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Di Giorgio A, Ferracci F, Bagalà C, Carbone C, Salvatore L, Strippoli A, Attalla El Halabieh M, Abatini C, Alfieri S, Pacelli F, Tortora G. Combined Nabpaclitaxel pressurized intraPeritoneal aerosol chemotherapy with systemic Nabpaclitaxel-Gemcitabine chemotherapy for pancreatic cancer peritoneal metastases: protocol of single-arm, open-label, phase II trial (Nab-PIPAC trial). Pleura Peritoneum 2024; 9:121-129. [PMID: 39544430 PMCID: PMC11558173 DOI: 10.1515/pp-2024-0010] [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: 06/18/2024] [Accepted: 09/24/2024] [Indexed: 11/17/2024] Open
Abstract
Objectives Current therapies show limited efficacy against peritoneal metastases (PM) from pancreatic cancer. Pressurized intra-peritoneal aerosol chemotherapy (PIPAC) has emerged as a novel intraperitoneal drug delivery method. Recently, a dose-escalation study identified the safe dose of Nabpaclitaxel for PIPAC administration, an ideal intraperitoneal chemotherapy agent against pancreatic cancer. Combining systemic NabPaclitaxel-Gemcitabine with NabPaclitaxel-PIPAC may enhance disease control in pancreatic cancer patients with PM. Methods The Nab-PIPAC trial is a single-center, prospective, open-label, phase II study (ClinicalTrials.gov identifier: NCT05371223). Its primary goal is to evaluate the antitumor activity of the combined treatment based on Disease Control Rate (DCR) using RECISTv.1.1 criteria. Secondary objectives include feasibility, safety, pathological response, progression-free and overall survival, nutritional status, quality of life, pharmacokinetics of NabPaclitaxel-PIPAC, and PM molecular evolution via translational research. The treatment protocol consists of three courses, each with two cycles of intravenous NabPaclitaxel-Gemcitabine and one cycle of NabPaclitaxel-PIPAC, with standard metastatic pancreatic cancer doses for the former and 112.5 mg/m2 for the latter. Sample size follows Simon's two-stage design: 12 patients in stage one and 26 in stage two (80 % power, 0.1 alpha). Results Partial results will be available after first stage enrollment. Conclusions This trial aims to determine the antitumor efficacy and safety of combining NabPaclitaxel-PIPAC with systemic NabPaclitaxel-Gemcitabine in pancreatic cancer patients with PM.
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Affiliation(s)
- Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Federica Ferracci
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Cinzia Bagalà
- Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Carmine Carbone
- Department of Medical and Surgical Science, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Lisa Salvatore
- Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Antonia Strippoli
- Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
| | - Miriam Attalla El Halabieh
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Carlo Abatini
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Sergio Alfieri
- Surgical Unit of Digestive Surgery, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Fabio Pacelli
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Catholic University of the Sacred Heart, Rome, Italy
| | - Giampaolo Tortora
- Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
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Yamashita K, Kumamoto Y. CAFs-Associated Genes (CAFGs) in Pancreatic Ductal Adenocarcinoma (PDAC) and Novel Therapeutic Strategy. Int J Mol Sci 2024; 25:6003. [PMID: 38892190 PMCID: PMC11172745 DOI: 10.3390/ijms25116003] [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: 04/11/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive cancer with striking fibrosis, and its mortality rate is ranked second across human cancers. Cancer-associated fibroblasts (CAFs) play a critical role in PDAC progression, and we reviewed the molecular understanding of PDAC CAFs and novel therapeutic potential at present. CAFs-associated genes (CAFGs) were tentatively classified into three categories by stroma specificity representing stroma/epithelia expression ratios (SE ratios). The recent classification using single cell transcriptome technology clarified that CAFs were composed of myofibroblasts (myCAFs), inflammatory CAFs (iCAFs), and other minor ones (e.g., POSTN-CAFs and antigen presenting CAFs, apCAFs). LRRC15 is a myCAFs marker, and myCAFs depletion by diphtheria toxin induces the rapid accumulation of cytotoxic T lymphocytes (CTLs) and therefore augment PDL1 antibody treatments. This finding proposes that myCAFs may be a critical regulator of tumor immunity in terms of PDAC progression. myCAFs are located in CAFs adjacent to tumor cells, while iCAFs marked by PDPN and/or COL14A1 are distant from tumor cells, where hypoxic and acidic environments being located in iCAFs putatively due to poor blood supply is consistent with HIF1A and GPR68 expressions. iCAFs may be shared with SASP (secretion-associated phenotypes) in senescent CAFs. myCAFs are classically characterized by CAFGs induced by TGFB1, while chemoresistant CAFs with SASP may dependent on IL6 expression and accompanied by STAT3 activation. Recently, it was found that the unique metabolism of CAFs can be targeted to prevent PDAC progression, where PDAC cells utilize glucose, whereas CAFs in turn utilize lactate, which may be epigenetically regulated, mediated by its target genes including CXCR4. In summary, CAFs have unique molecular characteristics, which have been rigorously clarified as novel therapeutic targets of PDAC progression.
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Affiliation(s)
- Keishi Yamashita
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara 252-0374, Japan
| | - Yusuke Kumamoto
- Department of General-Pediatric-Hepatobiliary Pancreatic Surgery, Kitasato University School of Medicine, Sagamihara 252-0374, Japan;
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Dochi H, Kondo S, Komura S, Moriyama-Kita M, Komori T, Nanbo A, Sakaguchi M, Fukuyo M, Hamabe-Horiike T, Tanaka M, Mizokami H, Kano M, Kitagawa Y, Kobayashi E, Hirai N, Ueno T, Nakanishi Y, Endo K, Sugimoto H, Hanayama R, Kaneda A, Yoshizaki T. Peritumoral SPARC expression induced by exosomes from nasopharyngeal carcinoma infected Epstein-Barr virus: A poor prognostic marker. Int J Cancer 2024; 154:895-911. [PMID: 37907830 DOI: 10.1002/ijc.34777] [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: 04/05/2023] [Revised: 09/10/2023] [Accepted: 09/21/2023] [Indexed: 11/02/2023]
Abstract
Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) cells have high metastatic potential. Recent research has revealed that the interaction of between tumor cells and the surrounding stroma plays an important role in tumor invasion and metastasis. In this study, we showed the prognostic value of expression of SPARC, an extracellular matrix protein with multiple cellular functions, in normal adjacent tissues (NAT) surrounding NPC. In the immunohistochemical analysis of 51 NPC biopsy specimens, SPARC expression levels were significantly elevated in the NAT of EBER (EBV-encoded small RNA)-positive NPC compared to that in the NAT of EBER-negative NPC. Moreover, increased SPARC expression in NAT was associated with a worsening of overall survival. The enrichment analysis of RNA-seq of publicly available NPC and NAT surrounding NPC data showed that high SPARC expression in NPC was associated with epithelial mesenchymal transition promotion, and there was a dynamic change in the gene expression profile associated with interference of cellular proliferation in NAT, including SPARC expression. Furthermore, EBV-positive NPC cells induce SPARC expression in normal nasopharyngeal cells via exosomes. Induction of SPARC in cancer-surrounding NAT cells reduced intercellular adhesion in normal nasopharyngeal structures and promoted cell competition between cancer cells and normal epithelial cells. These results suggest that epithelial cells loosen their own binding with the extracellular matrix as well as stromal cells, facilitating the invasion of tumor cells into the adjacent stroma by activating cell competition. Our findings reveal a new mechanism by which EBV creates a pro-metastatic microenvironment by upregulating SPARC expression in NPC.
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Affiliation(s)
- Hirotomo Dochi
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Satoru Kondo
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shigetaka Komura
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Makiko Moriyama-Kita
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takeshi Komori
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Asuka Nanbo
- Department of Virus Infection Dynamics, National Research Center for the Control and Prevention of Infectious Diseases, Nagasaki University, Nagasaki, Japan
| | - Miako Sakaguchi
- Central Laboratory, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
| | - Masaki Fukuyo
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Toshihide Hamabe-Horiike
- Division of Molecular Medicine, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Japan
| | - Mariko Tanaka
- Center for Biochemical Research and Education, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Harue Mizokami
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Makoto Kano
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yuki Kitagawa
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Eiji Kobayashi
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Nobuyuki Hirai
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takayoshi Ueno
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yosuke Nakanishi
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kazuhira Endo
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hisashi Sugimoto
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Rikinari Hanayama
- Department of Immunology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tomokazu Yoshizaki
- Division of Otolaryngology and Head and Neck Surgery, Graduate School of Medical science, Kanazawa University, Kanazawa, Ishikawa, Japan
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Wileński S, Koper A, Śledzińska P, Bebyn M, Koper K. Innovative strategies for effective paclitaxel delivery: Recent developments and prospects. J Oncol Pharm Pract 2024; 30:367-384. [PMID: 38204196 DOI: 10.1177/10781552231208978] [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] [Indexed: 01/12/2024]
Abstract
PURPOSE Paclitaxel is an effective chemotherapeutic agent against a variety of cancer types. However, the clinical utility of paclitaxel is restricted by its poor solubility in water and high toxicity, resulting in low drug tolerance. These difficulties could be resolved by using suitable pharmacological carriers. Hence, it is essential to determine innovative methods of administering this effective medication to overcome paclitaxel's inherent limitations. METHODS An extensive literature search was conducted using multiple electronic databases to identify relevant studies published. RESULTS In this comprehensive analysis, many different paclitaxel delivery systems are covered and discussed, such as albumin-bound paclitaxel, polymeric micelles, paclitaxel-loaded liposomes, prodrugs, cyclodextrins, and peptide-taxane conjugates. Moreover, the review also covers various delivery routes of conventional paclitaxel or novel paclitaxel formulations, such as oral administration, local applications, and intraperitoneal delivery. CONCLUSION In addition to albumin-bound paclitaxel, polymeric micelles appear to be the most promising formulations for innovative drug delivery systems at present. A variety of variants of polymeric micelles are currently undergoing advanced phases of clinical trials.
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Affiliation(s)
- Sławomir Wileński
- Department of Pharmaceutical Technology, Nicolaus Copernicus University in Torun, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
- Central Cytostatic Drug Department, Hospital Pharmacy, The F. Lukaszczyk Oncology Centre, Bydgoszcz, Poland
| | - Agnieszka Koper
- Department of Oncology and Brachytherapy, Nicolaus Copernicus University in Torun, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
- Department of Oncology, Franciszek Lukaszczyk Oncology Centre, Bydgoszcz, Poland
| | - Paulina Śledzińska
- Department of Neurosurgery, 10th Military Research Hospital and Polyclinic, Bydgoszcz, Poland
| | - Marek Bebyn
- Department of Neurosurgery, 10th Military Research Hospital and Polyclinic, Bydgoszcz, Poland
| | - Krzysztof Koper
- Department of Oncology, Franciszek Lukaszczyk Oncology Centre, Bydgoszcz, Poland
- Department of Clinical Oncology, and Nursing, Department of Oncological Surgery, Nicolaus Copernicus University in Torun, Ludwik Rydygier Collegium Medicum, Bydgoszcz, Poland
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Zhang L, Cascio S, Mellors JW, Buckanovich RJ, Osmanbeyoglu HU. Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer. Commun Biol 2024; 7:20. [PMID: 38182756 PMCID: PMC10770164 DOI: 10.1038/s42003-023-05733-x] [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: 06/22/2023] [Accepted: 12/20/2023] [Indexed: 01/07/2024] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a highstromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. In this work, we integrate single-cell transcriptomics of the HGSOC TME from public and in-house datasets (n = 20) and stratify tumors based upon high vs. low stromal cell content. Although our cohort size is small, our analyses suggest a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors have a lower fraction of certain T cells, natural killer (NK) cells, and macrophages, and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicate that epithelial cancer cells and CA-MSCs secrete CXCL12 that interacte with the CXCR4 receptor, which is overexpressed on NK and CD8+ T cells. Dual IHC staining show that tumor infiltrating CD8 T cells localize in proximity of CXCL12+ tumor area. Moreover, CXCL12 and/or CXCR4 antibodies confirm the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.
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Affiliation(s)
- Linan Zhang
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15206, USA
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Department of Applied Mathematics, School of Mathematics and Statistics, Ningbo University, Ningbo, Zhejiang, 315211, China
| | - Sandra Cascio
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA
- Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - John W Mellors
- Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA
| | - Ronald J Buckanovich
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA
- Magee-Womens Research Institute, Pittsburgh, PA, 15213, USA
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15232, USA
| | - Hatice Ulku Osmanbeyoglu
- Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15206, USA.
