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Gama JM, Oliveira RC. CD44 and Its Role in Solid Cancers - A Review: From Tumor Progression to Prognosis and Targeted Therapy. FRONT BIOSCI-LANDMRK 2025; 30:24821. [PMID: 40152366 DOI: 10.31083/fbl24821] [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: 05/13/2024] [Revised: 07/22/2024] [Accepted: 07/30/2024] [Indexed: 03/29/2025]
Abstract
Cluster of differentiation 44 (CD44) is a transmembrane protein expressed in normal cells but overexpressed in several types of cancer. CD44 plays a major role in tumor progression, both locally and systemically, by direct interaction with the extracellular matrix, inducing tissue remodeling, activation of different cellular pathways, such as Akt or mechanistic target of rapamycin (mTOR), and stimulation of angiogenesis. As a prognostic marker, CD44 has been identified as a major player in cancer stem cells (CSCs). CSCs with a CD44 phenotype are associated with chemoresistance, alone or in combination with other CSC markers, such as CD24 or aldehyde dehydrogenase 1 (ALDH1), and may be used for patient stratification. In the therapy setting, CD44 has been explored as a viable target, directly or indirectly. It has revealed promising potential, paving the way for its future use in the clinical setting. Immunohistochemistry effectively detects CD44 overexpression, enabling patients to be accurately selected for surgery and targeted anti-CD44 therapies. In this review, we highlight the properties of CD44, its expression in normal and tumoral tissues through immunohistochemistry and potential treatment options. We also discuss the clinical significance of this marker and its added value in therapeutic decision-making.
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Affiliation(s)
- João Martins Gama
- Serviço de Anatomia Patológica, Centro Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal
- Institute of Biomedical Sciences Abel Salazar, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal
| | - Rui Caetano Oliveira
- Centro de Investigação em Meio Ambiente, Genética e Oncobiologia-CIMAGO, Faculdade de Medicina, Universidade de Coimbra, 3004-535 Coimbra, Portugal
- Centro de Anatomia Patológica Germano de Sousa, 3000-377 Coimbra, Portugal
- Faculdade de Medicina, Universidade de Coimbra, 3004-535 Coimbra, Portugal
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2
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Stukan I, Żuk A, Pukacka K, Mierzejewska J, Pawłowski J, Kowalski B, Dąbkowska M. Wolf in Sheep's Clothing: Taming Cancer's Resistance with Human Serum Albumin? Int J Nanomedicine 2025; 20:3493-3525. [PMID: 40125439 PMCID: PMC11930253 DOI: 10.2147/ijn.s500997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/26/2025] [Indexed: 03/25/2025] Open
Abstract
Human serum albumin (HSA) has emerged as a promising carrier for nanodrug delivery, offering unique structural properties that can be engineered to overcome key challenges in cancer treatment, especially resistance to chemotherapy. This review focuses on the cellular uptake of albumin-based nanoparticles and the modifications that enhance their ability to bypass resistance mechanisms, particularly multidrug resistance type 1 (MDR1), by improving targeting to cancer cells. In our unique approach, we integrate the chemical properties of albumin, its interactions with cancer cells, and surface modifications of albumin-based delivery systems that enable to bypass resistance mechanisms, particularly those related to MDR1, and precisely target receptors on cancer cells to improve treatment efficacy. We discuss that while well-established albumin receptors such as gp60 and gp18/30 are crucial for cellular uptake and transcytosis, their biology remains underexplored, limiting their translational potential. Additionally, we explore the potential of emerging targets, such as cluster of differentiation 44 (CD44), cluster of differentiation (CD36) and transferrin receptor TfR1, as well as the advantages of using dimeric forms of albumin (dHSA) to further enhance delivery to resistant cancer cells. Drawing from clinical examples, including the success of albumin-bound paclitaxel (Abraxane) and new formulations like Pazenir and Fyarro (for Sirolimus), we identify gaps in current knowledge and propose strategies to optimize albumin-based systems. In conclusion, albumin-based nanoparticles, when tailored with appropriate modifications, have the potential to bypass multidrug resistance and improve the targeting of cancer cells. By enhancing albumin's ability to efficiently deliver therapeutic agents, these carriers represent a promising approach to addressing one of oncology's most persistent challenges, with substantial potential to improve cancer treatment outcomes.
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Affiliation(s)
- Iga Stukan
- Department of General Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Anna Żuk
- Independent Laboratory of Community Pharmacy, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Kamila Pukacka
- Department of Pharmaceutical Technology, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Julia Mierzejewska
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Jakub Pawłowski
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Bogusław Kowalski
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - Maria Dąbkowska
- Independent Laboratory of Pharmacokinetic and Clinical Pharmacy, Pomeranian Medical University in Szczecin, Szczecin, Poland
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Sethi A, Mishra S, Upadhyay V, Dubey P, Siddiqui S, Singh AK, Chowdhury S, Srivastava S, Srivastava P, Sahoo P, Bhatt MLB, Mishra A, Trivedi AK. USP10 deubiquitinates and stabilizes CD44 leading to enhanced breast cancer cell proliferation, stemness and metastasis. Biochem J 2024; 481:1877-1900. [PMID: 39564770 DOI: 10.1042/bcj20240611] [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: 10/07/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 11/21/2024]
Abstract
Despite extensive research, strategies to effectively combat breast cancer stemness and achieve a definitive cure remains elusive. CD44, a well-defined cancer stem cell (CSC) marker is reported to promote breast cancer tumorigenesis, metastasis, and chemoresistance. However, mechanisms leading to its enhanced expression and function is poorly understood. Here, we demonstrate that USP10 positively regulates CD44 protein levels and its downstream actions. While USP10 depletion prominently down-regulates CD44 protein levels and functions, its overexpression significantly enhances CD44 protein levels, leading to enhanced cluster tumor cell formation, stemness, and metastasis in breast cancer cells both in vitro and ex vivo in primary human breast tumor cells. USP10 interacts with CD44 and stabilizes it through deubiquitination both in breast cancer cell lines and human breast cancer-derived primary tumor cells. Stabilized CD44 shows enhanced interaction with cytoskeleton proteins Ezrin/Radixin/Moesin and potently activates PDGFRβ/STAT3 signaling which are involved in promoting CSC traits. Using USP10 stably expressing 4T1 cells, we further demonstrate that the USP10-CD44 axis potently promotes tumorigenicity in vivo in mice, while simultaneous depletion of CD44 in these cells renders them ineffective. In line with these findings, we further showed that inhibition of USP10 either through RNAi or the pharmacological inhibitor Spautin-1 significantly mitigated CD44 levels and its downstream function ex vivo in primary breast tumor cells. Finally, we demonstrated that primary breast tumor cells are more susceptible to chemotherapy when co-treated with USP10 inhibitor indicating that the USP10-CD44 axis could be an attractive therapeutic target in combination with chemotherapy in CD44 expressing breast cancers.
