Y, Maiti A, Hait N, Matsuyama R, Endo I, Takabe K. Sphingosine 1-phosphate (S1P) produced by sphingosine kinase 1 (SphK1) and exported via ABCC1 is related to hepatocellular carcinoma (HCC) progression. Am J Cancer Res 2021; 11:4394-4407. [PMID: 34659894 PMCID: PMC8493375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Accepted: 08/13/2021] [Indexed: 06/13/2023] Open
Abstract
Sphingosine-1-Phosphate (S1P) is produced by Sphingosine Kinase 1 (SphK1) in the cell and is transported out of the cells by ABCC1 transporter. S1P induces inflammation, angiogenesis and modulates tumor immune microenvironment (TIME) in autocrine and paracrine manner. We hypothesized that high S1P export is associated with hepatocellular carcinoma (HCC) progression and worse survival. Transcriptome linked with clinical data were obtained from a total of 533 patients from TCGA (The Cancer Genome Atlas)-HCC (n = 350), GSE6764 (n = 75), and GSE89377 (n = 108) cohorts. Both SphK1 and ABCC1 were expressed higher in aggressive HCC than normal liver or cirrhosis and correlated with MKi67 expression. High S1P export by high expression of both SphK1 and ABCC1 enriched gene sets related with cell proliferation (E2F targets, G2M checkpoint, MYC targets), inflammation (Inflammatory response, TNFα, IL6), angiogenesis, metastasis (TGF-β, epithelial-mesenchymal transition), and immune response (allograft rejection, complement, interferon-gamma) in gene set enrichment analysis. High S1P export was associated with elevation of HGF, HSP90AA1, TRAF2, and AKR1B10. It was also associated with high intratumor heterogeneity, leucocyte fraction, macrophage regulation and lymphocyte infiltration, as well as T helper type2 cells, macrophages, dendritic cells, CD4+ T memory activated cells, B-cells and cytolytic activity score in TIME. High S1P export was associated with significantly worse disease specific survival (P = 0.034) and overall survival (P = 0.004) compared to low S1P export group. In conclusion, simultaneous high expression of SphK1 and ABCC1 that reflect S1P export is associated with enhancement of both HCC progression and immune response. Given that S1P export was also associated with worse survival, we cannot help but speculate that pro-cancer pathways activated by S1P may overwhelm the anti-cancer immune response mediated by S1P.
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Affiliation(s)
- Vikas Satyananda
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological SurgeryYokohama, Kanagawa 236-004, Japan
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University School of Medicine1-1 Yanagido, Gifu 501-1194, Japan
| | - Aparna Maiti
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Nitai Hait
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Ryusei Matsuyama
- Department of Gastroenterological SurgeryYokohama, Kanagawa 236-004, Japan
| | - Itaru Endo
- Department of Gastroenterological SurgeryYokohama, Kanagawa 236-004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological SurgeryYokohama, Kanagawa 236-004, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New YorkBuffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, 160-8402 Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8510, Japan
- Department of Breast Surgery, Fukushima Medical UniversityFukushima, Japan
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25
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Chouliaras K, Oshi M, Asaoka M, Tokumaru Y, Khoury T, Endo I, Ishikawa T, Takabe K. Increased intratumor heterogeneity, angiogenesis and epithelial to mesenchymal transition pathways in metaplastic breast cancer. Am J Cancer Res 2021; 11:4408-4420. [PMID: 34659895 PMCID: PMC8493380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 07/16/2021] [Indexed: 06/13/2023] Open
Abstract
Metaplastic breast cancer (MBC) constitutes a rare but unique histologic entity with poor prognosis. We hypothesized that MBC possesses unique genetic profile and tumor immune microenvironment. MBC cases were identified from a total of 10827 breast cancer entries in the Cancer Genome Atlas Data Set (TCGA) and the AACR-GENIE (Genomics Evidence Neoplasia Information Exchange) cohorts. Tumor infiltrated immune cells were estimated by xCell. Baseline clinical characteristics were compared, and gene set enrichment analysis (GSEA) was performed. MBC comprised 0.66% of the cohorts (1.2% of TCGA and 0.6% of GENIE). MBC cases were predominantly triple-negative (TNBC) (8 (61.5%) vs 151 (14.4%), P<0.001), and high Nottingham histological grade (8 (61.5%) vs 222 (21.1%), P=0.02) compared to non-MBC in the TCGA cohort. Increased infiltration of M1 macrophages (P=0.012), dendritic cells (P<0.001) and eosinophils (P=0.036) was noted in the MBC cohort however there was no difference in cytolytic activity (P=0.806), CD4 memory (P=0.297) or CD8 T-cells (P=0.864). Tumor mutation burden was lower in the MBC compared to the non-MBC, median: 0.4 vs 1.6/Mb in the TCGA-TNBC cohort (P=0.67) and 3.0 vs 4.0/Mb (P=0.1) in the GENIE-cohort. MBC had increased intratumor heterogeneity (P<0.001), macrophage regulation (P=0.008) and TGF-beta response (P<0.001). Disease-specific survival was decreased in MBC (P=0.018). Angiogenesis and epithelial-to-mesenchymal transition pathways were enriched in triple-negative MBC by GSEA (P=0.004 and P<0.001, respectively). Our results suggest that high intratumor heterogeneity, enriched angiogenesis and EMT pathway expression represent possible mechanisms leading to worse disease-specific survival found in metaplastic breast cancer.