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15232, USA.
- Department of Bioengineering, University of Pittsburgh School of Engineering, Pittsburgh, PA, 15219, USA.
- Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, 15261, USA.
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Sharath NS, Misra R, Ghosh J. Application of hydrogel-based drug delivery system for pancreatic cancer. RECENT ADVANCES IN NANOCARRIERS FOR PANCREATIC CANCER THERAPY 2024:73-93. [DOI: 10.1016/b978-0-443-19142-8.00011-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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7
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Takayama H, Kobayashi S, Gotoh K, Sasaki K, Iwagami Y, Yamada D, Tomimaru Y, Akita H, Asaoka T, Noda T, Wada H, Takahashi H, Tanemura M, Doki Y, Eguchi H. SPARC accelerates biliary tract cancer progression through CTGF-mediated tumor-stroma interactions: SPARC as a prognostic marker of survival after neoadjuvant therapy. J Cancer Res Clin Oncol 2023; 149:10935-10950. [PMID: 37330435 DOI: 10.1007/s00432-023-04835-7] [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: 01/17/2023] [Accepted: 05/02/2023] [Indexed: 06/19/2023]
Abstract
PURPOSE In biliary tract cancer (BTC), malignancy is strongest at the invasion front. To improve the BTC prognosis, the invasion front should be controlled. We evaluated tumor-stroma crosstalk at the tumor center and at the invasion front of BTC lesions. We investigated the expression of SPARC, a marker of cancer-associated fibroblasts, and determined its ability to predict BTC prognosis after neoadjuvant chemoradiotherapy (NAC-RT). METHODS We performed immunohistochemistry to evaluate SPARC expression in resected specimens from patients that underwent BTC surgery. We established highly invasive (HI) clones in two BTC cell lines (NOZ, CCLP1), and performed mRNA microarrays to compare gene expression in parental and HI cells. RESULTS Among 92 specimens, stromal SPARC expression was higher at the invasion front than at the lesion center (p = 0.014). Among 50 specimens from patients treated with surgery alone, high stromal SPARC expression at the invasion front was associated with a poor prognosis (recurrence-free survival: p = 0.033; overall survival: p = 0.017). Coculturing fibroblasts with NOZ-HI cells upregulated fibroblast SPARC expression. mRNA microarrays showed that connective tissue growth factor (CTGF) was upregulated in NOZ-HI and CCLP1-HI cells. A CTGF knockdown suppressed cell invasion in NOZ-HI cells. Exogeneous CTGF upregulated SPARC expression in fibroblasts. SPARC expression at the invasion front was significantly lower after NAC-RT, compared to surgery alone (p = 0.003). CONCLUSION CTGF was associated with tumor-stroma crosstalk in BTC. CTGF activated stromal SPARC expression, which promoted tumor progression, particularly at the invasion front. SPARC expression at the invasion front after NAC-RT may serve as a prognosis predictor.
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Affiliation(s)
- Hirotoshi Takayama
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Kazuki Sasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Surgery, Osaka Police Hospital, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
- Department of Surgery, Rinku General Medical Center, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Du J, Zhang J, Wang L, Wang X, Zhao Y, Lu J, Fan T, Niu M, Zhang J, Cheng F, Li J, Zhu Q, Zhang D, Pei H, Li G, Liang X, Huang H, Cao X, Liu X, Shao W, Sheng J. Selective oxidative protection leads to tissue topological changes orchestrated by macrophage during ulcerative colitis. Nat Commun 2023; 14:3675. [PMID: 37344477 PMCID: PMC10284839 DOI: 10.1038/s41467-023-39173-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 06/01/2023] [Indexed: 06/23/2023] Open
Abstract
Ulcerative colitis is a chronic inflammatory bowel disorder with cellular heterogeneity. To understand the composition and spatial changes of the ulcerative colitis ecosystem, here we use imaging mass cytometry and single-cell RNA sequencing to depict the single-cell landscape of the human colon ecosystem. We find tissue topological changes featured with macrophage disappearance reaction in the ulcerative colitis region, occurring only for tissue-resident macrophages. Reactive oxygen species levels are higher in the ulcerative colitis region, but reactive oxygen species scavenging enzyme SOD2 is barely detected in resident macrophages, resulting in distinct reactive oxygen species vulnerability for inflammatory macrophages and resident macrophages. Inflammatory macrophages replace resident macrophages and cause a spatial shift of TNF production during ulcerative colitis via a cytokine production network formed with T and B cells. Our study suggests components of a mechanism for the observed macrophage disappearance reaction of resident macrophages, providing mechanistic hints for macrophage disappearance reaction in other inflammation or infection situations.
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Affiliation(s)
- Juan Du
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.
| | - Junlei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang University Cancer Centre, Zhejiang University, Hangzhou, 310002, China
| | - Lin Wang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang University Cancer Centre, Zhejiang University, Hangzhou, 310002, China
| | - Xun Wang
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang University Cancer Centre, Zhejiang University, Hangzhou, 310002, China
| | - Yaxing Zhao
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Zhejiang University Cancer Centre, Zhejiang University, Hangzhou, 310002, China
| | - Jiaoying Lu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Tingmin Fan
- Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Central Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310002, China
| | - Meng Niu
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Jie Zhang
- Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Fei Cheng
- Pathology Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Jun Li
- Pathology Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
| | - Qi Zhu
- College of Computer Science and Technology, Nanjing University of Aeronautics and Astronautics, No. 29 JiangJun Road, Jiang Ning District, Nanjing, Jiangsu, 211106, China
| | - Daoqiang Zhang
- College of Computer Science and Technology, Nanjing University of Aeronautics and Astronautics, No. 29 JiangJun Road, Jiang Ning District, Nanjing, Jiangsu, 211106, China
| | - Hao Pei
- MobiDrop (Zhejiang), No. 455 Heshun Road, Tongxiang, Zhejiang, 314500, China
| | - Guang Li
- Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing, 100024, China
| | - Xingguang Liang
- Department of Clinical Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China
- Central Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310002, China
| | - He Huang
- Frontiers Science Center for Synthetic Biology, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China
| | - Xiaocang Cao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
- Department of Hepato-Gastroenterology, Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, 300000, China.
| | - Xinjuan Liu
- Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Chaoyang District, Beijing, 100024, China.
| | - Wei Shao
- College of Computer Science and Technology, Nanjing University of Aeronautics and Astronautics, No. 29 JiangJun Road, Jiang Ning District, Nanjing, Jiangsu, 211106, China.
| | - Jianpeng Sheng
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310002, China.
- Zhejiang University Cancer Centre, Zhejiang University, Hangzhou, 310002, China.
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9
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Zhang L, Cascio S, Mellors JW, Buckanovich RJ, Osmanbeyoglu HU. Single-cell analysis reveals the stromal dynamics and tumor-specific characteristics in the microenvironment of ovarian cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.07.544095. [PMID: 37333262 PMCID: PMC10274812 DOI: 10.1101/2023.06.07.544095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
High-grade serous ovarian carcinoma (HGSOC) is a heterogeneous disease, and a high stromal/desmoplastic tumor microenvironment (TME) is associated with a poor outcome. Stromal cell subtypes, including fibroblasts, myofibroblasts, and cancer-associated mesenchymal stem cells, establish a complex network of paracrine signaling pathways with tumor-infiltrating immune cells that drive effector cell tumor immune exclusion and inhibit the antitumor immune response. Single-cell transcriptomics of the HGSOC TME from public and in-house datasets revealed a distinct transcriptomic landscape for immune and non-immune cells in high-stromal vs. low-stromal tumors. High-stromal tumors had a lower fraction of certain T cells, natural killer (NK) cells, and macrophages and increased expression of CXCL12 in epithelial cancer cells and cancer-associated mesenchymal stem cells (CA-MSCs). Analysis of cell-cell communication indicated that epithelial cancer cells and CA-MSCs secreted CXCL12 that interacted with the CXCR4 receptor, which was overexpressed on NK and CD8 + T cells. CXCL12 and/or CXCR4 antibodies confirmed the immunosuppressive role of CXCL12-CXCR4 in high-stromal tumors.
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10
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YANG HONG, LI WAN, REN LIWEN, YANG YIHUI, ZHANG YIZHI, GE BINBIN, LI SHA, ZHENG XIANGJIN, LIU JINYI, ZHANG SEN, DU GUANHUA, TANG BO, WANG HONGQUAN, WANG JINHUA. Progress on diagnostic and prognostic markers of pancreatic cancer. Oncol Res 2023; 31:83-99. [PMID: 37304241 PMCID: PMC10208033 DOI: 10.32604/or.2023.028905] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 02/15/2023] [Indexed: 06/13/2023] Open
Abstract
Pancreatic cancer is a malignant disease characterized by low survival and high recurrence rate, whose patients are mostly at the stage of locally advanced or metastatic disease when first diagnosed. Early diagnosis is particularly important because prognostic/predictive markers help guide optimal individualized treatment regimens. So far, CA19-9 is the only biomarker for pancreatic cancer approved by the FDA, but its effectiveness is limited by low sensitivity and specificity. With recent advances in genomics, proteomics, metabolomics, and other analytical and sequencing technologies, the rapid acquisition and screening of biomarkers is now possible. Liquid biopsy also occupies a significant place due to its unique advantages. In this review, we systematically describe and evaluate the available biomarkers that have the greatest potential as vital tools in diagnosing and treating pancreatic cancer.
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Affiliation(s)
- HONG YANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - WAN LI
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - LIWEN REN
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - YIHUI YANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - YIZHI ZHANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - BINBIN GE
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - SHA LI
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - XIANGJIN ZHENG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - JINYI LIU
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - SEN ZHANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - GUANHUA DU
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
| | - BO TANG
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - HONGQUAN WANG
- Department of Pancreatic Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China
| | - JINHUA WANG
- The State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing, 100050, China
- Key Laboratory of Drug Target Research and Drug Screen, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100050, China
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11
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Wieder R. Fibroblasts as Turned Agents in Cancer Progression. Cancers (Basel) 2023; 15:2014. [PMID: 37046676 PMCID: PMC10093070 DOI: 10.3390/cancers15072014] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/19/2023] [Accepted: 03/23/2023] [Indexed: 03/30/2023] Open
Abstract
Differentiated epithelial cells reside in the homeostatic microenvironment of the native organ stroma. The stroma supports their normal function, their G0 differentiated state, and their expansion/contraction through the various stages of the life cycle and physiologic functions of the host. When malignant transformation begins, the microenvironment tries to suppress and eliminate the transformed cells, while cancer cells, in turn, try to resist these suppressive efforts. The tumor microenvironment encompasses a large variety of cell types recruited by the tumor to perform different functions, among which fibroblasts are the most abundant. The dynamics of the mutual relationship change as the sides undertake an epic battle for control of the other. In the process, the cancer "wounds" the microenvironment through a variety of mechanisms and attracts distant mesenchymal stem cells to change their function from one attempting to suppress the cancer, to one that supports its growth, survival, and metastasis. Analogous reciprocal interactions occur as well between disseminated cancer cells and the metastatic microenvironment, where the microenvironment attempts to eliminate cancer cells or suppress their proliferation. However, the altered microenvironmental cells acquire novel characteristics that support malignant progression. Investigations have attempted to use these traits as targets of novel therapeutic approaches.
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Affiliation(s)
- Robert Wieder
- Rutgers New Jersey Medical School and the Cancer Institute of New Jersey, Newark, NJ 07103, USA
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12
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Tanaka HY, Nakazawa T, Enomoto A, Masamune A, Kano MR. Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment. Cancers (Basel) 2023; 15:cancers15030724. [PMID: 36765684 PMCID: PMC9913712 DOI: 10.3390/cancers15030724] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/19/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10-200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the "magic bullet"-both effective and safe-to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.