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Affiliation(s)
- Arppita Sethi
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Shivkant Mishra
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
| | - Vishal Upadhyay
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Parul Dubey
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
| | - Shumaila Siddiqui
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Anil Kumar Singh
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sangita Chowdhury
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
| | - Swati Srivastava
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
| | - Pragya Srivastava
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
| | - Prasannajit Sahoo
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | | | - Anand Mishra
- King George's Medical University, Lucknow, India
| | - Arun Kumar Trivedi
- Division of Cancer Biology, CSIR-Central Drug Research Institute, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow 226031, UP, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
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Wang K, Li C, Chen H, Gu P, Lu J, Zhao H, Zhuo X. Increased Expression of PDGFA Is Associated With Poor Prognosis and Immune Infiltration in Head and Neck Squamous Cell Carcinoma. J Oral Pathol Med 2024; 53:584-594. [PMID: 39295197 DOI: 10.1111/jop.13579] [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: 09/28/2023] [Revised: 06/11/2024] [Accepted: 08/02/2024] [Indexed: 09/21/2024]
Abstract
BACKGROUND Platelet-derived growth factor A (PDGFA) has been shown to be upregulated in several tumors, contributing to their malignant phenotypes. However, its expression and function in head and neck squamous cell carcinoma (HNSC) are not clearly understood. Thus, we aimed to evaluate this issue using bioinformatic analyses and primary experimental validation. METHODS The expression of PDGFA was analyzed using popular bio-databases and further validated by RT-PCR and immunohistochemical staining. Survival analyses were then performed. The association between PDGFA expression levels and immune cell infiltration in the immune microenvironment was assessed. RESULTS PDGFA has been found to be significantly upregulated in a variety of cancers, including HNSC, and increased PDGFA expression may be an independent prognostic factor associated with immune cell infiltration in HNSC. CONCLUSION Overexpression of PDGFA in HNSC is significantly associated with poor prognosis and immune cell infiltration in the tumor microenvironment (TME). PDGFA has potential as a molecular indicator for diagnosis, prognosis, and immune processes in HNSC.
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Affiliation(s)
- Kaiqin Wang
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Changya Li
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Huarong Chen
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Ping Gu
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Jiafeng Lu
- Department of Otolaryngology-Head and Neck Surgery, Anshun People's Hospital, Anshun, Guizhou Province, China
| | - Houyu Zhao
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
| | - Xianlu Zhuo
- Department of Otolaryngology-Head and Neck Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China
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Jin X, Lou X, Qi H, Zheng C, Li B, Siwu X, Liu R, Lv Q, Zhao A, Ruan J, Jiang M. NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma. Oncogenesis 2024; 13:35. [PMID: 39333079 PMCID: PMC11437035 DOI: 10.1038/s41389-024-00536-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 09/13/2024] [Accepted: 09/18/2024] [Indexed: 09/29/2024] Open
Abstract
The activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.
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Affiliation(s)
- Xiaoye Jin
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Xiayuan Lou
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Haoxiang Qi
- School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou, China
| | - Chao Zheng
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Bo Li
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Xuerong Siwu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Ren Liu
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China
| | - Qiaoli Lv
- Institute of Cancer Research, Jiangxi Cancer Hospital, Nanchang, China
| | - An Zhao
- Institute of Cancer Research, Zhejiang Cancer Hospital, Hangzhou, China
| | - Jian Ruan
- Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University and Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Hangzhou, China
| | - Ming Jiang
- Center for Genetic Medicine, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- Institute of Genetics, Zhejiang University International School of Medicine, Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China.
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Ishikawa K, Suzuki H, Ohishi T, Li G, Tanaka T, Kawada M, Ohkoshi A, Kaneko MK, Katori Y, Kato Y. Anti-CD44 Variant 10 Monoclonal Antibody Exerts Antitumor Activity in Mouse Xenograft Models of Oral Squamous Cell Carcinomas. Int J Mol Sci 2024; 25:9190. [PMID: 39273139 PMCID: PMC11395228 DOI: 10.3390/ijms25179190] [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: 08/02/2024] [Revised: 08/20/2024] [Accepted: 08/22/2024] [Indexed: 09/15/2024] Open
Abstract
CD44 regulates cell adhesion, proliferation, survival, and stemness and has been considered a tumor therapy target. CD44 possesses the shortest CD44 standard (CD44s) and a variety of CD44 variant (CD44v) isoforms. Since the expression of CD44v is restricted in epithelial cells and carcinomas compared to CD44s, CD44v has been considered a promising target for monoclonal antibody (mAb) therapy. We previously developed an anti-CD44v10 mAb, C44Mab-18 (IgM, kappa), to recognize the variant exon 10-encoded region. In the present study, a mouse IgG2a version of C44Mab-18 (C44Mab-18-mG2a) was generated to evaluate the antitumor activities against CD44-positive cells compared with the previously established anti-pan CD44 mAb, C44Mab-46-mG2a. C44Mab-18-mG2a exhibited higher reactivity compared with C44Mab-46-mG2a to CD44v3-10-overexpressed CHO-K1 (CHO/CD44v3-10) and oral squamous cell carcinoma cell lines (HSC-2 and SAS) in flow cytometry. C44Mab-18-mG2a exerted a superior antibody-dependent cellular cytotoxicity (ADCC) against CHO/CD44v3-10. In contrast, C44Mab-46-mG2a showed a superior complement-dependent cytotoxicity (CDC) against CHO/CD44v3-10. A similar tendency was observed in ADCC and CDC against HSC-2 and SAS. Furthermore, administering C44Mab-18-mG2a or C44Mab-46-mG2a significantly suppressed CHO/CD44v3-10, HSC-2, and SAS xenograft tumor growth compared with the control mouse IgG2a. These results indicate that C44Mab-18-mG2a could be a promising therapeutic regimen for CD44v10-positive tumors.