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Affiliation(s)
- Konstantinos Chouliaras
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY, USA
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Japan
| | - Mariko Asaoka
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY, USA
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu UniversityGifu, Japan
| | - Thaer Khoury
- Department of Pathology, Roswell Park Comprehensive Cancer CenterBuffalo, NY, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New YorkBuffalo, NY, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata, Japan
- Department of Breast Surgery, Fukushima Medical UniversityFukushima, Japan
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26
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The Unfolded Protein Response Is Associated with Cancer Proliferation and Worse Survival in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13174443. [PMID: 34503253 PMCID: PMC8430652 DOI: 10.3390/cancers13174443] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/25/2021] [Accepted: 08/27/2021] [Indexed: 12/25/2022] Open
Abstract
Simple Summary We studied the association between the unfolded protein response (UPR) and carcinogenesis, cancer progression, and survival in hepatocellular carcinoma (HCC). We studied 655 HCC patients from 4 independent cohorts using an UPR score. The UPR was enhanced as normal liver became cancerous and as HCC advanced in stage. The UPR was correlated with cancer cell proliferation that was confirmed by multiple parameters. Significantly, a high UPR score was associated with worse patient survival. Interestingly, though UPR was associated with a high mutational load, it was not associated with immune response, immune cell infiltration, or angiogenesis. To our knowledge, this is the first study to investigate the clinical relevance of the unfolded protein response in HCC. Abstract Hepatocellular carcinoma is a leading cause of cancer death worldwide. The unfolded protein response (UPR) has been revealed to confer tumorigenic capacity in cancer cells. We hypothesized that a quantifiable score representative of the UPR could be used as a biomarker for cancer progression in HCC. In this study, a total of 655 HCC patients from 4 independent HCC cohorts were studied to examine the relationships between enhancement of the UPR and cancer biology and patient survival in HCC utilizing an UPR score. The UPR correlated with carcinogenic sequence and progression of HCC consistently in two cohorts. Enhanced UPR was associated with the clinical parameters of HCC progression, such as cancer stage and multiple parameters of cell proliferation, including histological grade, mKI67 gene expression, and enrichment of cell proliferation-related gene sets. The UPR was significantly associated with increased mutational load, but not with immune cell infiltration or angiogeneis across independent cohorts. The UPR was consistently associated with worse survival across independent cohorts of HCC. In conclusion, the UPR score may be useful as a biomarker to predict prognosis and to better understand HCC.
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Danforth DN. The Role of Chronic Inflammation in the Development of Breast Cancer. Cancers (Basel) 2021; 13:3918. [PMID: 34359821 PMCID: PMC8345713 DOI: 10.3390/cancers13153918] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/20/2021] [Accepted: 07/27/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic inflammation contributes to the malignant transformation of several malignancies and is an important component of breast cancer. The role of chronic inflammation in the initiation and development of breast cancer from normal breast tissue, however, is unclear and needs to be clarified. A review of the literature was conducted to define the chronic inflammatory processes in normal breast tissue at risk for breast cancer and in breast cancer, including the role of lymphocyte and macrophage infiltrates, chronic active adipocytes and fibroblasts, and processes that may promote chronic inflammation including the microbiome and factors related to genomic abnormalities and cellular injury. The findings indicate that in healthy normal breast tissue there is systemic evidence to suggest inflammatory changes are present and associated with breast cancer risk, and adipocytes and crown-like structures in normal breast tissue may be associated with chronic inflammatory changes. The microbiome, genomic abnormalities, and cellular changes are present in healthy normal breast tissue, with the potential to elicit inflammatory changes, while infiltrating lymphocytes are uncommon in these tissues. Chronic inflammatory changes occur prominently in breast cancer tissues, with important contributions from tumor-infiltrating lymphocytes and tumor-associated macrophages, cancer-associated adipocytes and crown-like structures, and cancer-associated fibroblasts, while the microbiome and DNA damage may serve to promote inflammatory events. Together, these findings suggest that chronic inflammation may play a role in influencing the initiation, development and conduct of breast cancer, although several chronic inflammatory processes in breast tissue may occur later in breast carcinogenesis.
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Affiliation(s)
- David N Danforth
- Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
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Oshi M, Gandhi S, Angarita FA, Kim TH, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K. A novel five-gene score to predict complete pathological response to neoadjuvant chemotherapy in ER-positive/HER2-negative breast cancer. Am J Cancer Res 2021; 11:3611-3627. [PMID: 34354863 PMCID: PMC8332850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 04/25/2021] [Indexed: 06/13/2023] Open
Abstract
Neoadjuvant Chemotherapy (NAC) is not frequently used in ER-positive/HER2-negative breast cancer (BC) because around 10% patients achieve pathological complete response (pCR). Since NAC can result in cancer downstaging both in the breast and axilla and prevent a morbid surgery, thus a score to predict pCR in this population will be crucial to identify patients who can benefit from this approach. A total of 4038 patients from cohorts; GSE25066, GSE20194, Hess, GSE20181, TCGA-BRCA and METBRIC were analyzed. The score was generated by the 5 most highly expressed genes in the Hallmark E2F targets gene set amongst patients in the GSE25066 cohort with ER-positive/HER2-negative BC who achieved pCR. The area under the curve was significantly higher in the score than that for the E2F targets score. High score ER-positive/HER2-negative BCs were significantly associated with higher Nottingham pathological grade, AJCC cancer stage, MKI67 expression levels, intratumor heterogeneity, homologous recombination defects, mutation burden, neoantigen load, and infiltration of anti-cancer immune cells (CD4+, T helper type1, plasmacytoid dendritic cells, M1 macrophages). They also expressed lower abundance of stromal cells including fibroblasts, lymphatic endothelial cells, pericytes and adipocytes consistently in GSE25066, TCGA and METABRIC cohorts. All cell proliferation-related gene sets, G2M checkpoint, E2F targets, MYC targets v1 and v2, Mitotic Spindle, were strongly enriched in high score BCs consistently in 3 cohorts. The gene score was significantly associated with high pCR rate consistently in the GSE25066 (38%, P < 0.001), GSE20194 (16%, P = 0.006), and Hess cohort (23%, P = 0.037). In conclusion, the 5-gene score reflects cancer cell proliferation and immune cell infiltration, and predicts pCR after NAC in ER-positive/HER2-negative breast cancer.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer CenterElm & Carlton Streets, Buffalo, NY 14263, USA
| | - Fernando A Angarita
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
| | - Tae Hee Kim
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu UniversityYanagido, Gifu, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama, Kanagawa, Japan
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York, USA
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Murthy V, Oshi M, Tokumaru Y, Endo I, Takabe K. Increased apoptosis is associated with robust immune cell infiltration and cytolytic activity in breast cancer. Am J Cancer Res 2021; 11:3674-3687. [PMID: 34354867 PMCID: PMC8332871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 05/23/2021] [Indexed: 06/13/2023] Open
Abstract
Tumor infiltrating immune cells plays a critical role in cancer progression. Apoptosis is an autonomous cell death that counteracts tumor growth. To this end, we hypothesized that increased apoptosis in breast cancer is associated with immune cell killing. Apoptosis score of MSigDB Hallmark collection was used to analyze METABRIC cohort (n=1904) and TCGA (n=1069) as validation cohort. High apoptosis tumors enriched cancer promoting signaling pathways; hypoxia, KRAS, TGF-β, PI3K signaling, and was associated with low MKI67 expression and less cell proliferation gene sets, less homologous recombination defects, and less altered fraction. High apoptosis tumors also enriched angiogenesis and high infiltration of vascular endothelial cells, pericytes and stromal cells and significantly enriched inflammation and immune response-related gene sets and high infiltration of CD8, CD4 memory, dendritic cells, M1 and M2 macrophages and significant elevation of cytolytic activity and immune checkpoint molecules, consistently in both cohorts. In conclusion, breast cancer patients with high apoptosis are associated with angiogenesis, immune response, high immune cell infiltration and cytolytic activity. To the best of our knowledge, this is the first study to utilize in silico translational approach to demonstrate the clinical relevance of apoptosis in breast cancer patients in large cohorts.