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Affiliation(s)
- Hiroyoshi Y. Tanaka
- Department of Pharmaceutical Biomedicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi 700-8530, Okayama, Japan
| | - Takuya Nakazawa
- Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi 700-8530, Okayama, Japan
| | - Atsushi Enomoto
- Department of Pathology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya-shi 466-8550, Aichi, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai-shi 980-8574, Miyagi, Japan
| | - Mitsunobu R. Kano
- Department of Pharmaceutical Biomedicine, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University, 1-1-1 Tsushima-naka, Kita-ku, Okayama-shi 700-8530, Okayama, Japan
- Correspondence:
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13
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Feng H, Zhuo Y, Zhang X, Li Y, Li Y, Duan X, Shi J, Xu C, Gao Y, Yu Z. Tumor Microenvironment in Hepatocellular Carcinoma: Key Players for Immunotherapy. J Hepatocell Carcinoma 2022; 9:1109-1125. [PMID: 36320666 PMCID: PMC9618253 DOI: 10.2147/jhc.s381764] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains a serious medical therapeutic challenge as conventional curative avenues such as surgery and chemotherapy only benefit for few patients with limited tumor burden. Immunotherapy achieves clinical progress in the treatment of this prevalent malignant disease by virtue of the development of tumor immunology; however, most patients have experienced minimal or no clinical benefit in terms of overall survival. The complexity and diversity of tumor microenvironment (TME) built by immune and stromal cell subsets has been considered to be responsible for the insufficiency of immunotherapy. The advance of bioanalytical technology boosts the exploration of the composition and differentiation of these infiltrated cells, which reflect the immune state of the TME and impact the efficacy of the antitumor immune response. Targeting these cells to remodel the TME is one of the important immunotherapeutic approaches to improve HCC treatment. In this review, we focused on the role of these non-cancerous cells in the tumor progression, and elaborated their function on cancer immunotherapy when manipulating them as potential targets.
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Affiliation(s)
- Hai Feng
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yunhui Zhuo
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xuemei Zhang
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yuyao Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yue Li
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Xiangjuan Duan
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Jia Shi
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Chengbin Xu
- Department of Informatics, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China
| | - Yueqiu Gao
- Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Correspondence: Yueqiu Gao, Institute of Infectious Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
| | - Zhuo Yu
- Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China,Zhuo Yu, Department of Liver Disease, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China, Tel +86 21 20256507, Fax +86 21 20256699, Email
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14
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Yang X, Xia Y, Wang S, Sun C. Prognostic value of SPARC in hepatocellular carcinoma: A systematic review and meta-analysis. PLoS One 2022; 17:e0273317. [PMID: 35981080 PMCID: PMC9387809 DOI: 10.1371/journal.pone.0273317] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 08/06/2022] [Indexed: 01/30/2023] Open
Abstract
Objective
Hepatocellular carcinoma (HCC) is characterized by a high degree of malignancy, rapid proliferation of tumor cells, and early liver metastasis. Resistance to multiple drugs independent of the high expression of secreted protein acidic and rich in cysteine (SPARC) is associated with a high risk of recurrence and mortality. However, the prognostic value of SPARC in patients with HCC remains unclear. Therefore, we performed a meta-analysis to evaluate the relationship between the expression of SPARC and the prognosis of patients with HCC.
Methods
We searched for relevant articles in the CNKI, PubMed, EMBASE, and Web of Science databases. The 95% confidence intervals (CIs) were calculated for combined overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of expression of SPARC in patients with HCC.
Results
In six of the studies, SPARC expression status was significantly associated with OS (combined hazard ratio [HR], 1.38; 95% CI, 1.0–1.82; Z = 2.27, P = 0.02) but not with DFS (combined HR, 0.79; 95% CI, 0.16–4.00, Z = 0.28, P = 0.78). Therefore, it cannot be assumed that upregulated SPARC expression has an effect on DFS in patients with HCC.
Conclusion
Elevated SPARC expression is associated with a low survival rate but not with DFS in patients with HCC. Further studies are needed to confirm our conclusions.
Registration
INPLASY registration number: INPLASY202180115. https://inplasy.com/inplasy-2021-8-0115/.
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Affiliation(s)
- Xiaoyu Yang
- Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
| | - Yunhong Xia
- Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- * E-mail:
| | - Shuomin Wang
- Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
| | - Chen Sun
- Department of Oncology, The Fourth Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
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15
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He R, Yin T, Pan S, Wang M, Zhang H, Qin R. One hundred most cited article related to pancreaticoduodenectomy surgery: A bibliometric analysis. Int J Surg 2022; 104:106775. [PMID: 35840048 DOI: 10.1016/j.ijsu.2022.106775] [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: 01/13/2022] [Revised: 06/30/2022] [Accepted: 07/07/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND In light of the challenges associated with pancreaticoduodenectomy (PD) and recent key improvements, this bibliometric analysis aimed to analyze the 100 top-cited (T100) articles related to PD surgery to widen the awareness of relevant research on this procedure. METHODS The term "pancreaticoduodenectomy" was used to retrieve articles from the Web of Science Core Collection database. The 100 most cited manuscripts in the English language were identified and further analyzed by their countries of origin, publication journals, authors, and themes. RESULTS A thorough literature search was performed on the Web of Science until April 2020. The total number of citations for the T100 articles ranged from 227 to 3029. The T100 articles came from 18 different countries, with the USA accounting for the plurality (n = 72). Professor J.L. Cameron from Johns Hopkins Medicine USA published the most articles (n = 22), including one as the first author and two as a co-author. Furthermore, Johns Hopkins Medicine, USA, published the most articles on PD surgery (n = 24), with a total citation count of 14,151. The journal Annals of Surgery published 40 of the T100 articles, with 15,847 citations and an average citation count of 396. Among the T100 articles, the citation frequency following the year of publication showed a parabolic trend, with citations peaking in the 9th year following publication. CONCLUSION Our study identified and analyzed the T100 articles in PD surgery. The USA was the dominant country regarding articles, researchers, and institutions. The citations of the articles peaked in the 9th year after publication.
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Affiliation(s)
- Ruizhi He
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Taoyuan Yin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Department of Epidemiology and Biostatistics and State Key Laboratory of Environment Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Shutao Pan
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Min Wang
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Hang Zhang
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Renyi Qin
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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16
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Poomsawat S, Kosanwat T, Meesakul O, Sanguansin S. Epithelial and fibroblast SPARC expression patterns in oral leukoplakia and oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 134:e44-e50. [PMID: 35165061 DOI: 10.1016/j.oooo.2021.10.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 09/27/2021] [Accepted: 10/22/2021] [Indexed: 10/19/2022]
Abstract
OBJECTIVE This study evaluated and compared the expression of secreted protein acidic and rich in cysteine (SPARC) in epithelial cells and fibroblasts of oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) using normal oral mucosa as a control. STUDY DESIGN The expression of SPARC was determined in samples of normal oral mucosa (n = 12), OL without dysplasia (n = 31), OL with dysplasia (n = 54), and OSCC (n = 69) using immunohistochemistry. The percentage of positive cells in epithelial cells and fibroblasts was independently evaluated. RESULTS Epithelial SPARC was found in 33.3%, 35.5%, 25.9%, and 66.7% of normal oral mucosa, OL without dysplasia, OL with dysplasia, and OSCC, respectively. Fibroblast SPARC was found in 50.0%, 29.0%, 46.3%, and 84.1% of normal oral mucosa, OL without dysplasia, OL with dysplasia, and OSCC, respectively. OSCC had higher epithelial and fibroblast SPARC expression than normal oral mucosa, OL without dysplasia, and OL with dysplasia (P < .05). No significant differences were observed in epithelial and fibroblast SPARC among normal oral mucosa or OL with and without dysplasia. CONCLUSION Overexpression of epithelial and fibroblast SPARC was observed in OSCC but not in OL, suggesting that SPARC is involved in the late stage of oral carcinogenesis.
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Affiliation(s)
- Sopee Poomsawat
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University
| | - Theerachai Kosanwat
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University
| | - Ounruean Meesakul
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University
| | - Sirima Sanguansin
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
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17
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Noritake O, Aokage K, Suzuki A, Tane K, Miyoshi T, Samejima J, Yoshikawa T, Murata SC, Nakai T, Tsuboi M, Ishii G. Prognostic impact of the number of peri-tumoral alveolar macrophages in patients with stage I lung adenocarcinoma. J Cancer Res Clin Oncol 2022; 148:3437-3447. [PMID: 35779107 DOI: 10.1007/s00432-022-04056-4] [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: 08/27/2021] [Accepted: 04/19/2022] [Indexed: 11/24/2022]
Abstract
PURPOSE Intratumoral macrophages are reportedly involved in tumor progression in non-small cell lung cancer; however, little is known about the prognostic impact and function of alveolar macrophages (AMs). This study aims to investigate the prognostic impact of the number of peri-tumoral AMs in patients with stage I lung adenocarcinoma. METHODS We investigated 514 patients with pathological stage I lung adenocarcinoma who underwent complete resection with lobectomy or pneumonectomy. The numbers of peri-tumoral AMs were counted, and patients were classified into two groups based on the number of peri-tumoral AMs. Using the Cancer Genome Atlas (TCGA) database of stage I lung adenocarcinoma, we compared gene expression profiles of high and low peri-tumoral AM contents. RESULTS The median number of peri-tumoral AMs per alveolar space was 15.5. Patients with a high peri-tumoral AM content had significantly shorter disease-free survival and overall survival than patients with a low peri-tumoral AM content (both p < 0.01). In the multivariate analyses, a higher number of peri-tumoral AMs were an independent prognostic factor (p = 0.02). The analysis of TCGA database revealed that patients with a high peri-tumoral AM content had shorter disease-free survival than those with a low peri-tumoral AM content (p = 0.04). Gene expression analysis of TCGA stage I lung adenocarcinoma revealed enrichment of biological processes, such as chemotaxis and epithelial proliferation, in patients with a high peri-tumoral AM content. CONCLUSION The number of peri-tumoral AMs had a strong impact on disease-free survival in patients with stage I lung adenocarcinoma.
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Affiliation(s)
- Osamu Noritake
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan.,Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Keiju Aokage
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Ayako Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Chiba, Japan
| | - Kenta Tane
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Tomohiro Miyoshi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Joji Samejima
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Toyohumi Yoshikawa
- Department of Thoracic Surgery, The University of Nagoya Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Shawhay Charles Murata
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan
| | - Tokiko Nakai
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan
| | - Masahiro Tsuboi
- Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Genichiro Ishii
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Kashiwa, Chiba, 277-8577, Japan. .,Division of Innovative Pathology and Laboratory Medicine, Exploratory Research and Clinical Trial Center (EPOC), National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
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18
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Ammer-Herrmenau C, Wolf L, Nasrin SS, Ramu I, Roggiolani R, Goetze RG, Buchholz SM, Sendler M, Ellenrieder V, Neesse A. Activity of acute pancreatitis is modified by secreted protein acidic and rich in cysteine ablation. United European Gastroenterol J 2022; 10:544-555. [PMID: 35699570 PMCID: PMC9278565 DOI: 10.1002/ueg2.12262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 05/23/2022] [Indexed: 11/24/2022] Open
Abstract
Background Acute pancreatitis (AP) is a frequent cause for hospitalization. However, molecular determinants that modulate severity of experimental pancreatitis are only partially understood. Objective To investigate the role of secreted protein acidic and rich in cysteine (SPARC) during cerulein‐induced AP in mice. Methods AP was induced by repeated cerulein injections in SPARC knock‐out mice (SPARC−/−) and control littermates (SPARC+/+). Secreted protein acidic and rich in cysteine expression and severity of AP were determined by histopathological scoring, immunohistochemistry, and biochemical assays. For functional analysis, primary murine acinar cell cultures with subsequent amylase release assays were employed. Proteome profiler assay and ELISA were conducted from pancreatic tissue lysates, and co‐immunofluorescence was performed. Results Upon cerulein induction, SPARC expression was robustly induced in pancreatic stellate cells (PSCs) but not in acinar cells. Genetic SPARC ablation resulted in attenuated severity of AP with significantly reduced levels of pancreatic necrosis, apoptosis, immune cell infiltration, and reduced fibrosis upon chronic stimulation. However, the release of amylase upon cerulein stimulation in primary acinar cell culture from SPARC+/+ and SPARC−/− was indistinguishable. Notably, immune cell derived C‐C Motif Chemokine Ligand 2 (CCL2) was highly elevated in SPARC+/+ pancreatic tissue potentially linking PSC derived SPARC with CCL2 induction in AP. Conclusion SPARC mediates the severity of AP. The potential link between SPARC and the CCL2 axis could open new avenues for tailored therapeutic interventions in AP patients and warrants further investigations.