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Affiliation(s)
- Kenichiro Ishikawa
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
- Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (A.O.); (Y.K.)
| | - Hiroyuki Suzuki
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, 18-24 Miyamoto, Numazu-shi 410-0301, Shizuoka, Japan;
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan;
| | - Guanjie Li
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Laboratory of Oncology, Microbial Chemistry Research Foundation, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan;
| | - Akira Ohkoshi
- Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (A.O.); (Y.K.)
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
| | - Yukio Katori
- Department of Otolaryngology, Head and Neck Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (A.O.); (Y.K.)
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan; (K.I.); (G.L.); (T.T.); (M.K.K.)
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7
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Fu M, Gao Q, Xiao M, Li RF, Sun XY, Li SL, Peng X, Ge XY. Extracellular Vesicles Containing circMYBL1 Induce CD44 in Adenoid Cystic Carcinoma Cells and Pulmonary Endothelial Cells to Promote Lung Metastasis. Cancer Res 2024; 84:2484-2500. [PMID: 38657100 DOI: 10.1158/0008-5472.can-23-3508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 02/13/2024] [Accepted: 04/19/2024] [Indexed: 04/26/2024]
Abstract
Adenoid cystic carcinoma (ACC) is a rare malignant epithelial neoplasm that arises in secretory glands and commonly metastasizes to the lungs. MYBL1 is frequently overexpressed in ACC and has been suggested to be a driver of the disease. In this study, we identified a circular RNA (circRNA) derived from MYBL1 pre-mRNA that was accompanied by the overexpression of MYBL1 in ACC. Overexpression of circMYBL1 was correlated with increased lung metastasis and poor overall survival in patients with ACC. Ectopic circMYBL1 overexpression promoted malignant phenotypes and lung metastasis of ACC cells. Mechanistically, circMYBL1 formed a circRNA-protein complex with CCAAT enhancer-binding protein β (CEBPB), which inhibited ubiquitin-mediated degradation and promoted nuclear translocation of CEBPB. In the nucleus, circMYBL1 increased the binding of CEBPB to the CD44 promoter region and enhanced its transcription. In addition, circMYBL1 was enriched in small extracellular vesicles (sEV) isolated from the plasma of patients with ACC. Treatment with sEVs containing circMYBL1 in sEVs enhanced prometastatic phenotypes of ACC cells, elevated the expression of CD44 in human pulmonary microvascular endothelial cells (HPMEC), and enhanced the adhesion between HPMECs and ACC cells. Moreover, circMYBL1 encapsulated in sEVs increased the arrest of circulating ACC cells in the lung and enhanced lung metastatic burden. These data suggest that circMYBL1 is a tumor-promoting circRNA that could serve as a potential biomarker and therapeutic target for ACC. Significance: circMYBL1 stabilizes CEBPB and upregulates CD44 to promote adhesion between cancer cells and endothelial cells and enables lung metastasis of adenoid cystic carcinoma, suggesting that inhibition of this axis could improve patient outcomes.
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MESH Headings
- Humans
- Lung Neoplasms/secondary
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Lung Neoplasms/genetics
- Hyaluronan Receptors/metabolism
- Hyaluronan Receptors/genetics
- Carcinoma, Adenoid Cystic/pathology
- Carcinoma, Adenoid Cystic/metabolism
- Carcinoma, Adenoid Cystic/genetics
- Carcinoma, Adenoid Cystic/secondary
- Mice
- Animals
- Extracellular Vesicles/metabolism
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- RNA, Circular/genetics
- RNA, Circular/metabolism
- CCAAT-Enhancer-Binding Protein-beta/metabolism
- CCAAT-Enhancer-Binding Protein-beta/genetics
- Cell Line, Tumor
- Female
- Mice, Nude
- Male
- Gene Expression Regulation, Neoplastic
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins/genetics
- Mice, Inbred BALB C
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Affiliation(s)
- Min Fu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, PR China
- National Center for Stomatology, Beijing, PR China
- National Clinical Research Center for Oral Diseases, Beijing, PR China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
| | - Qian Gao
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
| | - Mian Xiao
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
| | - Rui-Feng Li
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
| | - Xin-Yi Sun
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
| | - Sheng-Lin Li
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, PR China
| | - Xin Peng
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
| | - Xi-Yuan Ge
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, PR China
- Central Laboratory, Peking University School and Hospital of Stomatology, Beijing, PR China
- National Center for Stomatology, Beijing, PR China
- National Clinical Research Center for Oral Diseases, Beijing, PR China
- National Engineering Research Center of Oral Biomaterials and Digital Medical Devices, Beijing, PR China
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8
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Sussman JH, Kim N, Kemp SB, Traum D, Katsuda T, Kahn BM, Xu J, Kim IK, Eskandarian C, Delman D, Beatty GL, Kaestner KH, Simpson AL, Stanger BZ. Multiplexed Imaging Mass Cytometry Analysis Characterizes the Vascular Niche in Pancreatic Cancer. Cancer Res 2024; 84:2364-2376. [PMID: 38695869 PMCID: PMC11250934 DOI: 10.1158/0008-5472.can-23-2352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 02/22/2024] [Accepted: 04/26/2024] [Indexed: 06/01/2024]
Abstract
Oncogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) are driven by complex interactions between the neoplastic component and the tumor microenvironment, which includes immune, stromal, and parenchymal cells. In particular, most PDACs are characterized by a hypovascular and hypoxic environment that alters tumor cell behavior and limits the efficacy of chemotherapy and immunotherapy. Characterization of the spatial features of the vascular niche could advance our understanding of inter- and intratumoral heterogeneity in PDAC. In this study, we investigated the vascular microenvironment of PDAC by applying imaging mass cytometry using a 26-antibody panel on 35 regions of interest across 9 patients, capturing more than 140,000 single cells. The approach distinguished major cell types, including multiple populations of lymphoid and myeloid cells, endocrine cells, ductal cells, stromal cells, and endothelial cells. Evaluation of cellular neighborhoods identified 10 distinct spatial domains, including multiple immune and tumor-enriched environments as well as the vascular niche. Focused analysis revealed differential interactions between immune populations and the vasculature and identified distinct spatial domains wherein tumor cell proliferation occurs. Importantly, the vascular niche was closely associated with a population of CD44-expressing macrophages enriched for a proangiogenic gene signature. Taken together, this study provides insights into the spatial heterogeneity of PDAC and suggests a role for CD44-expressing macrophages in shaping the vascular niche. Significance: Imaging mass cytometry revealed that pancreatic ductal cancers are composed of 10 distinct cellular neighborhoods, including a vascular niche enriched for macrophages expressing high levels of CD44 and a proangiogenic gene signature.