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Affiliation(s)
- Vijayashree Murthy
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 YanagidoGifu 501-1194, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 YanagidoGifu 501-1194, Japan
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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Tokumaru Y, Oshi M, Huyser MR, Yan L, Fukada M, Matsuhashi N, Futamura M, Akao Y, Yoshida K, Takabe K. Low expression of miR-29a is associated with aggressive biology and worse survival in gastric cancer. Sci Rep 2021; 11:14134. [PMID: 34239017 PMCID: PMC8266839 DOI: 10.1038/s41598-021-93681-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
Advanced gastric cancer (GC) is one of the most lethal cancer types, thus a better understanding of its biology in patients is urgently needed. MicroRNA (miR)-29a is a known tumor suppressive miR that is related to metastasis, but its clinical relevance in GC remains ambiguous. Here, using a large GC patient cohort we hypothesized that low expression of miR-29a in GC is associated with aggressive cancer biology and worse survival. We demonstrated that low miR-29a GC enriched cell proliferation, apoptosis, metastasis, and angiogenesis related gene sets, as well as the higher expression of related genes. Low miR-29a GC was associated with less anti-cancer immune cell infiltration as well as immune related scoring. Low miR-29a GC demonstrated a worse overall survival (OS) as well as disease specific survival (DSS) compared with high expressing miR-29a GC. Notably, low miR-29a expression was the only factor, other than residual tumor status, to be an independent prognostic biomarker of worse OS and DSS. In conclusion, low miR-29a GC was associated with aggressive cancer biology and worse OS as well as DSS. Additionally, low expression of miR-29a was an independent prognostic biomarker of OS and DSS in gastric cancer patients.
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Affiliation(s)
- Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.,Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA.,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan
| | - Michelle R Huyser
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA
| | - Masahiro Fukada
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Manabu Futamura
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Yukihiro Akao
- United Graduate School of Drug and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, 501-1194, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY, 14263, USA. .,Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan. .,Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, 951-8510, Japan. .,Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, 14263, USA. .,Department of Breast Oncology and Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku, Tokyo, 160-8402, Japan. .,Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, 960-1295, Japan.
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Tokumaru Y, Oshi M, Patel A, Katsuta E, Yan L, Angarita FA, Dasgupta S, Nagahashi M, Matsuhashi N, Futamura M, Yoshida K, Takabe K. Low expression of miR-195 is associated with cell proliferation, glycolysis and poor survival in estrogen receptor (ER)-positive but not in triple negative breast cancer. Am J Cancer Res 2021; 11:3320-3334. [PMID: 34249465 PMCID: PMC8263660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Accepted: 06/04/2021] [Indexed: 06/13/2023] Open
Abstract
MiR-195 is a tumor suppressive microRNA in breast cancer. Its clinical relevance remains debatable as it has only been studied via in vitro experiments or small cohort studies. We analyzed a total of 2,038 patients in the TCGA and METABRIC cohorts to assess whether low miR-195 expressing tumors are associated with aggressive cancer characteristics and poor prognostic outcomes. The median cutoff of miR-195 expression was used to split the groups into miR-195 high and low groups. Low miR-19 expressing tumors demonstrated high cell proliferating features by enriching the gene sets associated with cell proliferation, MKI67 expression and pathological grade. One-third of the top target miR-195 genes were related to cell proliferation. Low miR-195 expressing tumors were associated with both pro-cancerous and anti-cancerous immune cells. Low miR-195 expressing tumors were associated with enhanced glycolysis and poor survival in ER-positive tumors, but not other subtypes of breast cancer. In conclusion, low expression of miR-195 in ER-positive breast cancer was associated with enhanced cancer cell proliferation, glycolysis, and worse overall survival.
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Affiliation(s)
- Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Ankit Patel
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Eriko Katsuta
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Fernando A Angarita
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Subhamoy Dasgupta
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
| | - Masayuki Nagahashi
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8510, Japan
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Manabu Futamura
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, NY 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8510, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New YorkBuffalo, NY 14263, USA
- Department of Breast Oncology and Surgery, Tokyo Medical University6-7-1 Nishishinjuku, Shinjuku, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
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Adipogenesis in triple-negative breast cancer is associated with unfavorable tumor immune microenvironment and with worse survival. Sci Rep 2021; 11:12541. [PMID: 34131208 PMCID: PMC8206113 DOI: 10.1038/s41598-021-91897-7] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 05/30/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer-associated adipocytes are known to cause inflammation; however, the role of adipogenesis, the formation of adipocytes, in breast cancer is unclear. We hypothesized that intra-tumoral adipogenesis reflects a different cancer biology than abundance of intra-tumoral adipocytes. The Molecular Signatures Database Hallmark adipogenesis gene set of gene set variant analysis was used to quantify adipogenesis. Total of 5,098 breast cancer patients in multiple cohorts (training; GSE96058 (n = 3273), validation; TCGA (n = 1069), treatment response; GSE25066 (n = 508) and GSE20194 (n = 248)) were analyzed. Adipogenesis did not correlate with abundance of adipocytes. Adipogenesis was significantly lower in triple negative breast cancer (TNBC). Elevated adipogenesis was significantly associated with worse survival in TNBC, but not in the other subtypes. High adipogenesis TNBC was significantly associated with low homologous recombination deficiency, but not with mutation load. High adipogenesis TNBC enriched metabolism-related gene sets, but neither of cell proliferation- nor inflammation-related gene sets, which were enriched to adipocytes. High adipogenesis TNBC was infiltrated with low CD8+ T cells and high M2 macrophages. Although adipogenesis was not associated with neoadjuvant chemotherapy response, high adipogenesis TNBC was significantly associated with low expression of PD-L1 and PD-L2 genes, and immune checkpoint molecules index. In conclusion, adipogenesis in TNBC was associated with cancer metabolism and unfavorable tumor immune microenvironment, which is different from abundance of adipocytes.