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Affiliation(s)
- Christoph Ammer-Herrmenau
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Laurin Wolf
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Syeda S Nasrin
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Iswarya Ramu
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Roberta Roggiolani
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Robert G Goetze
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Soeren M Buchholz
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Mathias Sendler
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Volker Ellenrieder
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
| | - Albrecht Neesse
- Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Gottingen, Germany
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19
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Sakoda T, Uemura K, Kondo N, Sumiyoshi T, Okada K, Seo S, Otsuka H, Murakami Y, Takahashi S. Impact of disintegrin and metalloproteinase domain-containing protein 12 on pancreatic ductal adenocarcinoma treated with surgical resection and perioperative chemotherapy. Pancreatology 2022; 22:479-487. [PMID: 35365420 DOI: 10.1016/j.pan.2022.03.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 02/15/2022] [Accepted: 03/23/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES A disintegrin and metalloproteinase domain-containing protein 12 (ADAM12) has been reported to influence tumor progression and chemosensitivity in human cancers. We assessed the prognostic impact of ADAM12 and its predictive value for neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC) treated with surgical resection. METHODS ADAM12 expression was immunohistochemically examined in 428 patients with PDAC who underwent surgical resection. The association of ADAM12 expression with clinicopathological factors and survival was also analyzed. RESULTS Patients with high ADAM12 expression exhibited significantly shorter median disease-free survival (DFS) (high ADAM12: 17.8 vs. low ADAM12: 37.9 months; P < 0.001) and overall survival (OS) (high ADAM12: 33.1 vs. low ADAM12: 65.0 months; P < 0.001). A multivariate analysis revealed that high ADAM12 expression was an independent risk factor for poor DFS (P < 0.001) and OS (P < 0.001) in all eligible patients. Of 100 patients who received neoadjuvant chemotherapy (NAC), high ADAM12 expression was significantly associated with poor DFS in a subset of patients treated with the nab-paclitaxel (PTX) neoadjuvant regimen (P = 0.03), whereas the prognostic value of ADAM12 was not evident in patients not treated with nab-PTX (P = 0.12). CONCLUSIONS A negative prognostic value of high ADAM12 expression was observed in patients with PDAC treated with surgical resection, which was enhanced in patients treated with NAC, including nab-PTX. These results suggested that ADAM12 expression can predict nab-PTX chemosensitivity in PDAC and reflect PDAC progression.
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Affiliation(s)
- Takuya Sakoda
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Uemura
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.
| | - Naru Kondo
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Tatsuaki Sumiyoshi
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Kenjiro Okada
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Shingo Seo
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Hiroyuki Otsuka
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
| | - Yoshiaki Murakami
- Department of Advanced Medicine, Hiroshima University, Hiroshima, Japan
| | - Shinya Takahashi
- Department of Surgery, Graduate School of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan
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20
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Current Limitations and Novel Perspectives in Pancreatic Cancer Treatment. Cancers (Basel) 2022; 14:cancers14040985. [PMID: 35205732 PMCID: PMC8870068 DOI: 10.3390/cancers14040985] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/03/2022] [Accepted: 02/14/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary This review article presents a synopsis of the key clinical developments, their limitations, and future perspectives in the treatment of pancreatic cancer. In the first part, we summarize the available treatments for pancreatic cancer patients according to tumor stage, as well as the most relevant clinical trials over the past two decades. Despite this progress, there is still much to be improved in terms of patient survival. Therefore, in the second part, we consider various components of the tumor microenvironment in pancreatic cancer, looking for the key drivers of therapy resistance and tumor progression, which may lead to the discovery of new potential targets. We also discuss the most prominent molecules targeting the stroma and immune compartment that are being investigated in either preclinical or clinical trials. Finally, we also outline interesting venues for further research, such as possible combinations of therapies that may have the potential for clinical application. Abstract Pancreatic cancer is one of the deadliest cancers worldwide, largely due to its aggressive development. Consequently, treatment options are often palliative, as only one-fifth of patients present with potentially curable tumors. The only available treatment with curative intent is surgery followed by adjuvant chemotherapy. However, even for patients that are eligible for surgery, the 5-year OS remains below 10%. Hence, there is an urgent need to find new therapeutic regimens. In the first part of this review, we discuss the tumor staging method and its impact on the corresponding current standard-of-care treatments for PDAC. We also consider the key clinical trials over the last 20 years that have improved patient survival. In the second part, we provide an overview of the major components and cell types involved in PDAC, as well as their respective roles and interactions with each other. A deeper knowledge of the interactions taking place in the TME may lead to the discovery of potential new therapeutic targets. Finally, we discuss promising treatment strategies targeting specific components of the TME and potential combinations thereof. Overall, this review provides an overview of the current challenges and future perspectives in the treatment of pancreatic cancer.
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21
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SPARC-mediated long-term retention of nab-paclitaxel in pediatric sarcomas. J Control Release 2021; 342:81-92. [PMID: 34974029 DOI: 10.1016/j.jconrel.2021.12.035] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 12/29/2022]
Abstract
Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein overexpressed by several cancers. Because SPARC shows high binding affinity to albumin, we reasoned that pediatric sarcoma xenografts expressing SPARC would show enhanced uptake and accumulation of nanoparticle albumin-bound (nab)-paclitaxel, a potent anticancer drug formulation. We first evaluated the expression of SPARC in patient-derived xenografts (PDXs) of Ewing sarcoma, rhabdomyosarcoma and osteosarcoma, finding variable SPARC gene expression that correlated well with SPARC protein measured by immunoblotting. We revealed that the activity of the fusion gene chimera EWSR1-FLI1, the genetic driver of Ewing sarcoma, leads to lower expression of the gene SPARC in these tumors, likely due to enriched acetylation marks of the histone H3 lysine 27 at regions including the SPARC promoter and potential enhancers. Then, we used SPARC-edited Ewing sarcoma cells (A673 line) to demonstrate that SPARC knocked down (KD) cells accumulated significantly less amount of nab-paclitaxel in vitro than SPARC wild type (WT) cells. In vivo, SPARC KD and SPARC WT subcutaneous xenografts in mice achieved similar maximum intratumoral concentrations of nab-paclitaxel, though drug clearance from SPARC WT tumors was significantly slower. We confirmed such SPARC-mediated long-term intratumoral accumulation of nab-paclitaxel in Ewing sarcoma PDX with high expression of SPARC, which accumulated significantly more nab-paclitaxel than SPARC-low PDX. SPARC-high PDX responded better to nab-paclitaxel than SPARC-low tumors, although these results should be taken cautiously, given that the PDXs were established from different patients that could have specific determinants predisposing response to paclitaxel. In addition, SPARC KD Ewing sarcoma xenografts responded better to soluble docetaxel and paclitaxel than to nab-paclitaxel, while SPARC WT ones showed similar response to soluble and albumin-carried drugs. Overall, our results show that pediatric sarcomas expressing SPARC accumulate nab-paclitaxel for longer periods of time, which could have clinical implications for chemotherapy efficacy.
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22
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Hu C, Yin L, Chen Z, Waldron RT, Lugea A, Lin Y, Zhai X, Wen L, Han YP, Pandol SJ, Deng L, Xia Q. The unique pancreatic stellate cell gene expression signatures are associated with the progression from acute to chronic pancreatitis. Comput Struct Biotechnol J 2021; 19:6375-6385. [PMID: 34938413 PMCID: PMC8649580 DOI: 10.1016/j.csbj.2021.11.031] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 11/16/2021] [Accepted: 11/20/2021] [Indexed: 02/05/2023] Open
Abstract
Early recognition of chronic pancreatitis (CP) is still lacking. In the setting of CP injury, activated pancreatic stellate cell (PSC) is the central mediator of pancreatic fibrosis. We systematically define highly and uniquely expressed PSC genes and show that these genes are enriched in pancreatic diseases. Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. We demonstrated subset genes that may be associated with the progression from AP to CP. Furthermore, SPARC was identified as a candidate marker for the disease progression. Increased expression of SPARC and canonical PSC genes were verified during AP recovery, especially in recurrent AP mice models. Chronic pancreatitis (CP) is characterized by irreversible fibro-inflammatory changes induced by pancreatic stellate cell (PSC). Unresolved or recurrent injury causes dysregulation of biological process following AP, which would cause CP. Here, we systematically identify genes whose expressions are unique to PSC by comparing transcriptome profiles among total pancreas, pancreatic stellate, acinar, islet and immune cells. We then identified candidate genes and correlated them with the pancreatic disease continuum by performing intersection analysis among total PSC and activated PSC genes, and genes persistently differentially expressed during acute pancreatitis (AP) recovery. Last, we examined the association between candidate genes and AP, and substantiated their potential as biomarkers in experimental AP and recurrent AP (RAP) models. A total of 68 genes were identified as highly and uniquely expressed in PSC. The PSC signatures were highly enriched with extracellular matrix remodeling genes and were significantly enriched in AP pancreas compared to healthy control tissues. Among PSC signature genes that comprised a fibrotic phenotype, 10 were persistently differentially expressed during AP recovery. SPARC was determined as a candidate marker for the pancreatic disease continuum, which was not only persistently differentially expressed even five days after AP injury, but also highly expressed in two clinical datasets of CP. Sparc was also validated as highly elevated in RAP compared to AP mice. This work highlights the unique transcriptional profiles of PSC. These PSC signatures’ expression may help to identify patients with high risk of AP progression to CP.
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Affiliation(s)
- Cheng Hu
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Liyuan Yin
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Zhiyao Chen
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Richard T Waldron
- Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Aurelia Lugea
- Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Yiyun Lin
- Graduate School of Biomedical Sciences, UT MD Anderson Cancer Center, University of Texas, Houston, TX, United States
| | - Xiaoqian Zhai
- Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Li Wen
- Department of Gastroenterology and Shanghai Key Laboratory of Pancreatic Disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan-Ping Han
- Center for Growth, Metabolism and Aging, College of Life Sciences, Sichuan University, Chengdu, China
| | - Stephen J Pandol
- Department of Medicine and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, United States.,Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
| | - Lihui Deng
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Xia
- Department and Laboratory of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Center and West China-Liverpool Biomedical Research Center, West China Hospital, Sichuan University, Chengdu, China
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23
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Chen B, Deng T, Deng L, Yu H, He B, Chen K, Zheng C, Wang D, Wang Y, Chen G. Identification of tumour immune microenvironment-related alternative splicing events for the prognostication of pancreatic adenocarcinoma. BMC Cancer 2021; 21:1211. [PMID: 34772375 PMCID: PMC8590242 DOI: 10.1186/s12885-021-08962-7] [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: 07/29/2021] [Accepted: 11/01/2021] [Indexed: 11/10/2022] Open
Abstract
PURPOSE Pancreatic adenocarcinoma (PAAD) is characterized by low antitumour immune cell infiltration in an immunosuppressive microenvironment. This study aimed to systematically explore the impact on prognostic alternative splicing events (ASs) of tumour immune microenvironment (TIME) in PAAD. METHODS The ESTIMATE algorithm was implemented to compute the stromal/immune-related scores of each PAAD patient, followed by Kaplan-Meier (KM) survival analysis of patients with different scores grouped by X-tile software. TIME-related differentially expressed ASs (DEASs) were determined and evaluated through functional annotation analysis. In addition, Cox analyses were implemented to construct a TIME-related signature and an AS clinical nomogram. Moreover, comprehensive analyses, including gene set enrichment analysis (GSEA), immune infiltration, immune checkpoint gene expression, and tumour mutation were performed between the two risk groups to understand the potential mechanisms. Finally, Cytoscape was implemented to illuminate the AS-splicing factor (SF) regulatory network. RESULTS A total of 437 TIME-related DEASs significantly related to PAAD tumorigenesis and the formation of the TIME were identified. Additionally, a robust TIME-related prognostic signature based on seven DEASs was generated, and an AS clinical nomogram combining the signature and four clinical predictors also exhibited prominent discrimination by ROC (0.762 ~ 0.804) and calibration curves. More importantly, the fractions of CD8 T cells, regulatory T cells and activated memory CD4 T cells were lower, and the expression of four immune checkpoints-PD-L1, CD47, CD276, and PVR-was obviously higher in high-risk patients. Finally, functional analysis and tumour mutations revealed that aberrant immune signatures and activated carcinogenic pathways in high-risk patients may be the cause of the poor prognosis. CONCLUSION We extracted a list of DEASs associated with the TIME through the ESTIMATE algorithm and constructed a prognostic signature on the basis of seven DEASs to predict the prognosis of PAAD patients, which may guide advanced decision-making for personalized precision intervention.