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Affiliation(s)
- Jonathan H. Sussman
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
- Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Nathalia Kim
- Department of Biomedical and Molecular Sciences/School of Computing, Queen’s University, Kingston, Ontario, Canada
| | - Samantha B Kemp
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
| | - Daniel Traum
- Department of Genetics, University of Pennsylvania, Philadelphia, PA
| | - Takeshi Katsuda
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
| | - Benjamin M. Kahn
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
| | - Jason Xu
- Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Il-Kyu Kim
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
| | - Cody Eskandarian
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
| | - Devora Delman
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Gregory L. Beatty
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Klaus H. Kaestner
- Department of Genetics, University of Pennsylvania, Philadelphia, PA
| | - Amber L. Simpson
- Department of Biomedical and Molecular Sciences/School of Computing, Queen’s University, Kingston, Ontario, Canada
| | - Ben Z. Stanger
- Department of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA
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Xu Y, Bai Z, Lan T, Fu C, Cheng P. CD44 and its implication in neoplastic diseases. MedComm (Beijing) 2024; 5:e554. [PMID: 38783892 PMCID: PMC11112461 DOI: 10.1002/mco2.554] [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: 08/01/2023] [Revised: 03/20/2024] [Accepted: 04/01/2024] [Indexed: 05/25/2024] Open
Abstract
CD44, a nonkinase single span transmembrane glycoprotein, is a major cell surface receptor for many other extracellular matrix components as well as classic markers of cancer stem cells and immune cells. Through alternative splicing of CD44 gene, CD44 is divided into two isoforms, the standard isoform of CD44 (CD44s) and the variant isoform of CD44 (CD44v). Different isoforms of CD44 participate in regulating various signaling pathways, modulating cancer proliferation, invasion, metastasis, and drug resistance, with its aberrant expression and dysregulation contributing to tumor initiation and progression. However, CD44s and CD44v play overlapping or contradictory roles in tumor initiation and progression, which is not fully understood. Herein, we discuss the present understanding of the functional and structural roles of CD44 in the pathogenic mechanism of multiple cancers. The regulation functions of CD44 in cancers-associated signaling pathways is summarized. Moreover, we provide an overview of the anticancer therapeutic strategies that targeting CD44 and preclinical and clinical trials evaluating the pharmacokinetics, efficacy, and drug-related toxicity about CD44-targeted therapies. This review provides up-to-date information about the roles of CD44 in neoplastic diseases, which may open new perspectives in the field of cancer treatment through targeting CD44.
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Affiliation(s)
- Yiming Xu
- Department of BiotherapyLaboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ziyi Bai
- Department of BiotherapyLaboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Tianxia Lan
- Department of BiotherapyLaboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Chenying Fu
- Laboratory of Aging and Geriatric Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ping Cheng
- Department of Biotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan UniversityChengduChina
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10
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Sun S, Su M, Xiao H, Yin X, Liu Y, Yang W, Chen Y. Self-powered biosensing platform for Highly sensitive detection of soluble CD44 protein. Talanta 2024; 272:125824. [PMID: 38422906 DOI: 10.1016/j.talanta.2024.125824] [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: 11/24/2023] [Revised: 02/05/2024] [Accepted: 02/21/2024] [Indexed: 03/02/2024]
Abstract
In this study, a self-powered biosensor based on an enzymatic biofuel cell was proposed for the first time for the ultrasensitive detection of soluble CD44 protein. The as-prepared biosensor was composed of the co-exist aptamer and glucose oxidase bioanode and bilirubin oxidase modified biocathode. Initially, the electron transfer from bioanode to biocathode was hindered due to the presence of the aptamer with high insulation, generating a low open-circuit voltage (EOCV). Once the target CD44 protein was present, it was recognized and captured by the aptamer at the bioanode, thus the interaction between the target CD44 protein and the immobilized aptamer caused the structural change at the surface of the electrode, which facilitated the transfer of electrons. The EOCV showed a good linear relationship with the logarithm of the CD44 protein concentrations in the range of 0.5-1000 ng mL-1 and the detection limit was 0.052 ng mL-1 (S/N = 3). The sensing platform showed excellent anti-interference performance and outstanding stability that maintained over 97% of original EOCV after 15 days. In addition, the relative standard deviation (1.40-1.96%) and recovery (100.23-101.31%) obtained from detecting CD44 protein in real-life blood samples without special pre-treatment indicated that the constructed biosensor had great potential for early cancer diagnosis.
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Affiliation(s)
- Shanshan Sun
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China
| | - Meng Su
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China
| | - Han Xiao
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China
| | - Xiaoshuang Yin
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China
| | - Ying Liu
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China
| | - Wenzhong Yang
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China
| | - Yun Chen
- School of Chemistry and Molecular Engineering, Nanjing Tech University, No. 30 Puzhu Road (S), Nanjing 211816, China.
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11
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Li H, Dai L, Huang Q, Song J, Liu L, Li Y, Ma H, Wei Q. FeNi-MIL-88B-based electrochemiluminescence immunosensor for ultra-sensitive detection of CD44 protein via dual-quenching strategy. Anal Chim Acta 2024; 1303:342520. [PMID: 38609255 DOI: 10.1016/j.aca.2024.342520] [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: 11/19/2023] [Revised: 02/26/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024]
Abstract
BACKGROUND Cluster of Differentiation 44 (CD44) is considered an important biomarker for various cancers, and achieving highly sensitive detection of CD44 is crucial, which plays a significant role in tumor invasion and metastasis, providing essential information for clinical tumor diagnosis. Commonly used methods for analysis include fluorescence spectroscopy (FL), photoelectrochemical analysis (PEC), electrochemical analysis (EC), and commercial ELISA kits. Although these methods offer high sensitivity, they can be relatively complex to perform experimentally. Electrochemiluminescence (ECL) has gained widespread research attention due to its high sensitivity, ease of operation, effective spatiotemporal control, and close to zero background signal. RESULTS In this work, a sandwich-type ECL immunosensor for detecting CD44 was constructed using luminol as a luminophore. In this sensing platform, bimetallic MOFs (Pd@FeNi-MIL-88B) loaded with palladium nanoparticles (Pd NPs) were used as a novel enzyme mimic, exhibiting excellent catalytic performance towards the electroreduction of H2O2. The hybrids provided a strong support platform for luminol and antibodies, significantly enhancing the initial ECL signal of luminol. Subsequently, core-shell Au@MnO2 nanocomposites were synthesised by gold nanoparticles (Au NPs) encapsulated in manganese dioxide (MnO2) thin layers, as labels. In the luminol/H2O2 system, Au@MnO2 exhibited strong light absorption in the broad UV-vis spectrum, similar to the black body effect, and the scavenging effect of Mn2+ on O2•-, which achieved the dual-quenching of ECL signal. Under the optimal experimental conditions, the immunosensor demonstrated a detection range of 0.1 pg mL-1 - 100 ng mL-1, with a detection limit of 0.069 pg mL-1. SIGNIFICANCE Based on Pd@FeNi-MIL-88B nanoenzymes and Au@MnO2 nanocomposites, a dual-quenching sandwich-type ECL immunosensor for the detection of CD44 was constructed. The proposed immunosensor exhibited excellent reproducibility, stability, selectivity, and sensitivity, and provided a valuable analytical strategy and technical platform for the accurate detection of disease biomarkers, and opened up potential application prospects for early clinical treatment.