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Okano M, Oshi M, Mukhopadhyay S, Qi Q, Yan L, Endo I, Ohtake T, Takabe K. Octogenarians' Breast Cancer Is Associated with an Unfavorable Tumor Immune Microenvironment and Worse Disease-Free Survival. Cancers (Basel) 2021; 13:2933. [PMID: 34208219 PMCID: PMC8230790 DOI: 10.3390/cancers13122933] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/05/2021] [Accepted: 06/08/2021] [Indexed: 01/26/2023] Open
Abstract
Elderly patients are known to have a worse prognosis for breast cancer. This is commonly blamed on their medical comorbidities and access to care. However, in addition to these social issues, we hypothesized that the extreme elderly (octogenarians-patients over 80 years old) have biologically worse cancer with unfavorable tumor immune microenvironment. The Cancer Genomic Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were analyzed. The control (aged 40-65) and octogenarians numbered 668 and 53 in TCGA and 979 and 118 in METABRIC, respectively. Octogenarians had significantly worse breast cancer-specific survival in both cohorts (p < 0.01). Octogenarians had a higher ER-positive subtype rate than controls in both cohorts. Regarding PAM50 classification, luminal-A and -B subtypes were significantly higher in octogenarians, whereas basal and claudin-low subtypes were significantly lower (p < 0.05) in octogenarians. There was no difference in tumor mutation load, intratumor heterogeneity, or cytolytic activity by age. However, the octogenarian cohort was significantly associated with high infiltration of pro-cancer immune cells, M2 macrophage, and regulatory T cells in both cohorts (p < 0.05). Our results demonstrate that octogenarians' breast cancer is associated with worse survival and with an unfavorable tumor immune microenvironment.
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Affiliation(s)
- Maiko Okano
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.O.); (S.M.)
- Department of Breast Surgery, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan;
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.O.); (S.M.)
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan;
| | - Swagoto Mukhopadhyay
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.O.); (S.M.)
| | - Qianya Qi
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Q.Q.); (L.Y.)
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Q.Q.); (L.Y.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan;
| | - Toru Ohtake
- Department of Breast Surgery, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan;
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.O.); (S.M.)
- Department of Breast Surgery, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan;
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan;
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14263, USA
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Gandhi S, Oshi M, Murthy V, Repasky EA, Takabe K. Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment. Cancers (Basel) 2021; 13:2559. [PMID: 34071012 PMCID: PMC8197168 DOI: 10.3390/cancers13112559] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/07/2021] [Accepted: 05/19/2021] [Indexed: 12/11/2022] Open
Abstract
Mild cold stress induced by housing mice with a 4T1 triple-negative breast cancer (TNBC) cell implantation model at 22 °C increases tumor growth rate with a pro-tumorigenic immune microenvironment (lower CD8 +T cells, higher myeloid-derived suppressor cells (MDSCs) and regulatory T-cells (Tregs)). Since cold stress also activates thermogenesis, we hypothesized that enhanced thermogenesis is associated with more aggressive cancer biology and unfavorable tumor microenvironment (TME) in TNBC patients. A total of 6479 breast cancer patients from METABRIC, TCGA, GSE96058, GSE20194, and GSE25066 cohorts were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score. High-thermogenesis TNBC was associated with a trend towards worse survival and with angiogenesis, adipogenesis, and fatty acid metabolism pathways. On the other hand, low-thermogenesis TNBC enriched most of the hallmark cell-proliferation-related gene sets (i.e., mitotic spindle, E2F targets, G2M checkpoint, MYC targets), as well as immune-related gene sets (i.e., IFN-α and IFN-γ response). Favorable cytotoxic T-cell-attracting chemokines CCL5, CXCL9, CXCL10, and CXCL11 were lower; while the MDSC- and Treg-attracting chemokine CXCL12 was higher. There were higher M2 but lower M1 macrophages and Tregs. In conclusion, high-thermogenesis TNBC is associated with pro-tumor immune microenvironment and may serve as biomarker for testing strategies to overcome this immunosuppression.
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Affiliation(s)
- Shipra Gandhi
- Department of Medical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (V.M.); (K.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
| | - Vijayashree Murthy
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (V.M.); (K.T.)