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Affiliation(s)
- Bo Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Tuo Deng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Liming Deng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Haitao Yu
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bangjie He
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Kaiyu Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Chongming Zheng
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Daojie Wang
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Yi Wang
- Division of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China.
| | - Gang Chen
- Key Laboratory of Diagnosis and Treatment of Severe Hepato-Pancreatic Diseases of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. .,Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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24
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Truong LH, Pauklin S. Pancreatic Cancer Microenvironment and Cellular Composition: Current Understandings and Therapeutic Approaches. Cancers (Basel) 2021; 13:5028. [PMID: 34638513 PMCID: PMC8507722 DOI: 10.3390/cancers13195028] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/01/2021] [Accepted: 10/06/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal human solid tumors, despite great efforts in improving therapeutics over the past few decades. In PDAC, the distinct characteristic of the tumor microenvironment (TME) is the main barrier for developing effective treatments. PDAC TME is characterized by a dense stroma, cancer-associated fibroblasts, and immune cells populations that crosstalk to the subpopulations of neoplastic cells that include cancer stem cells (CSCs). The heterogeneity in TME is also exhibited in the diversity and dynamics of acellular components, including the Extracellular matrix (ECM), cytokines, growth factors, and secreted ligands to signaling pathways. These contribute to drug resistance, metastasis, and relapse in PDAC. However, clinical trials targeting TME components have often reported unexpected results and still have not benefited patients. The failures in those trials and various efforts to understand the PDAC biology demonstrate the highly heterogeneous and multi-faceted TME compositions and the complexity of their interplay within TME. Hence, further functional and mechanistic insight is needed. In this review, we will present a current understanding of PDAC biology with a focus on the heterogeneity in TME and crosstalk among its components. We also discuss clinical challenges and the arising therapeutic opportunities in PDAC research.
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Affiliation(s)
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Old Road, University of Oxford, Oxford OX3 7LD, UK;
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25
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Knolle M, Kaissis G, Jungmann F, Ziegelmayer S, Sasse D, Makowski M, Rueckert D, Braren R. Efficient, high-performance semantic segmentation using multi-scale feature extraction. PLoS One 2021; 16:e0255397. [PMID: 34411138 PMCID: PMC8375977 DOI: 10.1371/journal.pone.0255397] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 07/15/2021] [Indexed: 11/19/2022] Open
Abstract
The success of deep learning in recent years has arguably been driven by the availability of large datasets for training powerful predictive algorithms. In medical applications however, the sensitive nature of the data limits the collection and exchange of large-scale datasets. Privacy-preserving and collaborative learning systems can enable the successful application of machine learning in medicine. However, collaborative protocols such as federated learning require the frequent transfer of parameter updates over a network. To enable the deployment of such protocols to a wide range of systems with varying computational performance, efficient deep learning architectures for resource-constrained environments are required. Here we present MoNet, a small, highly optimized neural-network-based segmentation algorithm leveraging efficient multi-scale image features. MoNet is a shallow, U-Net-like architecture based on repeated, dilated convolutions with decreasing dilation rates. We apply and test our architecture on the challenging clinical tasks of pancreatic segmentation in computed tomography (CT) images as well as brain tumor segmentation in magnetic resonance imaging (MRI) data. We assess our model's segmentation performance and demonstrate that it provides performance on par with compared architectures while providing superior out-of-sample generalization performance, outperforming larger architectures on an independent validation set, while utilizing significantly fewer parameters. We furthermore confirm the suitability of our architecture for federated learning applications by demonstrating a substantial reduction in serialized model storage requirement as a surrogate for network data transfer. Finally, we evaluate MoNet's inference latency on the central processing unit (CPU) to determine its utility in environments without access to graphics processing units. Our implementation is publicly available as free and open-source software.
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Affiliation(s)
- Moritz Knolle
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Institute for Artificial Intelligence and Informatics in Medicine, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Georgios Kaissis
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Institute for Artificial Intelligence and Informatics in Medicine, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- OpenMined
- Department of Computing, Imperial College London, London, United Kingdom
| | - Friederike Jungmann
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Sebastian Ziegelmayer
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Daniel Sasse
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Marcus Makowski
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
| | - Daniel Rueckert
- Institute for Artificial Intelligence and Informatics in Medicine, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
- Department of Computing, Imperial College London, London, United Kingdom
| | - Rickmer Braren
- Department of Diagnostic and Interventional Radiology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
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Li FL, Guan KL. The two sides of Hippo pathway in cancer. Semin Cancer Biol 2021; 85:33-42. [PMID: 34265423 DOI: 10.1016/j.semcancer.2021.07.006] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/09/2021] [Accepted: 07/11/2021] [Indexed: 02/08/2023]
Abstract
The Hippo signaling pathway was originally characterized by genetic studies in Drosophila to regulate tissue growth and organ size, and the core components of this pathway are highly conserved in mammals. Studies over the past two decades have revealed critical physiological and pathological functions of the Hippo tumor-suppressor pathway, which is tightly regulated by a broad range of intracellular and extracellular signals. These properties enable the Hippo pathway to serve as an important controller in organismal development and adult tissue homeostasis. Dysregulation of the Hippo signaling has been observed in many cancer types, suggesting the possibility of cancer treatment by targeting the Hippo pathway. The general consensus is that Hippo has tumor suppressor function. However, growing evidence also suggests that the function of the Hippo pathway in malignancy is cancer context dependent as recent studies indicating tumor promoting function of LATS. This article surveys the Hippo pathway signaling mechanisms and then reviews both the tumor suppressing and promoting function of this pathway. A comprehensive understanding of the dual roles of the Hippo pathway in cancer will benefit future therapeutic targeting of the Hippo pathway for cancer treatment.
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Affiliation(s)
- Fu-Long Li
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
| | - Kun-Liang Guan
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA; Moores Cancer Center, University of California San Diego, La Jolla, CA, USA.
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Belhabib I, Zaghdoudi S, Lac C, Bousquet C, Jean C. Extracellular Matrices and Cancer-Associated Fibroblasts: Targets for Cancer Diagnosis and Therapy? Cancers (Basel) 2021; 13:3466. [PMID: 34298680 PMCID: PMC8303391 DOI: 10.3390/cancers13143466] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 12/12/2022] Open
Abstract
Solid cancer progression is dictated by neoplastic cell features and pro-tumoral crosstalks with their microenvironment. Stroma modifications, such as fibroblast activation into cancer-associated fibroblasts (CAFs) and extracellular matrix (ECM) remodeling, are now recognized as critical events for cancer progression and as potential therapeutic or diagnostic targets. The recent appreciation of the key, complex and multiple roles of the ECM in cancer and of the CAF diversity, has revolutionized the field and raised innovative but challenging questions. Here, we rapidly present CAF heterogeneity in link with their specific ECM remodeling features observed in cancer, before developing each of the impacts of such ECM modifications on tumor progression (survival, angiogenesis, pre-metastatic niche, chemoresistance, etc.), and on patient prognosis. Finally, based on preclinical studies and recent results obtained from clinical trials, we highlight key mechanisms or proteins that are, or may be, used as potential therapeutic or diagnostic targets, and we report and discuss benefits, disappointments, or even failures, of recently reported stroma-targeting strategies.
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Affiliation(s)
| | | | | | | | - Christine Jean
- Centre de Recherche en Cancérologie de Toulouse (CRCT), INSERM U1037, Université Toulouse III Paul Sabatier, ERL5294 CNRS, 31037 Toulouse, France; (I.B.); (S.Z.); (C.L.); (C.B.)
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Alzhrani R, Alsaab HO, Vanamal K, Bhise K, Tatiparti K, Barari A, Sau S, Iyer AK. Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes. ADVANCED THERAPEUTICS 2021; 4:2000262. [PMID: 34212073 PMCID: PMC8240487 DOI: 10.1002/adtp.202000262] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.
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Affiliation(s)
- Rami Alzhrani
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Kushal Vanamal
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ketki Bhise
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Katyayani Tatiparti
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ayatakshi Barari
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Samaresh Sau
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Arun K. Iyer
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States
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Pan K, Huang X, Jia X. SPARC promotes pancreatic cancer cell proliferation and migration through autocrine secretion into the extracellular milieu. Oncol Lett 2021; 21:485. [PMID: 33968201 PMCID: PMC8100956 DOI: 10.3892/ol.2021.12746] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Accepted: 03/24/2021] [Indexed: 01/12/2023] Open
Abstract
SPARC is a secreted glycoprotein that plays a complex and multifaceted role in tumour formation and progression. However, whether SPARC is an oncogene or a tumour suppressor is still unclear. Moreover, SPARC demonstrates potential in clinical pancreatic adenocarcinoma (PAAD) treatment, although it has been identified as an oncogene in some studies and a tumor suppressor in others. In the present study, a pan-cancer analysis of SPARC was carried out using The Cancer genome Atlas data, which demonstrated that SPARC was an oncogene in most cancer types and a cancer suppressor in others. In addition, SPARC expression was significantly upregulated in PAAD and associated with poor prognosis. SPARC also promoted the proliferation and migration of PANC-1 and SW1990 cell lines in vitro. SPARC was detected in the culture supernatant of PAAD cells and pancreatic acinar AR42J cells. SPARC regulated PAAD cell proliferation only when secreted into the extracellular milieu, thus explaining why the prognosis of patients with PAAD is correlated with the SPARC expression of both tumour cells and stromal cells. Collectively, the present findings demonstrated that the function of SPARC was associated with tumour type and that SPARC may represent an important oncogene in PAAD that merits further study.
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Affiliation(s)
- Kehua Pan
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xince Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Xiufen Jia
- Department of Radiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Yoshida S, Asanoma K, Yagi H, Onoyama I, Hori E, Matsumura Y, Okugawa K, Yahata H, Kato K. Fibronectin mediates activation of stromal fibroblasts by SPARC in endometrial cancer cells. BMC Cancer 2021; 21:156. [PMID: 33579227 PMCID: PMC7881467 DOI: 10.1186/s12885-021-07875-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 02/03/2021] [Indexed: 12/29/2022] Open
Abstract
Background Matricellular glycoprotein, SPARC is a secreted molecule, that mediates the interaction between cells and extracellular matrix. SPARC functions as a regulator of matrix organization and modulates cell behavior. In various kinds of cancer, strong SPARC expression was observed in stromal tissues as well as in cancer epithelial cells. The function of SPARC in cancer cells is somewhat controversial and its impact on peritumoral stromal cells remains to be resolved. Methods We investigated the effects of SPARC expression in endometrial cancer cells on the surrounding stromal fibroblasts using in vitro co-culture system. Changes in characteristics of fibroblasts were examined by analysis of fibroblast-specific markers and in vitro contraction assay. Results SPARC induced AKT phosphorylation and epithelial-to-mesenchymal transition, consistent with previous reports. Cancer-associated fibroblasts of endometrial cancer expressed higher levels of mesenchymal- and fibroblast-associated factors and had a stronger contraction ability. Unexpectedly, cancer-associated fibroblasts expressed comparable levels of SPARC compared with fibroblasts from normal endometrium. However, co-culture of normal fibroblasts with SPARC-expressing Ishikawa cells resulted in activation of the fibroblasts. Immunodepletion of SPARC did not affect the activation of fibroblasts. Conclusions Our data indicated that SPARC activated fibroblasts only in the presence of fibronectin, which was abundantly secreted from SPARC-expressing endometrial cancer cells. These results suggested that a SPARC-fibronectin-mediated activation of fibroblasts might be involved in enhanced mobility and invasion of cancer cells. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-07875-9.