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Affiliation(s)
- Haiyang Li
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China
| | - Li Dai
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China
| | - Qiuyu Huang
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China
| | - Jianxi Song
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China
| | - Lipeng Liu
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China
| | - Yan Li
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China.
| | - Hongmin Ma
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China.
| | - Qin Wei
- Collaborative Innovation Center for Green Chemical Manufacturing and Accurate Detection, Key Laboratory of Interfacial Reaction & Sensing Analysis in Universities of Shandong, School of Chemistry and Chemical Engineering, University of Jinan, Jinan, 250022, Shandong, China; Department of Chemistry, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
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12
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Wang Y, Zhang Q, Deng X, Wang Y, Tian X, Zhang S, Shen Y, Zhou X, Zeng X, Chen Q, Jiang L, Li J. PA28γ induces dendritic cell maturation and activates T-cell immune responses in oral lichen planus. MedComm (Beijing) 2024; 5:e561. [PMID: 38721005 PMCID: PMC11077662 DOI: 10.1002/mco2.561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 03/24/2024] [Accepted: 04/06/2024] [Indexed: 01/06/2025] Open
Abstract
Oral lichen planus (OLP) is a common chronic inflammatory disease of the oral mucosa, the mechanism of its inflammatory progression has not yet been fully elucidated. PA28γ plays a significant role in a variety of immune-related diseases. However, the exact role of PA28γ in the pathogenesis of OLP remains unclear. Here, we demonstrated that PA28γ is overexpressed in epithelial cells and inflammatory cells of OLP tissues but has no significant relationship with OLP subtypes. Functionally, keratinocytes with high PA28γ expression could induce dendritic cell (DC) maturation and promote the T-cell differentiation into Th1 cells in response to the immune response. In addition, we found that a high level of PA28γ expression is associated with high numbers of infiltrating mature DCs and activated T-cells in OLP tissues. Mechanistically, keratinocytes with high PA28γ expression could promote the secretion of C-C motif chemokine (CCL)5, blocking CCL5 or/and its receptor CD44 could inhibit the induction of T-cell differentiation by keratinocytes with high PA28γ expression. In conclusion, we reveal that keratinocytes with high expression of PA28γ in OLP can induce DC maturation and promote T-cell differentiation through the CCL5-CD44 pathway, providing previously unidentified mechanistic insights into the mechanism of inflammatory progression in OLP.
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Affiliation(s)
- Yimei Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Qiyue Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Xiaoting Deng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
- Yunnan Maternal and Child Health HospitalKunmingPR China
| | - Ying Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Xin Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Shiyu Zhang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Yingqiang Shen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Xikun Zhou
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center for BiotherapyChengduPR China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Lu Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of StomatologySichuan UniversityChengduSichuanPR China
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13
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Zhao Z, Sun X, Tu P, Ma Y, Guo Y, Zhang Y, Liu M, Wang L, Chen X, Si L, Li G, Pan Y. Mechanisms of vascular invasion after cartilage injury and potential engineering cartilage treatment strategies. FASEB J 2024; 38:e23559. [PMID: 38502020 DOI: 10.1096/fj.202302391rr] [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: 11/21/2023] [Revised: 02/26/2024] [Accepted: 03/01/2024] [Indexed: 03/20/2024]
Abstract
Articular cartilage injury is one of the most common diseases in orthopedic clinics. Following an articular cartilage injury, an inability to resist vascular invasion can result in cartilage calcification by newly formed blood vessels. This process ultimately leads to the loss of joint function, significantly impacting the patient's quality of life. As a result, developing anti-angiogenic methods to repair damaged cartilage has become a popular research topic. Despite this, tissue engineering, as an anti-angiogenic strategy in cartilage injury repair, has not yet been adequately investigated. This exhaustive literature review mainly focused on the process and mechanism of vascular invasion in articular cartilage injury repair and summarized the major regulatory factors and signaling pathways affecting angiogenesis in the process of cartilage injury. We aimed to discuss several potential methods for engineering cartilage repair with anti-angiogenic strategies. Three anti-angiogenic tissue engineering methods were identified, including administering angiogenesis inhibitors, applying scaffolds to manage angiogenesis, and utilizing in vitro bioreactors to enhance the therapeutic properties of cultured chondrocytes. The advantages and disadvantages of each strategy were also analyzed. By exploring these anti-angiogenic tissue engineering methods, we hope to provide guidance for researchers in related fields for future research and development in cartilage repair.