| | - Elizabeth A. Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (V.M.); (K.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
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Triulzi T. Special Issue: "Unraveling the Involvement of Adipose Tissue in Breast Cancer Progression". Int J Mol Sci 2021; 22:ijms22105107. [PMID: 34065952 PMCID: PMC8151020 DOI: 10.3390/ijms22105107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 05/10/2021] [Indexed: 11/30/2022] Open
Affiliation(s)
- Tiziana Triulzi
- Molecular Targeting Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
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Satyananda V, Oshi M, Endo I, Takabe K. High BRCA2 Gene Expression is Associated with Aggressive and Highly Proliferative Breast Cancer. Ann Surg Oncol 2021; 28:7356-7365. [PMID: 33966140 DOI: 10.1245/s10434-021-10063-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/04/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Mutations of BRCA genes are the most studied in breast cancer, but the clinical relevance of BRCA2 gene expression has been less well studied. Given that BRCA2 is a DNA repair gene, we hypothesized that high BRCA2 expression is associated with highly proliferative and aggressive biology in breast cancer. MATERIALS AND METHODS A total of 4342 breast cancer patients were analyzed from The Cancer Genome Atlas (TCGA, n = 1069) as the testing cohort and Gene Expression Omnibus (GEO) dataset GSE96058 (n = 3273) as a validation cohort. RESULTS There was no relationship between BRCA2 mutation and BRCA2 gene expression. BRCA2 high expression breast cancer was associated with higher Nottingham grade (p < 0.001), with high proliferation (MKI-67, p < 0.001), and with higher intratumor heterogeneity, homologous recombination deficiency, mutation rate, fraction altered, and neoantigens (all p < 0.001). BRCA2 high expression was associated with E2F1, RB1, PALB2, and PARP, as well as cell proliferation-related gene sets, E2F targets, G2M checkpoints, and mitotic spindle, and with less ESR1 and ER response early and late gene sets. They were associated with significantly reduced number of stroma cells and with high infiltration of both favorable and unfavorable immune cells. BRCA2 high expression significantly correlated with response to olaparib, a PARP inhibitor, and inversely with cyclophosphamide in ER-positive/HER2-negative tumors, but not in TNBC. CONCLUSIONS BRCA2 high gene expression was associated with highly proliferative and aggressive breast cancer that was highly immunogenic with better response to PARP inhibitors in ER-positive patients. BRCA2 gene expression may become a candidate marker for aggressive biology and to tailor specific treatment strategies in the future.
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Affiliation(s)
- Vikas Satyananda
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Itaru Endo
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA. .,Department of Surgery, Yokohama City University, Yokohama, Japan. .,Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan. .,Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan. .,Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA.
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Oshi M, Satyananda V, Angarita FA, Kim TH, Tokumaru Y, Yan L, Matsuyama R, Endo I, Nagahashi M, Takabe K. Angiogenesis is associated with an attenuated tumor microenvironment, aggressive biology, and worse survival in gastric cancer patients. Am J Cancer Res 2021; 11:1659-1671. [PMID: 33948380 PMCID: PMC8085878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 01/27/2021] [Indexed: 06/12/2023] Open
Abstract
Angiogenesis is a cornerstone of cancer as it allows tumors to receive oxygen and nutrients. A high level of angiogenesis within a tumor may therefore be indicative of its aggressiveness. In this study, we examined this hypothesis in gastric cancer. Gene set variation analysis was used to measure the level of angiogenesis in tumors in 1,348 gastric cancer patients using the Hallmark_angiogenesis gene set to score tumor transcriptomes. As we predicted, there was a significant correlation between angiogenesis score and expression of angiogenesis-related genes. The score moderately correlated with abundance of vessel-related stromal cells, fibroblasts and chondrocytes in the tumor microenvironment (TME). Tumors with high score had low infiltration of T helper type 1 and 2 cells but a greater infiltration of M1 macrophages and dendritic cells. They also had enriched expression of gene sets for coagulation, hypoxia, epithelial mesenchymal transition (EMT), and TGF-β signaling. High angiogenesis score was significantly associated with advanced AJCC stage and higher T- but not N-parameters in the TNM staging system. Patients with a high score also had shorter survival. In conclusion, bulk tumor transcriptome-based quantification of tumor angiogenesis using a computational algorithm may serve to identify patients with worse survival in gastric cancer.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Vikas Satyananda
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Fernando A Angarita
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Tae Hee Kim
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer CenterBuffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of MedicineYokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New YorkBuffalo, New York 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental SciencesNiigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of MedicineFukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical UniversityTokyo 160-8402, Japan
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Tokumaru Y, Oshi M, Patel A, Tian W, Yan L, Matsuhashi N, Futamura M, Yoshida K, Takabe K. Organoids Are Limited in Modeling the Colon Adenoma-Carcinoma Sequence. Cells 2021; 10:cells10030488. [PMID: 33668713 PMCID: PMC7996178 DOI: 10.3390/cells10030488] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/19/2021] [Accepted: 02/21/2021] [Indexed: 12/14/2022] Open
Abstract
The colon adenoma-carcinoma sequence is a multistep genomic-altering process that occurs during colorectal cancer (CRC) carcinogenesis. Organoids are now commonly used to model both non-cancerous and cancerous tissue. This study aims to investigate how well organoids mimic tissues in the adenoma-carcinoma sequence by comparing their transcriptomes. A total of 234 tissue samples (48 adenomas and 186 CRC) and 60 organoid samples (15 adenomas and 45 CRC) were analyzed. We found that cell-proliferation-related gene sets were consistently enriched in both CRC tissues and organoids compared to adenoma tissues and organoids by gene set enrichment analysis (GSEA). None of the known pathways in the colon adenoma-carcinoma sequence were consistently enriched in CRC organoids. There was no enrichment of the tumor microenvironment-related gene sets in CRC organoids. CRC tissues enriched immune-response-related gene sets, whereas CRC organoids did not. The proportions of infiltrating immune cells were different between tissues and organoids, whereas there was no difference between cancer and adenoma organoids. The amounts of cancer stem cells and progenitor cells were not different between CRC and adenoma organoids, whereas a difference was noted between CRC and adenoma tissues. In conclusion, we demonstrated that organoids model only part of the adenoma-carcinoma sequence and should be used with caution after considering their limitations.
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Affiliation(s)
- Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (A.P.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (A.P.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Ankit Patel
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (A.P.)
| | - Wanqing Tian
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (W.T.); (L.Y.)
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (W.T.); (L.Y.)