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Affiliation(s)
- Sachiko Yoshida
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kazuo Asanoma
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Hiroshi Yagi
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Ichiro Onoyama
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Emiko Hori
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yumiko Matsumura
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kaoru Okugawa
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hideaki Yahata
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kiyoko Kato
- Department of Obstetrics and Gynecology, Faculty of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Jones CE, Sharick JT, Colbert SE, Shukla VC, Zent JM, Ostrowski MC, Ghadiali SN, Sizemore ST, Leight JL. Pten regulates collagen fibrillogenesis by fibroblasts through SPARC. PLoS One 2021; 16:e0245653. [PMID: 33534863 PMCID: PMC7857610 DOI: 10.1371/journal.pone.0245653] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 01/06/2021] [Indexed: 12/21/2022] Open
Abstract
Collagen deposition contributes to both high mammographic density and breast cancer progression. Low stromal PTEN expression has been observed in as many as half of breast tumors and is associated with increases in collagen deposition, however the mechanism connecting PTEN loss to increased collagen deposition remains unclear. Here, we demonstrate that Pten knockout in fibroblasts using an Fsp-Cre;PtenloxP/loxP mouse model increases collagen fiber number and fiber size within the mammary gland. Pten knockout additionally upregulated Sparc transcription in fibroblasts and promoted collagen shuttling out of the cell. Interestingly, SPARC mRNA expression was observed to be significantly elevated in the tumor stroma as compared to the normal breast in several patient cohorts. While SPARC knockdown via shRNA did not affect collagen shuttling, it notably decreased assembly of exogenous collagen. In addition, SPARC knockdown decreased fibronectin assembly and alignment of the extracellular matrix in an in vitro fibroblast-derived matrix model. Overall, these data indicate upregulation of SPARC is a mechanism by which PTEN regulates collagen deposition in the mammary gland stroma.
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Affiliation(s)
- Caitlin E. Jones
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
| | - Joe T. Sharick
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
| | - Sheila E. Colbert
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
| | - Vasudha C. Shukla
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
| | - Joshua M. Zent
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
| | - Michael C. Ostrowski
- Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America
| | - Samir N. Ghadiali
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
- Dorothy M. Davis Heart and Lung Research Institute, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
- Department of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine and Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Steven T. Sizemore
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America
- The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
| | - Jennifer L. Leight
- Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, Ohio, United States of America
- The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America
- * E-mail:
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Robinson CM, Talty A, Logue SE, Mnich K, Gorman AM, Samali A. An Emerging Role for the Unfolded Protein Response in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13020261. [PMID: 33445669 PMCID: PMC7828145 DOI: 10.3390/cancers13020261] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and one of the leading causes of cancer-associated deaths in the world. It is characterised by dismal response rates to conventional therapies. A major challenge in treatment strategies for PDAC is the presence of a dense stroma that surrounds the tumour cells, shielding them from treatment. This unique tumour microenvironment is fuelled by paracrine signalling between pancreatic cancer cells and supporting stromal cell types including the pancreatic stellate cells (PSC). While our molecular understanding of PDAC is improving, there remains a vital need to develop effective, targeted treatments. The unfolded protein response (UPR) is an elaborate signalling network that governs the cellular response to perturbed protein homeostasis in the endoplasmic reticulum (ER) lumen. There is growing evidence that the UPR is constitutively active in PDAC and may contribute to the disease progression and the acquisition of resistance to therapy. Given the importance of the tumour microenvironment and cytokine signalling in PDAC, and an emerging role for the UPR in shaping the tumour microenvironment and in the regulation of cytokines in other cancer types, this review explores the importance of the UPR in PDAC biology and its potential as a therapeutic target in this disease.
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Affiliation(s)
- Claire M. Robinson
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Aaron Talty
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Susan E. Logue
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
- Research Institute in Oncology and Hematology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
| | - Katarzyna Mnich
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Adrienne M. Gorman
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
| | - Afshin Samali
- Apoptosis Research Centre, School of Natural Sciences, National University of Ireland, H91 W2TY Galway, Ireland; (C.M.R.); (A.T.); (K.M.); (A.M.G.)
- Correspondence:
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Mosca L, Ilari A, Fazi F, Assaraf YG, Colotti G. Taxanes in cancer treatment: Activity, chemoresistance and its overcoming. Drug Resist Updat 2021; 54:100742. [PMID: 33429249 DOI: 10.1016/j.drup.2020.100742] [Citation(s) in RCA: 159] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/12/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
Since 1984, when paclitaxel was approved by the FDA for the treatment of advanced ovarian carcinoma, taxanes have been widely used as microtubule-targeting antitumor agents. However, their historic classification as antimitotics does not describe all their functions. Indeed, taxanes act in a complex manner, altering multiple cellular oncogenic processes including mitosis, angiogenesis, apoptosis, inflammatory response, and ROS production. On the one hand, identification of the diverse effects of taxanes on oncogenic signaling pathways provides opportunities to apply these cytotoxic drugs in a more rational manner. On the other hand, this may facilitate the development of novel treatment modalities to surmount anticancer drug resistance. In the latter respect, chemoresistance remains a major impediment which limits the efficacy of antitumor chemotherapy. Taxanes have shown impact on key molecular mechanisms including disruption of mitotic spindle, mitosis slippage and inhibition of angiogenesis. Furthermore, there is an emerging contribution of cellular processes including autophagy, oxidative stress, epigenetic alterations and microRNAs deregulation to the acquisition of taxane resistance. Hence, these two lines of findings are currently promoting a more rational and efficacious taxane application as well as development of novel molecular strategies to enhance the efficacy of taxane-based cancer treatment while overcoming drug resistance. This review provides a general and comprehensive picture on the use of taxanes in cancer treatment. In particular, we describe the history of application of taxanes in anticancer therapeutics, the synthesis of the different drugs belonging to this class of cytotoxic compounds, their features and the differences between them. We further dissect the molecular mechanisms of action of taxanes and the molecular basis underlying the onset of taxane resistance. We further delineate the possible modalities to overcome chemoresistance to taxanes, such as increasing drug solubility, delivery and pharmacokinetics, overcoming microtubule alterations or mitotic slippage, inhibiting drug efflux pumps or drug metabolism, targeting redox metabolism, immune response, and other cellular functions.
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Affiliation(s)
- Luciana Mosca
- Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P. le A. Moro 5, 00185 Rome, Italy
| | - Andrea Ilari
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
| | - Francesco Fazi
- Dept. Anatomical, Histological, Forensic & Orthopedic Sciences, Section of Histology and Medical Embryology, Sapienza University, Via A. Scarpa 14-16, 00161 Rome, Italy
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 3200003, Israel
| | - Gianni Colotti
- Institute of Molecular Biology and Pathology, Italian National Research Council (IBPM-CNR), c/o Department of Biochemical Sciences "A. Rossi Fanelli", Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy.
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Stromal Protein-Mediated Immune Regulation in Digestive Cancers. Cancers (Basel) 2021; 13:cancers13010146. [PMID: 33466303 PMCID: PMC7795083 DOI: 10.3390/cancers13010146] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/21/2020] [Accepted: 12/24/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary Solid cancers are surrounded by a network of non-cancerous cells comprising different cell types, including fibroblasts, and acellular protein structures. This entire network is called the tumor microenvironment (TME) and it provides a physical barrier to the tumor shielding it from infiltrating immune cells, such as lymphocytes, or therapeutic agents. In addition, the TME has been shown to dampen efficient immune responses of infiltrated immune cells, which are key in eliminating cancer cells from the organism. In this review, we will discuss how TME proteins in particular are involved in this dampening effect, known as immunosuppression. We will focus on three different types of digestive cancers: pancreatic cancer, colorectal cancer, and gastric cancer. Moreover, we will discuss current therapeutic approaches using TME proteins as targets to reverse their immunosuppressive effects. Abstract The stromal tumor microenvironment (TME) consists of immune cells, vascular and neural structures, cancer-associated fibroblasts (CAFs), as well as extracellular matrix (ECM), and favors immune escape mechanisms promoting the initiation and progression of digestive cancers. Numerous ECM proteins released by stromal and tumor cells are crucial in providing physical rigidity to the TME, though they are also key regulators of the immune response against cancer cells by interacting directly with immune cells or engaging with immune regulatory molecules. Here, we discuss current knowledge of stromal proteins in digestive cancers including pancreatic cancer, colorectal cancer, and gastric cancer, focusing on their functions in inhibiting tumor immunity and enabling drug resistance. Moreover, we will discuss the implication of stromal proteins as therapeutic targets to unleash efficient immunotherapy-based treatments.
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Hessmann E, Buchholz SM, Demir IE, Singh SK, Gress TM, Ellenrieder V, Neesse A. Microenvironmental Determinants of Pancreatic Cancer. Physiol Rev 2020; 100:1707-1751. [DOI: 10.1152/physrev.00042.2019] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.
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Affiliation(s)
- Elisabeth Hessmann
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Soeren M. Buchholz
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Ihsan Ekin Demir
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Shiv K. Singh
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Thomas M. Gress
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Volker Ellenrieder
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Albrecht Neesse
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
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Kalloger SE, Karasinska JM, Keung MS, Thompson DL, Ho J, Chow C, Gao D, Topham JT, Warren C, Wong HL, Lee MKC, Renouf DJ, Schaeffer DF. Stroma vs epithelium-enhanced prognostics through histologic stratification in pancreatic ductal adenocarcinoma. Int J Cancer 2020; 148:481-491. [PMID: 32955725 DOI: 10.1002/ijc.33304] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 08/10/2020] [Accepted: 09/07/2020] [Indexed: 01/05/2023]
Abstract
The mixture of epithelial and stromal components in pancreatic ductal adenocarcinoma (PDAC) may confound sequencing-based studies of tumor gene expression. Virtual microdissection has been suggested as a bioinformatics approach to segment the aforementioned components, and subsequent prognostic gene sets have emerged from this research. We examined the prognostic signature from the epithelial gene set of one such study using laser capture microdissected (LCM) epithelial samples. We also examined this gene set in matched stromal samples to determine whether prognostic findings were specific to the epithelium. LCM samples from 48 long-term and 48 short-term PDAC survivors were obtained. The resultant epithelial and stromal components were subjected to direct mRNA quantification using a 49 gene published PDAC classifier. Component-specific unsupervised hierarchical clustering was used to derive groups and survival differences were quantified. Immunohistochemical validation of particular genes was performed in an independent cohort. Clustering in the epithelial component yielded prognostic differences in univariable analysis (P = .02), but those differences were not significant when controlled for other clinicopathologic covariates (P = .06). Clustering in the stromal component yielded prognostic differences that persisted in the presence of other clinicopathologic covariates (P = .0005). Validation of selected genes in the epithelium (KRT6A-negative prognostic [P = .004]) and stroma (LY6D-improved prognostic [P = .01] and CTSV-negative prognostic [P = .0002]) demonstrated statistical independence in multivariable analysis. Although the genes used in this study were originally identified as being representative of the epithelial component of PDAC, their expression in the stroma appears to provide additional information that may aid in improved prognostication.
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Affiliation(s)
- Steve E Kalloger
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Joanna M Karasinska
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Martin S Keung
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Danielle L Thompson
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Julie Ho
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Christine Chow
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Dongxia Gao
- Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - James T Topham
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Cassia Warren
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada
| | - Hui-Li Wong
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Michael Kuan-Ching Lee
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.,Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Daniel J Renouf
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.,Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - David F Schaeffer
- Pancreas Centre BC, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Division of Anatomical Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada.,Genetic Pathology Evaluation Centre, University of British Columbia, Vancouver, British Columbia, Canada
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Increased SPARC expression is associated with neoadjuvant therapy in resectable pancreatic ductal adenocarcinoma. Pract Lab Med 2020; 21:e00171. [PMID: 32548230 PMCID: PMC7284134 DOI: 10.1016/j.plabm.2020.e00171] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 03/27/2020] [Accepted: 05/18/2020] [Indexed: 01/04/2023] Open
Abstract
Secreted Protein Acid and Rich in Cysteine (SPARC) is an extracellular glycoprotein secreted by fibroblasts and osteoblasts in normal tissues. SPARC overexpression occurs in multiple tumors including pancreatic ductal adenocarcinoma (PDAC) and may predict favorable response to nab-paclitaxel. The prognostic significance of SPARC expression in PDAC is unclear - some reports indicate SPARC overexpression associates with poor outcomes and others find no correlation. Considering neoadjuvant therapy enhances the stromal fibrosis of PDAC and taking into account that SPARC is a component of PDAC stromal fibrosis, we hypothesized that SPARC expression would be greater in neoadjuvant-treated versus treatment-naive PDAC. Quantitative immunohistochemistry was used to measure SPARC expression in resected PDAC in 74 cases of neoadjuvant treated PDAC and 95 cases of treatment-naïve PDAC. SPARC expression was increased 54% in neoadjuvant treated PDAC compared to treatment-naïve PDAC. These data indicate that increased SPARC expression correlates with neoadjuvant therapy in PDAC.