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Affiliation(s)
- Zitong Zhao
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Xiaoxian Sun
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Pengcheng Tu
- Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Yong Ma
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, P.R. China
| | - Yang Guo
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, P.R. China
| | - Yafeng Zhang
- Jiangsu CM Clinical Innovation Center of Degenerative Bone & Joint Disease, Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi, P.R. China
| | - Mengmin Liu
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Lining Wang
- School of Integrated Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, P.R. China
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Xinyu Chen
- Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Lin Si
- Affiliated Hospital, Nanjing University of Chinese Medicine, Nanjing, P.R. China
| | - Guangguang Li
- Orthopedics and traumatology department, Yixing Traditional Chinese Medicine Hospital, Yixing, P.R. China
| | - Yalan Pan
- Laboratory of New Techniques of Restoration and Reconstruction of Orthopedics and Traumatology, Nanjing University of Chinese Medicine, Nanjing, P.R. China
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14
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Bose A, Datta S, Mandal R, Ray U, Dhar R. Increased heterogeneity in expression of genes associated with cancer progression and drug resistance. Transl Oncol 2024; 41:101879. [PMID: 38262110 PMCID: PMC10832509 DOI: 10.1016/j.tranon.2024.101879] [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: 10/27/2023] [Revised: 12/16/2023] [Accepted: 12/29/2023] [Indexed: 01/25/2024] Open
Abstract
Fluctuations in the number of regulatory molecules and differences in timings of molecular events can generate variation in gene expression among genetically identical cells in the same environmental condition. This variation, termed as expression noise, can create differences in metabolic state and cellular functions, leading to phenotypic heterogeneity. Expression noise and phenotypic heterogeneity have been recognized as important contributors to intra-tumor heterogeneity, and have been associated with cancer growth, progression, and therapy resistance. However, how expression noise changes with cancer progression in actual cancer patients has remained poorly explored. Such an analysis, through identification of genes with increasing expression noise, can provide valuable insights into generation of intra-tumor heterogeneity, and could have important implications for understanding immune-suppression, drug tolerance and therapy resistance. In this work, we performed a genome-wide identification of changes in gene expression noise with cancer progression using single-cell RNA-seq data of lung adenocarcinoma patients at different stages of cancer. We identified 37 genes in epithelial cells that showed an increasing noise trend with cancer progression, many of which were also associated with cancer growth, EMT and therapy resistance. We found that expression of several of these genes was positively associated with expression of mitochondrial genes, suggesting an important role of mitochondria in generation of heterogeneity. In addition, we uncovered substantial differences in sample-specific noise profiles which could have implications for personalized prognosis and treatment.
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Affiliation(s)
- Anwesha Bose
- Department of Bioscience and Biotechnology, Indian Institute of Technology (IIT) Kharagpur, India
| | - Subhasis Datta
- Department of Bioscience and Biotechnology, Indian Institute of Technology (IIT) Kharagpur, India
| | - Rakesh Mandal
- Department of Bioscience and Biotechnology, Indian Institute of Technology (IIT) Kharagpur, India
| | - Upasana Ray
- Department of Bioscience and Biotechnology, Indian Institute of Technology (IIT) Kharagpur, India
| | - Riddhiman Dhar
- Department of Bioscience and Biotechnology, Indian Institute of Technology (IIT) Kharagpur, India.
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15
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Sadat Kalaki N, Ahmadzadeh M, Najafi M, Mobasheri M, Ajdarkosh H, Karbalaie Niya MH. Systems biology approach to identify biomarkers and therapeutic targets for colorectal cancer. Biochem Biophys Rep 2024; 37:101633. [PMID: 38283191 PMCID: PMC10821538 DOI: 10.1016/j.bbrep.2023.101633] [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: 08/18/2023] [Revised: 12/24/2023] [Accepted: 12/27/2023] [Indexed: 01/30/2024] Open
Abstract
Background Colorectal cancer (CRC), is the third most prevalent cancer across the globe, and is often detected at advanced stage. Late diagnosis of CRC, leave the chemotherapy and radiotherapy as the main options for the possible treatment of the disease which are associated with severe side effects. In the present study, we seek to explore CRC gene expression data using a systems biology framework to identify potential biomarkers and therapeutic targets for earlier diagnosis and treatment of the disease. Methods The expression data was retrieved from the gene expression omnibus (GEO). Differential gene expression analysis was conducted using R/Bioconductor package. The PPI network was reconstructed by the STRING. Cystoscope and Gephi software packages were used for visualization and centrality analysis of the PPI network. Clustering analysis of the PPI network was carried out using k-mean algorithm. Gene-set enrichment based on Gene Ontology (GO) and KEGG pathway databases was carried out to identify the biological functions and pathways associated with gene groups. Prognostic value of the selected identified hub genes was examined by survival analysis, using GEPIA. Results A total of 848 differentially expressed genes were identified. Centrality analysis of the PPI network resulted in identification of 99 hubs genes. Clustering analysis dissected the PPI network into seven interactive modules. While several DEGs and the central genes in each module have already reported to contribute to CRC progression, survival analysis confirmed high expression of central genes, CCNA2, CD44, and ACAN contribute to poor prognosis of CRC patients. In addition, high expression of TUBA8, AMPD3, TRPC1, ARHGAP6, JPH3, DYRK1A and ACTA1 was found to associate with decreased survival rate. Conclusion Our results identified several genes with high centrality in PPI network that contribute to progression of CRC. The fact that several of the identified genes have already been reported to be relevant to diagnosis and treatment of CRC, other highlighted genes with limited literature information may hold potential to be explored in the context of CRC biomarker and drug target discovery.
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Affiliation(s)
- Niloufar Sadat Kalaki
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
- International Institute of New Sciences (IINS), Tehran, Iran
| | - Mozhgan Ahmadzadeh
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Mohammad Najafi
- Department of Biochemistry, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Meysam Mobasheri
- Department of Biotechnology, Faculty of Advanced Sciences and Technology, Tehran Islamic Azad University of Medical Sciences, Tehran, Iran
- International Institute of New Sciences (IINS), Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hadi Karbalaie Niya
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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Liu YS, Pan JQ, Pan XB, Kong FS, Zhang JQ, Wei ZY, Xu ZH, Rao JH, Wang JH, Chen JH. Comparative Analysis of Molecular Landscape in Mouse Models and Patients Reveals Conserved Inflammation Pathways in Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci 2024; 65:13. [PMID: 38175639 PMCID: PMC10774692 DOI: 10.1167/iovs.65.1.13] [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: 06/18/2023] [Accepted: 11/19/2023] [Indexed: 01/05/2024] Open
Abstract
Purpose The purpose of this study was to identify key genes and their regulatory networks that are conserved in mouse models of age-related macular degeneration (AMD) and human AMD. Methods Retinal RNA-Seq was performed in laser-induced choroidal neovascularization (CNV) mice at day 3 and day 7 after photocoagulation. Mass spectrometry-based proteomic analysis was performed with retinas collected at day 3. Retinal RNA-Seq data was further compared among mouse models of laser-induced CNV and NaIO3-induced retinal degeneration (RD) and a large AMD cohort. Results Retinal RNA-Seq revealed upregulated genes and pathways related to innate immunity and inflammation in mice with CNV, with more profound changes at the early stage (day 3). Proteomic analysis further validated these differentially expressed genes and their networks in retinal inflammation during CNV. Notably, the most evident overlap in the retina of mice with laser-induced CNV and NaIO3-induced RD was the upregulation of inflammation-related genes, pointing to a common vital role of retinal inflammation in the early stage for both mouse AMD models. Further comparative transcriptomic analysis of the mouse AMD models and human AMD identified 48 conserved genes mainly involved in inflammation response. Among them, B2M, C3, and SERPING1 were upregulated in all stages of human AMD and the mouse AMD models compared to controls. Conclusions Our study demonstrates conserved molecular changes related to retinal inflammation in mouse AMD models and human AMD and provides new insight into the translational application of these mouse models in studying AMD mechanisms and treatments.