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Manabu Futamura
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (N.M.); (M.F.); (K.Y.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (Y.T.); (M.O.); (A.P.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY 14263, USA
- Department of Breast Oncology and Surgery, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku, Tokyo 160-8402, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Correspondence:
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Oshi M, Kim TH, Tokumaru Y, Yan L, Matsuyama R, Endo I, Cherkassky L, Takabe K. Enhanced DNA Repair Pathway is Associated with Cell Proliferation and Worse Survival in Hepatocellular Carcinoma (HCC). Cancers (Basel) 2021; 13:cancers13020323. [PMID: 33477315 PMCID: PMC7830462 DOI: 10.3390/cancers13020323] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary We studied the relationship between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in 749 hepatocellular carcinoma (HCC) patients from 5 cohorts using a DNA repair pathway score. We show that the DNA repair pathway was enhanced by the stepwise carcinogenic process of HCC, notably in grade 3 compared to grade 1 or 2 HCC. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor cytolytic activity. The expression of proliferation- and other cancer aggressiveness-related gene sets was also increased. Interestingly, these features were more pronounced in low-grade compared to high-grade HCC. In conclusion, the DNA repair score may be used to understand the role of DNA repair pathways in patient prognosis and treatment sensitivity and be used to improve patient outcome. To our knowledge, this is the first study using DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of cancer-related deaths worldwide. In this study, a total of 749 HCC patients from 5 cohorts were studied to examine the relationships between enhancement of DNA repair and cancer aggressiveness, tumor immune microenvironment, and patient survival in HCC, utilizing a DNA repair pathway score. Our findings suggest that the DNA repair pathway was not only enhanced by the stepwise carcinogenic process of HCC, but also significantly enhanced in grade 3 HCC compared with grade 1 and 2 tumors. DNA repair high HCC was associated with worse survival, elevated intratumor heterogeneity, and mutation load, but not with the fraction of immune cell infiltration nor immune response. HCC tumors with a DNA repair high score enriched the cell proliferation- and other cancer aggressiveness-related gene sets. Interestingly, these features were more pronounced in grade 1 and 2 HCC compared to grade 3 HCC. To our knowledge, this is the first study to use DNA repair pathway-related gene set expression data to examine and validate the clinical relevance of DNA repair pathway activity in HCC. The DNA repair score may be used to better understand and predict prognosis in HCC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Tae Hee Kim
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Leonid Cherkassky
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (T.H.K.); (Y.T.); (L.C.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
- Correspondence: ; Tel.: +1-716-8455540; Fax: +1-716-8451668
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Le L, Tokumaru Y, Oshi M, Asaoka M, Yan L, Endo I, Ishikawa T, Futamura M, Yoshida K, Takabe K. Th2 cell infiltrations predict neoadjuvant chemotherapy response of estrogen receptor-positive breast cancer. Gland Surg 2021; 10:154-165. [PMID: 33633972 DOI: 10.21037/gs-20-571] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background High infiltration of Th2 is linked to breast cancer progression and metastasis through the induction of cytokine release and T-cell anergy. The estrogen receptor (ER)-positive subtype, which accounts for 70% of breast cancer, is known to respond less to neoadjuvant chemotherapy (NAC) due to its low potential for proliferation. We hypothesized that Th2 high tumors are highly proliferative, and thus more likely to respond to NAC in ER-positive breast cancer. Methods We obtained clinicopathological data and overall survival information on 1,069 breast cancer patients from The Cancer Genome Atlas (TCGA). Computational algorithms and CIBERSORT were used to estimate immune cell infiltration. Additionally, xCell was used for validation. Results Th2 high tumors did not consistently associate with an unfavorable immune cell composition and tumor immune microenvironment but were found to be significantly elevated in the cancer stage. Th2 high tumors also correlated with high Nottingham pathological grade, as well as with Ki-67 and proliferation score in ER-positive subtypes. High Th2 tumors achieved a pathological complete response (pCR) significantly higher in ER-positive breast cancer. Conclusions In conclusion, high levels of Th2 are associated with aggressive features of breast cancer. Th2 levels may be a biomarker in patient selection for NAC in ER-positive breast cancer.
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Affiliation(s)
- Lan Le
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Mariko Asaoka
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan
| | - Manabu Futamura
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.,Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY, USA.,Department of Gastroenterological Surgery, Yokohama City University, Yokohama, Japan.,Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo, Japan.,Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.,Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
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Oshi M, Angarita FA, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K. High Expression of NRF2 Is Associated with Increased Tumor-Infiltrating Lymphocytes and Cancer Immunity in ER-Positive/HER2-Negative Breast Cancer. Cancers (Basel) 2020; 12:E3856. [PMID: 33371179 PMCID: PMC7766649 DOI: 10.3390/cancers12123856] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 12/16/2020] [Indexed: 12/19/2022] Open
Abstract
Nuclear factor erythroid 2-related factor 2 (NRF2) is a key modifier in breast cancer. It is unclear whether NRF2 suppresses or promotes breast cancer progression. We studied the clinical relevance of NRF2 expression by conducting in silico analyses in 5443 breast cancer patients from several large patient cohorts (METABRIC, GSE96058, GSE25066, GSE20194, and GSE75688). NRF2 expression was significantly associated with better survival, low Nottingham pathological grade, and ER-positive/HER2-negative and triple negative breast cancer (TNBC). High NRF2 ER-positive/HER2-negative breast cancer enriched inflammation- and immune-related gene sets by GSEA. NRF2 expression was elevated in immune, stromal, and cancer cells. High NRF2 tumors were associated with high infiltration of immune cells (CD8+, CD4+, and dendritic cells (DC)) and stromal cells (adipocyte, fibroblasts, and keratinocytes), and with low fraction of Th1 cells. NRF2 expression significantly correlated with area under the curve (AUC) of several drug response in multiple ER-positive breast cancer cell lines, however, there was no significant association between NRF2 and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in human samples. Finally, high NRF2 breast cancer was associated with high expression of immune checkpoint molecules. In conclusion, NRF2 expression was associated with enhanced tumor-infiltrating lymphocytes in ER-positive/HER2-negative breast cancer.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Fernando A. Angarita