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Abstract
Cancer is a complex disease with high incidence and mortality rates. The important role played by the tumor microenvironment in regulating oncogenesis, tumor growth, and metastasis is by now well accepted in the scientific community. SPARC is known to participate in tumor-stromal interactions and impact cancer growth in ambiguous ways, which either enhance or suppress cancer aggressiveness, in a context-dependent manner. p53 transcription factor, a well-established tumor suppressor, has been reported to promote tumor growth in certain situations, such as hypoxia, thus displaying a duality in its action. Although both proteins are being tested in clinical trials, the synergistic relation between them is yet to be explored in clinical practice. In this review, we address the controversial roles of SPARC and p53 as double agents in cancer, briefly summarizing the interaction found between these two molecules and its importance in cancer.
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Van de Sande L, Cosyns S, Willaert W, Ceelen W. Albumin-based cancer therapeutics for intraperitoneal drug delivery: a review. Drug Deliv 2020; 27:40-53. [PMID: 31858848 PMCID: PMC6968566 DOI: 10.1080/10717544.2019.1704945] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Albumin is a remarkable carrier protein with multiple cellular receptor and ligand binding sites, which are able to bind and transport numerous endogenous and exogenous compounds. The development of albumin-bound drugs is gaining increased importance in the targeted delivery of cancer therapy. Intraperitoneal (IP) drug delivery represents an attractive strategy for the local treatment of peritoneal metastasis (PM). PM is characterized by the presence of widespread metastatic tumor nodules on the peritoneum, mostly originating from gastro-intestinal or gynaecological cancers. Albumin as a carrier for chemotherapy holds considerable promise for IP delivery in patients with PM. Data from recent (pre)clinical trials suggest that IP albumin-bound chemotherapy may result in superior efficacy in the treatment of PM compared to standard chemotherapy formulations. Here, we review the evidence on albumin-bound chemotherapy with a focus on IP administration and its efficacy in PM.
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Affiliation(s)
- Leen Van de Sande
- Laboratory of Experimental Surgery, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
| | - Sarah Cosyns
- Laboratory of Experimental Surgery, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
| | - Wouter Willaert
- Laboratory of Experimental Surgery, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
| | - Wim Ceelen
- Laboratory of Experimental Surgery, Department of Human Structure and Repair, Ghent University, Ghent, Belgium.,Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
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40
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Munasinghe A, Malik K, Mohamedi F, Moaraf S, Kocher H, Jones L, Hill NJ. Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer. Cancer Lett 2020; 477:88-96. [DOI: 10.1016/j.canlet.2020.02.031] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/30/2020] [Accepted: 02/23/2020] [Indexed: 12/11/2022]
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Sadoughi F, Mansournia MA, Mirhashemi SM. The potential role of chitosan-based nanoparticles as drug delivery systems in pancreatic cancer. IUBMB Life 2020; 72:872-883. [PMID: 32057169 DOI: 10.1002/iub.2252] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/03/2020] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer (PC) is one of the most lethal cancers and 12th most common cancer in the world. Due to the inaccessible anatomical position of the pancreas and asymptomatic early stages of this disease, PC has a high mortality rate. Therefore, providing reliable diagnostic and therapeutic tools are the keys to increase the PC survival rate. Nanotechnology is an inchoate field of science that previously scientists' tendency to enhance the efficacy of current preventive, diagnostic, and therapeutic methods has oriented them to build a bridge between this science and medicine. In the case of PC, nanotechnology suggests using drug delivery devices for a more effective and targeted therapy. Chitosan is a natural polymer that recently has attracted a lot of attention for being renewable, nontoxic, and bioabsorbable. In this article, we tend to look for the answer to this question: has nanotechnology been successful in using chitosan-based nanoformulations as carriers for preventing more individuals from suffering or at least increasing the 5-year survival of the PC patients?
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Affiliation(s)
- Fatemeh Sadoughi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed Mehdi Mirhashemi
- Metabolic Diseases Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
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Nii T, Makino K, Tabata Y. A cancer invasion model of cancer-associated fibroblasts aggregates combined with TGF-β1 release system. Regen Ther 2020; 14:196-204. [PMID: 32154334 PMCID: PMC7058408 DOI: 10.1016/j.reth.2020.02.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 02/02/2020] [Accepted: 02/06/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction The objective of this study is to design a cancer invasion model where the cancer invasion rate can be regulated in vitro. Methods Cancer-associated fibroblasts (CAF) aggregates incorporating gelatin hydrogel microspheres (GM) containing various concentrations of transforming growth factor-β1 (TGF-β1) (CAF-GM-TGF-β1) were prepared. Alpha-smooth muscle actin (α-SMA) for the CAF aggregates was measured to investigate the CAF activation level by changing the concentration of TGF-β1. An invasion assay was performed to evaluate the cancer invasion rate by co-cultured of cancer cells with various CAF-GM-TGF-β1. Results The expression level of α-SMA for CAF increased with an increased in the TGF-β1 concentration. When co-cultured with various types of CAF-GM-TGF-β1, the cancer invasion rate was well correlated with the α-SMA level. It is conceivable that the TGF-β1 concentration could modify the level of CAF activation, leading to the invasion rate of cancer cells. In addition, at the high concentrations of TGF-β1, the effect of a matrix metalloproteinase (MMP) inhibitor on the cancer invasion rate was observed. The higher invasion rate would be achieved through the higher MMP production. Conclusions The present model is promising to realize the cancer invasion whose rate can be modified by changing the TGF-β1 concentration.
This invasion model would be a promising tool for anti-cancer drug screening. TGF-β1 was controlled release from gelatin hydrogel microspheres. CAF were activated by increased TGF-β1 concentration. There was a good correlation between invasion rate and TGF-β1 concentration. Higher invasion rate would be achieved through matrix metalloproteinase production.
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Key Words
- 2D, two-dimensional
- 3D, three-dimensional
- Anti-cancer drug screening
- CAF, cancer-associated fibroblasts
- Cancer invasion model
- DDW, double-distilled water
- Drug delivery system
- ELISA, enzyme-linked immunosolvent assay
- FCS, fetal calf serum
- GM, gelatin hydrogel microspheres
- Gelatin hydrogel microspheres
- MEM, minimum essential medium
- MMP, matrix metalloproteinase
- PBS, phosphate buffered-saline
- PLGA, poly (lactic-co-glycolic acid)
- PVA, poly (vinyl alcohol)
- TGF-β1, transforming growth factor-β1
- Three-dimensional cell culture
- α-SMA, alpha-smooth muscle actin
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Affiliation(s)
- Teruki Nii
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.,Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, 278-8510, Japan
| | - Kimiko Makino
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641, Yamazaki, Noda, 278-8510, Japan.,Center for Drug Delivery Research, Tokyo University of Science, 2641, Yamazaki, Noda, 278-8510, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawara-cho Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan
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Gad MM, Găman MA, Saad AM, Al-Husseini MJ, Shehata OA, Saleh MA, Nelson AD, Simons-Linares CR. Temporal trends of incidence and mortality in Asian-Americans with pancreatic adenocarcinoma: an epidemiological study. Ann Gastroenterol 2020; 33:210-218. [PMID: 32127743 PMCID: PMC7049244 DOI: 10.20524/aog.2020.0450] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 12/02/2019] [Indexed: 12/24/2022] Open
Abstract
Background Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States, with an estimated 45,750 deaths in 2019. Mortality outcomes seem to differ based on the ethnicity of the patients, with most studies focusing on the mortality and survival of Caucasians and African Americans. Little attention has been given, however, to Asian-American patients diagnosed with pancreatic adenocarcinoma (PAC). In this study, we aimed to investigate mortality rates in Asian-American patients with PAC. Methods The SEER 13 registries (Surveillance, Epidemiology, and End-Results) of the National Cancer Institute were used to study PAC cases during 1992-2015. The incidence and incidence-based mortality rates per 100,000 person-years, and the annual percentage changes were calculated using SEER*stat software and Joinpoint regression software. Results A total of 5814 PAC cases in Asian-American patients were identified. Most patients were older than 60 years (77.6%) and had metastatic disease (55.8%). The overall incidence of PAC among Asian-Americans was 5.740 per 100,000 person-years (95% confidence interval [CI] 5.592-5.891]. Incidence rates were highest among males and patients older than 60 years. PAC incidence rates among Asian-Americans increased by 1.503% (95%CI 1.051-1.956; P<0.001) per year over the study period. PAC incidence rates increased over the study period for all sex, age, and stage subgroups. PAC incidence-based mortality among Asian-Americans increased by 4.535% (95%CI 3.538-5.541; P<0.001) per year over the study period. Conclusion The incidence of PAC in Asian-Americans, as well as incidence-based mortality rates, are on the rise, irrespective of age, sex or stage subgroup.
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Affiliation(s)
- Mohamed M Gad
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA (Mohamed M. Gad, Anas M. Saad, Mohannad Abou Saleh, Alfred D. Nelson, Carlos Roberto Simons-Linares).,Department of Global Public Health, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA (Mohamed M. Gad)
| | - Mihnea-Alexandru Găman
- Department of Hematology and Oncology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania and Center of Hematology and d) Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania (Mihnea-Alexandru Găman)
| | - Anas M Saad
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA (Mohamed M. Gad, Anas M. Saad, Mohannad Abou Saleh, Alfred D. Nelson, Carlos Roberto Simons-Linares).,Faculty of Medicine, Ain Shams University, Cairo, Egypt (Anas M. Saad, Muneer J. Al-Husseini, Omar A. Shehata)
| | - Muneer J Al-Husseini
- Faculty of Medicine, Ain Shams University, Cairo, Egypt (Anas M. Saad, Muneer J. Al-Husseini, Omar A. Shehata).,Department of Medicine, Ascension St John Hospital, Detroit, MI, USA (Muneer J. Al-Husseini)
| | - Omar A Shehata
- Faculty of Medicine, Ain Shams University, Cairo, Egypt (Anas M. Saad, Muneer J. Al-Husseini, Omar A. Shehata)
| | - Mohannad Abou Saleh
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA (Mohamed M. Gad, Anas M. Saad, Mohannad Abou Saleh, Alfred D. Nelson, Carlos Roberto Simons-Linares)
| | - Alfred D Nelson
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA (Mohamed M. Gad, Anas M. Saad, Mohannad Abou Saleh, Alfred D. Nelson, Carlos Roberto Simons-Linares)
| | - Carlos Roberto Simons-Linares
- Department of Internal Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA (Mohamed M. Gad, Anas M. Saad, Mohannad Abou Saleh, Alfred D. Nelson, Carlos Roberto Simons-Linares)
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Ma Y, Chen H, Ma H, Yao Z, Hu J, Ma J, Zhang X, Chen G, Liu Y. Prognostic role of secreted protein acidic and rich in cysteine in patients with solid tumors. Saudi Med J 2020; 40:755-765. [PMID: 31423511 PMCID: PMC6718847 DOI: 10.15537/smj.2019.8.24379] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES To analyze the heterogeneous functions of secreted protein acidic and rich in cysteine (SPARC) from different origins and in different tumor microenvironments with the purpose of determining its clinical significance. Methods: The PubMed, CINAHL, Cochrane, Web of Science and Embase databases were utilized. Studies that focused on the effects of SPARC expression on solid tumor progression and clinical implications were used. The different outcomes including overall survival and disease-free survival were analyzed to evaluate their relations with tumor- and stroma-derived SPARC expression. Results: A total of 26 studies including 5,939 patients were enrolled in the present meta-analysis. Tumor-derived SPARC overexpression was significantly related with poor overall survival (hazard ratio: 1.478; 95% CI: 1.143-1.910; p=0.003), and a similar tendency was also observed in disease-free survival (hazard ratio: 1.476; 95% CI: 0.993-2.195; p=0.054). However, the hazard ratios for overall survival and disease-free survival did not present a statistical trend in stromal SPARC overexpression. Tumor type subgroup analysis revealed marked heterogeneity among outcomes. In pancreatic cancer, SPARC overexpression in the stroma was significantly associated with poorer overall survival and disease-free survival. In colorectal cancer, SPARC overexpression in the stroma was associated with better disease-free survival. Conclusion: For the majority of solid tumors, SPARC in cancer cells may be an unfavorable indicator for long-term survival for patients. As for stromal expression, SPARC indicates a poorer prognosis in pancreatic cancer, but a better disease-free survival in colorectal cancer. Secreted protein acidic and rich in cysteine might be a potential biomarker for solid tumor prognosis.