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Affiliation(s)
- Yan-Shan Liu
- Department of Pediatric Laboratory, Affiliated Children's Hospital of Jiangnan University (Wuxi Children's Hospital), Wuxi, Jiangsu, China
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Jia-Qi Pan
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Xu-Bin Pan
- Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Fan-Sheng Kong
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Jing-Qian Zhang
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Zhi-Yuan Wei
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Zhou-Heng Xu
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Jun-Hua Rao
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
| | - Ji-Hong Wang
- Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China
| | - Jian-Huan Chen
- Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Wuxi, Jiangsu, China
- Joint Primate Research Center for Chronic Diseases, Institute of Zoology, Guangdong Academy of Science, Guangzhou, Guangdong, China
- Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, China
- Jiangnan University & Xinshijie Hospital Ophthalmic Research Center, Jiangnan University, Wuxi, Jiangsu, China
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17
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Everest‐Dass A, Nersisyan S, Maar H, Novosad V, Schröder‐Schwarz J, Freytag V, Stuke JL, Beine MC, Schiecke A, Haider M, Kriegs M, Elakad O, Bohnenberger H, Conradi L, Raygorodskaya M, Krause L, von Itzstein M, Tonevitsky A, Schumacher U, Maltseva D, Wicklein D, Lange T. Spontaneous metastasis xenograft models link CD44 isoform 4 to angiogenesis, hypoxia, EMT and mitochondria-related pathways in colorectal cancer. Mol Oncol 2024; 18:62-90. [PMID: 37849446 PMCID: PMC10766209 DOI: 10.1002/1878-0261.13535] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 08/10/2023] [Accepted: 10/12/2023] [Indexed: 10/19/2023] Open
Abstract
Hematogenous metastasis limits the survival of colorectal cancer (CRC) patients. Here, we illuminated the roles of CD44 isoforms in this process. Isoforms 3 and 4 were predominantly expressed in CRC patients. CD44 isoform 4 indicated poor outcome and correlated with epithelial-mesenchymal transition (EMT) and decreased oxidative phosphorylation (OxPhos) in patients; opposite associations were found for isoform 3. Pan-CD44 knockdown (kd) independently impaired primary tumor formation and abrogated distant metastasis in CRC xenografts. The xenograft tumors mainly expressed the clinically relevant CD44 isoforms 3 and 4. Both isoforms were enhanced in the paranecrotic, hypoxic tumor regions but were generally absent in lung metastases. Upon CD44 kd, tumor angiogenesis was increased in the paranecrotic areas, accompanied by reduced hypoxia-inducible factor-1α and CEACAM5 but increased E-cadherin expression. Mitochondrial genes and proteins were induced upon pan-CD44 kd, as were OxPhos genes. Hypoxia increased VEGF release from tumor spheres, particularly upon CD44 kd. Genes affected upon CD44 kd in xenografts specifically overlapped concordantly with genes correlating with CD44 isoform 4 (but not isoform 3) in patients, validating the clinical relevance of the used model and highlighting the metastasis-promoting role of CD44 isoform 4.
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Affiliation(s)
- Arun Everest‐Dass
- Institute for GlycomicsGriffith University, Gold Coast CampusAustralia
| | - Stepan Nersisyan
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Institute of Molecular BiologyThe National Academy of Sciences of the Republic of ArmeniaYerevanArmenia
- Armenian Bioinformatics Institute (ABI)YerevanArmenia
- Present address:
Computational Medicine CenterThomas Jefferson UniversityPhiladelphiaPAUSA
| | - Hanna Maar
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Victor Novosad
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Shemyakin‐Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia
| | | | - Vera Freytag
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Johanna L. Stuke
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Mia C. Beine
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Alina Schiecke
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Marie‐Therese Haider
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Malte Kriegs
- Department of Radiobiology and Radiation OncologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Omar Elakad
- Institute of PathologyUniversity Medical Center GöttingenGermany
| | | | - Lena‐Christin Conradi
- Clinic for General, Visceral and Pediatric SurgeryUniversity Medical Center GöttingenGermany
| | | | - Linda Krause
- Institute of Medical Biometry and EpidemiologyUniversity Medical Center Hamburg‐EppendorfGermany
| | - Mark von Itzstein
- Institute for GlycomicsGriffith University, Gold Coast CampusAustralia
| | - Alexander Tonevitsky
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
- Shemyakin‐Ovchinnikov Institute of Bioorganic ChemistryRussian Academy of SciencesMoscowRussia
- Art Photonics GmbHBerlinGermany
| | - Udo Schumacher
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Medical School BerlinGermany
| | - Diana Maltseva
- Faculty of Biology and BiotechnologyHSE UniversityMoscowRussia
| | - Daniel Wicklein
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Department of Anatomy and Cell BiologyUniversity of MarburgGermany
| | - Tobias Lange
- Institute of Anatomy and Experimental MorphologyUniversity Medical Center Hamburg‐EppendorfGermany
- Institute of Anatomy IJena University HospitalGermany
- Comprehensive Cancer Center Central Germany (CCCG)Jena and LeipzigGermany
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18
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Vukovic Đerfi K, Vasiljevic T, Matijevic Glavan T. Recent Advances in the Targeting of Head and Neck Cancer Stem Cells. APPLIED SCIENCES 2023; 13:13293. [DOI: 10.3390/app132413293] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a very heterogeneous cancer with a poor overall response to therapy. One of the reasons for this therapy resistance could be cancer stem cells (CSCs), a small population of cancer cells with self-renewal and tumor-initiating abilities. Tumor cell heterogeneity represents hurdles for therapeutic elimination of CSCs. Different signaling pathway activations, such as Wnt, Notch, and Sonic-Hedgehog (SHh) pathways, lead to the expression of several cancer stem factors that enable the maintenance of CSC features. Identification and isolation of CSCs are based either on markers (CD133, CD44, and aldehyde dehydrogenase (ALDH)), side populations, or their sphere-forming ability. A key challenge in cancer therapy targeting CSCs is overcoming chemotherapy and radiotherapy resistance. However, in novel therapies, various approaches are being employed to address this hurdle such as targeting cell surface markers, other stem cell markers, and different signaling or metabolic pathways, but also, introducing checkpoint inhibitors and natural compounds into the therapy can be beneficial.