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K. Inflammation Is Associated with Worse Outcome in the Whole Cohort but with Better Outcome in Triple-Negative Subtype of Breast Cancer Patients. J Immunol Res 2020; 2020:5618786. [PMID: 33457427 PMCID: PMC7787871 DOI: 10.1155/2020/5618786] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 11/24/2020] [Accepted: 11/28/2020] [Indexed: 02/07/2023] Open
Abstract
Inflammation has been linked with cancer, but whether it is part of the problem or part of the solution remains to be a matter of debate in breast cancer. Our group and others have demonstrated that inflammation aggravates cancer progression; however, some claim that inflammation may support immune cell infiltration and suppress cancer. We defined the gene set variation analysis of the Molecular Signatures Database Hallmark inflammatory response gene set as the inflammatory pathway score and analyzed 3632 tumors in total from 4 breast cancer cohorts (METABRIC, TCGA, GSE25066, and GSE21094). In the whole breast cancer cohort, high-score tumors were associated with aggressive clinical characteristics, such as worse disease specific survival, higher Nottingham histological grade, and younger age. Inflammatory score was significantly higher in triple-negative (TNBC) as well as basal and normal subtypes compared with the other subtypes, which suggest that the detrimental effect of high level of inflammation may be because it includes a more aggressive subtype. On the contrary, high score within TNBC was significantly associated with better survival. TNBC with high score enriched not only IFN-α, IFN-γ response, IL-2/STAT5 signaling, Allograft rejection, Complement, p53 pathway, Reactive Oxygen, and Apoptosis but also TNF-α signaling, IL6-JAK-STAT signaling, TGF-β signaling, Coagulation, Angiogenesis, EMT, KRAS signaling, and PI3K-AKT-MTOR signaling gene sets. High score was associated with mainly favorable anticancerous immune cell infiltration as well as Leukocyte fraction, TIL regional fraction, Lymphocyte infiltration, IFN-γ response, TGF-β response, and cytolytic activity scores. Although the inflammatory pathway score was not associated with neoadjuvant treatment response, it associated with expressions of immune checkpoint molecules. In conclusion, inflammation was associated with worse outcome in the whole breast cancer cohort, but with better outcome in TNBC, which was associated with favorable anticancerous immune response and immune cell infiltrations.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Stephanie Newman
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York 14263, USA
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14263, USA
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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Oshi M, Tokumaru Y, Patel A, Yan L, Matsuyama R, Endo I, Katz MH, Takabe K. A Novel Four-Gene Score to Predict Pathologically Complete (R0) Resection and Survival in Pancreatic Cancer. Cancers (Basel) 2020; 12:E3635. [PMID: 33291601 PMCID: PMC7761977 DOI: 10.3390/cancers12123635] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 11/24/2020] [Accepted: 12/02/2020] [Indexed: 12/17/2022] Open
Abstract
Pathologically complete (R0) resection is essential for prolonged survival in pancreatic cancer. Survival depends not only on surgical technique, but also on cancer biology. A biomarker to predict survival is a critical need in pancreatic treatment. We hypothesized that this 4-gene score, which was reported to reflect cell proliferation, is a translatable predictive biomarker for pancreatic cancer. A total of 954 pancreatic cancer patients from multiple cohorts were analyzed and validated. Pancreatic cancer had the 10th highest median score of 32 cancers in The Cancer Genome Atlas (TCGA) cohort. The four-gene score significantly correlated with pathological grade and MKI67 expression. The high four-gene score enriched cell proliferation-related and cancer aggressiveness-related gene sets. The high score was associated with activation of KRAS, p53, transforming growth factor (TGF)-β, and E2F pathways, and with high alteration rate of KRAS and CDKN2A genes. The high score was also significantly associated with reduced CD8+ T cell infiltration of tumors, but with high levels of interferon-γ and cytolytic activity in tumors. The four-gene score correlated with the area under the curve of irinotecan and sorafenib in primary pancreatic cancer, and with paclitaxel and doxorubicin in metastatic pancreatic cancer. The high four-gene score was associated with significantly fewer R0 resections and worse survival. The novelty of the study is in the application of the four-gene score to pancreatic cancer, rather than the bioinformatics technique itself. Future analyses of inoperable lesions are expected to clarify the utility of our score as a predictive biomarker of systemic treatments.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (Y.T.); (A.P.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (Y.T.); (A.P.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Ankit Patel
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (Y.T.); (A.P.)
| | - Li Yan
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Matthew H.G. Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (Y.T.); (A.P.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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Oshi M, Tokumaru Y, Angarita FA, Yan L, Matsuyama R, Endo I, Takabe K. Degree of Early Estrogen Response Predict Survival after Endocrine Therapy in Primary and Metastatic ER-Positive Breast Cancer. Cancers (Basel) 2020; 12:E3557. [PMID: 33260779 PMCID: PMC7760577 DOI: 10.3390/cancers12123557] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/22/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
Endocrine therapy is the gold-standard treatment for ER-positive/HER2-negative breast cancer. Although its clear benefit, patient compliance is poor (50-80%) due to its long administration period and adverse effects. Therefore, a predictive biomarker that can predict whether endocrine therapy is truly beneficial may improve patient compliance. In this study, we use estrogen response early gene sets of gene set enrichment assay algorithm as the score. We hypothesize that the score could predict the response to endocrine therapy and survival of breast cancer patients. A total of 6549 breast cancer from multiple patient cohorts were analyzed. The score was highest in ER-positive/HER2-negative compared to the other subtypes. Earlier AJCC stage, as well as lower Nottingham pathological grade, were associated with a high score. Low score tumors enriched only allograft rejection gene set, and was significantly infiltrated with immune cells, and high cytolytic activity score. A low score was significantly associated with a worse response to endocrine therapy and worse survival in both primary and metastatic breast cancer patients. The hazard ratio was double that of ESR1 expression. In conclusion, the estrogen response early score predicts response to endocrine therapy and is associated with survival in primary and metastatic breast cancer.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (Y.T.); (F.A.A.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (Y.T.); (F.A.A.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Fernando A. Angarita
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (Y.T.); (F.A.A.)