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Affiliation(s)
- Yongchen Ma
- Department of General Surgery, Peking University First Hospital, Beijing, People's Republic of China. E-mail.
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Hasselluhn MC, Klein L, Patzak MS, Buchholz SM, Ströbel P, Ellenrieder V, Maisonneuve P, Neesse A. Stromal Features of the Primary Tumor Are Not Prognostic in Genetically Engineered Mice of Pancreatic Cancer. Cells 2019; 9:cells9010058. [PMID: 31878349 PMCID: PMC7017324 DOI: 10.3390/cells9010058] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 12/16/2019] [Accepted: 12/17/2019] [Indexed: 12/12/2022] Open
Abstract
The KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse model is frequently employed for preclinical therapeutic testing, in particular in regard to antistromal therapies. Here, we investigate the prognostic implications of histopathological features that may guide preclinical trial design. Pancreatic tumor tissue from n = 46 KPC mice was quantitatively analyzed using immunohistochemistry and co-immunofluorescence for proliferation (Ki67), mitotic rate (phospho-Histone 3, PHH3), apoptosis (cleaved caspase-3, CC3), collagen content, secreted protein acidic and rich in cysteine (SPARC), hyaluronic acid (HA), and α-smooth muscle actin (α-SMA). Furthermore, mean vessel density (MVD), mean lumen area (MLA), grading, activated stroma index (ASI), and fibroblast-proliferation rate (α-SMA/Ki67) were assessed. Univariate analysis using the Kaplan–Meier estimator and Cox regression model for continuous variables did not show association between survival and any of the analyzed parameters. Spearman correlation demonstrated that desmoplasia was inversely correlated with differentiated tumor grade (ρ = −0.84). Ki67 and PHH3 synergized as proliferation markers (ρ = 0.54), while SPARC expression was positively correlated with HA content (ρ = 0.37). MVD and MLA were correlated with each other (ρ = 0.31), while MLA positively correlated with CC3 (ρ = 0.45). Additionally, increased MVD was correlated with increased fibroblast proliferation rate (α-SMA + Ki67; ρ = 0.36). Our pilot study provides evidence that individual histopathological parameters of the primary tumor of KPC mice are not associated with survival, and may hint at the importance of systemic tumor-related effects such as cachexia.
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Affiliation(s)
- Marie C. Hasselluhn
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany; (M.C.H.); (L.K.); (V.E.)
| | - Lukas Klein
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany; (M.C.H.); (L.K.); (V.E.)
| | - Melanie S. Patzak
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany; (M.C.H.); (L.K.); (V.E.)
| | - Sören M. Buchholz
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany; (M.C.H.); (L.K.); (V.E.)
| | - Philipp Ströbel
- Institute of Pathology, University Medical Center, 37075 Göttingen, Germany;
| | - Volker Ellenrieder
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany; (M.C.H.); (L.K.); (V.E.)
| | - Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO Istituto Europeo di Oncologia IRCCS, P.I. 08691440153 Milan, Italy;
| | - Albrecht Neesse
- Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center, 37075 Göttingen, Germany; (M.C.H.); (L.K.); (V.E.)
- Correspondence: ; Tel.: +49-551-39-63201
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Shao S, Zhou NM, Dai DQ. Aberrant methylation of secreted protein acidic and rich in cysteine gene and its significance in gastric cancer. World J Gastroenterol 2019; 25:6713-6727. [PMID: 31857774 PMCID: PMC6920660 DOI: 10.3748/wjg.v25.i46.6713] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/15/2019] [Accepted: 10/21/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Aberrant methylation in DNA regulatory regions could downregulate tumor suppressor genes without changing the sequences. However, our knowledge of secreted protein acidic and rich in cysteine (SPARC) and its aberrant methylation in gastric cancer (GC) is still inadequate. In the present research, we performed fundamental research to clarify the precise function of methylation on SPARC and its significance in GC.
AIM To investigate promoter methylation and the effects of the SPARC gene in GC cells and tissues and to evaluate its clinical significance.
METHODS Plasmids that overexpressed the SPARC gene were transfected into human GC BGC-823 cells; non-transfected cells were used as a control group (NC group). Quantitative real-time polymerase chain reaction and western blotting (WB) were then used to detect the expression of SPARC. Methylation-specific polymerase chain reaction was executed to analyze the gene promoter methylation status. Cell viability was measured by the cell counting kit-8 assay. The migration and invasion ability of cells were detected by scratch assays and transwell chamber assays, respectively. Cell cycle events and apoptosis were observed with a flow cytometer.
RESULTS The expression of SPARC mRNA in GC tissues and cells was significantly lower and showed differing degrees of hypermethylation, respectively, than that in normal adjacent tissues and control cells. Treatment with 5-Aza-2’-deoxycytidine (5-Aza-Cdr) was able to restore the expression of SPARC and reverse promoter hypermethylation. Overexpression of the SPARC gene significantly inhibited proliferation, migration, and invasion of GC cells, while also causing cell cycle arrest and apoptosis; the NC group exhibited the opposite effects.
CONCLUSION This study demonstrated that SPARC could function as a tumor suppressor and might be silenced by promoter hypermethylation. Furthermore, in GC cells, SPARC inhibited migration, invasion, and proliferation, caused cell cycle arrest at the G0/G1 phase, and promoted apoptosis.
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Affiliation(s)
- Shuai Shao
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Nuo-Ming Zhou
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
| | - Dong-Qiu Dai
- Department of Gastrointestinal Surgery, the Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning Province, China
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Nii T, Makino K, Tabata Y. A Cancer Invasion Model Combined with Cancer-Associated Fibroblasts Aggregates Incorporating Gelatin Hydrogel Microspheres Containing a p53 Inhibitor. Tissue Eng Part C Methods 2019; 25:711-720. [DOI: 10.1089/ten.tec.2019.0189] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Teruki Nii
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
| | - Kimiko Makino
- Department of Pharmacy, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Japan
- Center for Drug Delivery Research, Tokyo University of Science, Noda, Japan
| | - Yasuhiko Tabata
- Laboratory of Biomaterials, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan
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Wang Z, Li Y, Zhan S, Zhang L, Zhang S, Tang Q, Li M, Tan Z, Liu S, Xing X. SMAD4 Y353C promotes the progression of PDAC. BMC Cancer 2019; 19:1037. [PMID: 31684910 PMCID: PMC6829834 DOI: 10.1186/s12885-019-6251-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 10/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background SMAD4 is frequently inactivated and associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Abnormal SMAD4 expression also plays an important role in the malignant progression of PDAC. Methods We investigated SMAD4 status in PDAC by immunohistochemical methods to explore the relationships between SMAD4 expression and clinicopathological features and then detected SMAD4 mutations by Sanger sequencing in 95 patients with PDAC to identify new mutation sites in PDAC. We further evaluated the effects of a missense mutation, Y353C, in the SMAD4 MH2 domain, on cell proliferation and migration in vitro. Results Immunohistochemistry showed that the expression of SMAD4 in PDAC carcinoma tissue was significantly lower than that in normal pancreatic tissue, and negative SMAD4 expression was closely related to tumour diameter, staging, lymph node metastasis and differentiation. Sanger sequencing analysis showed that the rate of SMAD4 mutation was 11.8% in 85 PDAC cases, and the novel SMAD4 Y353C missense mutation identified in this study promoted cell migration and invasion without affecting cell proliferation in vitro. Furthermore, SMAD4 Y353C resulted in reduced expression of E-cadherin and increased expression of Vimentin compared with wild-type SMAD4 overexpression. Conclusion This study supports the key role of SMAD4 as a tumour suppressor gene in PDAC and shows that SMAD4 Y353C is associated with poor progression of PDAC.
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Affiliation(s)
- Zusen Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yongxing Li
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shixiong Zhan
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Zhang
- Prenatal Diagnosis Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shun Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qian Tang
- Prenatal Diagnosis Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Miaomiao Li
- Prenatal Diagnosis Center, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zhen Tan
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shiguo Liu
- Prenatal Diagnosis Center, Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Xiaoming Xing
- Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, China.
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Sahai V, Catalano PJ, Zalupski MM, Lubner SJ, Menge MR, Nimeiri HS, Munshi HG, Benson AB, O'Dwyer PJ. Nab-Paclitaxel and Gemcitabine as First-line Treatment of Advanced or Metastatic Cholangiocarcinoma: A Phase 2 Clinical Trial. JAMA Oncol 2019; 4:1707-1712. [PMID: 30178032 DOI: 10.1001/jamaoncol.2018.3277] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Importance Gemcitabine with platinum has limited efficacy for treatment of advanced cholangiocarcinoma, necessitating an evaluation of alternative drug combinations. Recent evidence suggests that paclitaxel may potentiate gemcitabine activity. Objective To evaluate whether gemcitabine plus nanoparticle albumin-bound (nab)-paclitaxel is safe and effective for treatment of advanced cholangiocarcinoma. Design, Setting, and Participants This single-arm, 2-stage, phase 2 clinical trial was conducted at 23 community and academic centers across the United States and Europe. Patients aged 18 years or older enrolled between September 2014 and March 2016 had confirmed advanced or metastatic cholangiocarcinoma without prior systemic therapy, and had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 and a Child-Pugh score less than 8. Previous surgery, radiation, or liver-directed therapies were permitted. Interventions Patients received intravenous nab-paclitaxel, 125 mg/m2, followed by gemcitabine, 1000 mg/m2, on days 1, 8, and 15 of each 28-day treatment cycle until disease progression or unacceptable toxic effects. Main Outcomes and Measures The primary outcome was improvement in 6-month progression-free survival (PFS) rate (null and alternative hypotheses of 55% and 70%, respectively) in the evaluable population. Secondary outcomes included median overall survival (OS), PFS, time to progression, best overall response rate, disease control rate, safety and toxicity, and association of change in carbohydrate antigen 19-9 with survival. Results Seventy-four patients with a median age of 62 (range, 36-87) years, including 44 women (60%), were enrolled. Patients received a median of 6 (range, 1-18) treatment cycles, and the median follow-up was 10.2 (range, 0.6-27.3) months. The observed 6-month PFS rate of 61% (95% CI, 48%-73%) did not favor the alternative hypothesis. Median PFS was 7.7 (95% CI, 5.4-13.1) months, median OS was 12.4 (95% CI, 9.2-15.9) months, and median time to progression was 7.7 (95% CI, 6.1-13.1) months. The confirmed best overall response rate and disease control rate were 30% and 66%, respectively. Hazard ratios for an association between a change in serum carbohydrate antigen 19-9 and median PFS as well as median OS were 2.02 (95% CI, 0.86-4.75) (P = .10) and 1.54 (95% CI, 0.64-3.71) (P = .34), respectively. The most common treatment-related hematologic and nonhematologic adverse events at grade 3 or higher were neutropenia (43%) and fatigue (14%), respectively. Conclusions and Relevance Although the trial did not meet its primary efficacy end point, the results indicate that a nab-paclitaxel plus gemcitabine regimen was well tolerated and may be an alternative option to current therapeutic approaches for advanced cholangiocarcinoma. Trial Registration ClinicalTrials.gov identifier: NCT02181634.
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Affiliation(s)
- Vaibhav Sahai
- Department of Internal Medicine, University of Michigan, Ann Arbor
| | | | - Mark M Zalupski
- Department of Internal Medicine, University of Michigan, Ann Arbor
| | | | - Mark R Menge
- Frauenshuh Cancer Center, Park Nicollet Health Services, Minneapolis, Minnesota
| | | | | | - Al Bowen Benson
- Robert H. Lurie Cancer Center of Northwestern University, Chicago, Illinois
| | - Peter J O'Dwyer
- Abramson Cancer Center, University of Pennsylvania, Philadelphia
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50
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Lafaro KJ, Melstrom LG. The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:44-57. [PMID: 30558722 DOI: 10.1016/j.ajpath.2018.09.009] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 08/28/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has become evident that the TME, including both the stroma and extracellular component, plays an important role in tumor progression and chemoresistance of PDAC. This review will discuss the multiple components of the TME, their specific impact on tumorigenesis, and the multiple therapeutic targets.
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Affiliation(s)
- Kelly J Lafaro
- Department of Surgery, City of Hope National Medical Center, Duarte, California
| | - Laleh G Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, California.
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