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, NY 14263, USA; (M.O.); (Y.T.); (F.A.A.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, School of Medicine, Fukushima Medical University, Fukushima 960-1295, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Kalinski P, Endo I, Takabe K. Plasmacytoid Dendritic Cell (pDC) Infiltration Correlate with Tumor Infiltrating Lymphocytes, Cancer Immunity, and Better Survival in Triple Negative Breast Cancer (TNBC) More Strongly than Conventional Dendritic Cell (cDC). Cancers (Basel) 2020; 12:E3342. [PMID: 33198125 PMCID: PMC7697894 DOI: 10.3390/cancers12113342] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 10/30/2020] [Accepted: 11/11/2020] [Indexed: 02/07/2023] Open
Abstract
Dendritic cells (DC) represent a major antigen-presenting cell type in the tumor immune microenvironment (TIME) and play an essential role in cancer immunity. Conventional DC (cDC) and plasmacytoid DC (pDC) were defined by the xCell algorithm and a total of 2968 breast cancer patients (TCGA and METABRIC) were analyzed. We found that triple-negative breast cancer (TNBC) had a high fraction of cDC and pDC compared to the other subtypes. In contrast to cDC, high pDC in TNBC was significantly associated with better disease-specific and disease-free survival consistently in both cohorts. High cDC TNBC tumors enriched not only inflammation and immune-related, but also metastasis-related gene sets in Gene Set Enrichment Analysis, whereas high pDC TNBC enriched inflammation and immune -related gene sets including IFN-γ signaling more strongly than cDC. pDC TNBC correlated with CD8+, CD4+ memory, IFN-γ score, and cytolytic activity stronger than cDC TNBC. High pDC TNBC were associated with a high fraction of anti-cancer immune cells and high expression of all the immune check point molecules examined. In conclusion, pDC levels correlated with the infiltration of immune cells and patient survival in TNBC more strongly than cDC; this is the first study suggesting the clinical relevance of pDC infiltration in TNBC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (S.N.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Stephanie Newman
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (S.N.); (Y.T.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (S.N.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Pawel Kalinski
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (S.N.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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MYC Targets Scores Are Associated with Cancer Aggressiveness and Poor Survival in ER-Positive Primary and Metastatic Breast Cancer. Int J Mol Sci 2020; 21:ijms21218127. [PMID: 33143224 PMCID: PMC7663719 DOI: 10.3390/ijms21218127] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 10/25/2020] [Accepted: 10/29/2020] [Indexed: 12/18/2022] Open
Abstract
MYC is one of the most studied oncogenes that is known to promote cell proliferation. We utilized MYC targets v1 and MYC targets v2 scores of gene set variation analysis and hypothesized that these scores correlate with tumor aggressiveness and survival outcomes. We examined a total of 3109 breast cancer patients from TCGA, METABRIC, and GSE124647 cohorts. In each cohort, the patients were divided into high- and low-score groups using the upper third value as the cut off. As expected, higher scores were related to increased cell proliferation and worse clinical and pathologic features. High MYC targets scores were associated with worse survival, specifically in primary ER-positive breast cancer, consistently in both TCGA and METABRIC cohorts. In ER-positive breast cancer, high MYC targets v1, but not v2 score, was associated with high mutation load, and high MYC targets v1 and v2 scores were both associated with increased infiltration of pro- and anti-cancerous immune cells. We found that high MYC scores were associated with worse survival in metastatic breast cancer. Our findings show that the MYC targets v1 and v2 scores are associated with tumor aggressiveness and poor prognosis in ER-positive primary tumors, as well as in metastatic breast cancer.
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Oshi M, Asaoka M, Tokumaru Y, Angarita FA, Yan L, Matsuyama R, Zsiros E, Ishikawa T, Endo I, Takabe K. Abundance of Regulatory T Cell (Treg) as a Predictive Biomarker for Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Cancers (Basel) 2020; 12:E3038. [PMID: 33086518 PMCID: PMC7603157 DOI: 10.3390/cancers12103038] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 10/12/2020] [Accepted: 10/16/2020] [Indexed: 02/07/2023] Open
Abstract
Regulatory CD4+ T cell (Treg), a subset of tumor-infiltrating lymphocytes (TILs), are known to suppress anticancer immunity but its clinical relevance in human breast cancer remains unclear. In this study, we estimated the relative abundance of Tregs in breast cancer of multiple patient cohorts by using the xCell algorithm on bulk tumor gene expression data. In total, 5177 breast cancer patients from five independent cohorts (TCGA-BRCA, GSE96058, GSE25066, GSE20194, and GSE110590) were analyzed. Treg abundance was not associated with cancer aggressiveness, patient survival, or immune activity markers, but it was lower in metastatic tumors when compared to matched primary tumors. Treg was associated with a high mutation rate of TP53 genes and copy number mutations as well as with increased tumor infiltration of M2 macrophages and decreased infiltration of T helper type 1 (Th1) cells. Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) was significantly associated with low Treg abundance in triple negative breast cancer (TNBC) but not in ER-positive/Her2-negative subtype. High Treg abundance was significantly associated with high tumor expression of multiple immune checkpoint inhibitor genes. In conclusion, Treg abundance may have potential as a predictive biomarker of pCR after NAC in TNBC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.); (F.A.A.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Mariko Asaoka
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.); (F.A.A.)
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan;
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.); (F.A.A.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Fernando A. Angarita
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.); (F.A.A.)
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Emese Zsiros
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
- Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan;
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.); (F.A.A.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan;
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
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Oshi M, Asaoka M, Tokumaru Y, Yan L, Matsuyama R, Ishikawa T, Endo I, Takabe K. CD8 T Cell Score as a Prognostic Biomarker for Triple Negative Breast Cancer. Int J Mol Sci 2020; 21:E6968. [PMID: 32971948 PMCID: PMC7555570 DOI: 10.3390/ijms21186968] [Citation(s) in RCA: 140] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/24/2022] Open
Abstract
CD8 T cell is an essential component of tumor-infiltrating lymphocytes (TIL) and tumor immune microenvironment (TIME). Using the xCell CD8 T cell score of whole tumor gene expression data, we estimated these cells in total of 3837 breast cancer patients from TCGA, METABRIC and various GEO cohorts. The CD8 score correlated strongly with expression of CD8 genes. The score was highest for triple-negative breast cancer (TNBC), and a high score was associated with high tumor immune cytolytic activity and better survival in TNBC but not other breast cancer subtypes. In TNBC, tumors with a high CD8 score had enriched expression of interferon (IFN)-α and IFN-γ response and allograft rejection gene sets, and greater infiltration of anti-cancerous immune cells. The score strongly correlated with CD4 memory T cells in TNBC, and tumors with both a high CD8 score and high CD4 memory T cell abundance had significantly better survival. Finally, a high CD8 score was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, a high CD8 T cell score is associated with better survival in TNBC, particularly when tumor CD4 memory T cells were elevated. Our findings also suggest a possible use of the score as a predictive biomarker for response to immune checkpoint therapy.
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Affiliation(s)
- Masanori Oshi
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Mariko Asaoka
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.)
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan;
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Takashi Ishikawa
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan;
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (M.O.); (M.A.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (R.M.); (I.E.)
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan;
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
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