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Affiliation(s)
- Kristina Vukovic Đerfi
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tea Vasiljevic
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
| | - Tanja Matijevic Glavan
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Boskovic Institute, Bijenicka 54, 10000 Zagreb, Croatia
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Chandra J, Molugulu N, Annadurai S, Wahab S, Karwasra R, Singh S, Shukla R, Kesharwani P. Hyaluronic acid-functionalized lipoplexes and polyplexes as emerging nanocarriers for receptor-targeted cancer therapy. ENVIRONMENTAL RESEARCH 2023; 233:116506. [PMID: 37369307 DOI: 10.1016/j.envres.2023.116506] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/17/2023] [Accepted: 06/23/2023] [Indexed: 06/29/2023]
Abstract
Cancer is an intricate disease that develops as a response to a combination of hereditary and environmental risk factors, which then result in a variety of changes to the genome. The cluster of differentiation (CD44) is a type of transmembrane glycoprotein that serves as a potential biomarker for cancer stem cells (CSC) and viable targets for therapeutic intervention in the context of cancer therapy. Hyaluronic acid (HA) is a linear polysaccharide that exhibits a notable affinity for the CD44 receptor. This characteristic renders it a promising candidate for therapeutic interventions aimed at selectively targeting CD44-positive cancer cells. Treating cancer via non-viral vector-based gene delivery has changed the notion of curing illness through the incorporation of therapeutic genes into the organism. The objective of this review is to provide an overview of various hyaluronic acid-modified lipoplexes and polyplexes as potential drug delivery methods for specific forms of cancer by effectively targeting CD44.
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Affiliation(s)
- Jyoti Chandra
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India
| | - Nagashekhara Molugulu
- School of Pharmacy, Monash University, Bandar Sunway, Jalan Lagoon Selatan, 47500, Malaysia
| | - Sivakumar Annadurai
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Shadma Wahab
- Department of Pharmacognosy, College of Pharmacy, King Khalid University, Abha 62529, Saudi Arabia
| | - Ritu Karwasra
- Central Council for Research in Unani Medicine (CCRUM), Ministry of AYUSH, Government of India, Janakpuri, New Delhi 110058, India
| | - Surender Singh
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Rahul Shukla
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER-Raebareli), Bijnor-Sisendi Road, Sarojini Nagar, Near CRPF Base Camp, Lucknow, UP, 226002, India
| | - Prashant Kesharwani
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, 110062, India; Department of Pharmacology, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
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20
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Shanmugam M, Kuthala N, Kong X, Chiang CS, Hwang KC. Combined Gadolinium and Boron Neutron Capture Therapies for Eradication of Head-and-Neck Tumor Using Gd 10B 6 Nanoparticles under MRI/CT Image Guidance. JACS AU 2023; 3:2192-2205. [PMID: 37654578 PMCID: PMC10466345 DOI: 10.1021/jacsau.3c00250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/16/2023] [Accepted: 07/26/2023] [Indexed: 09/02/2023]
Abstract
Eradication of head-and-neck (H&N) tumors is very difficult and challenging because of the characteristic feature of frequent recurrence and the difficulty in killing cancer stem cells. Neutron capture therapy (NCT) is emerging as a noninvasive potential modality for treatments of various types of tumors. Herein, we report that 98.5% 10B-enriched anti-EGFR-Gd10B6 nanoparticles can not only deliver large doses of 158 μg 10B/g tumor tissues as well as 56.8 μg 157Gd/g tumor tissues with a very high tumor-to-blood (T/B) 10B ratio of 4.18, but also exert very effective CT/MRI image-guided combined GdBNCT effects on killing cancer stem cells and eradication of recurrent head-and-neck (H&N) tumors. This leads to a long average half-lifespan of 81 days for H&N tumor-bearing mice, which is a record-making result, and surpasses the best result reported in the literature using combined radiotherapy and T cell-mediated immunotherapy (70 d).
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Affiliation(s)
- Munusamy Shanmugam
- Department
of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan ROC
| | - Naresh Kuthala
- Department
of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan ROC
| | - Xiangyi Kong
- Department
of Breast Surgical Oncology, National Cancer Center/National Clinical
Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chi-Shiun Chiang
- Department
of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan R.O.C.
| | - Kuo Chu Hwang
- Department
of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan ROC
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21
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Fan X, Huang Y, Zhong Y, Yan Y, Li J, Fan Y, Xie F, Luo Q, Zhang Z. A new marker constructed from immune-related lncRNA pairs can be used to predict clinical treatment effects and prognosis: in-depth exploration of underlying mechanisms in HNSCC. World J Surg Oncol 2023; 21:250. [PMID: 37592311 PMCID: PMC10433616 DOI: 10.1186/s12957-023-03066-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: 03/18/2022] [Accepted: 06/04/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Long non-coding RNA (lncRNA) plays a vital role in tumor proliferation, migration, and treatment. Since it is challenging to standardize the gene expression levels detected by different platforms, the signatures composed of many immune-related single lncRNAs are still inaccurate. Utilizing a gene pair formed of two immune-related lncRNAs and strategically assigning values can effectively meet the demand for a higher-accuracy dual biomarker combination. METHODS Co-expression and differential expression analyses were performed on immune genes and lncRNAs data from The Cancer Genome Atlas and the ImmPort database to obtain differentially expressed immune-related lncRNAs for pairwise pairing. The prognostic-related differentially expressed immune-related lncRNAs (PR-DE-irlncRNAs) pairs were then identified by univariate Cox regression and used for lasso regression to construct a prognostic model. Various methods were used to validate the predictive prognostic performance of the model. Additionally, we explored the potential guiding value of the model in immunotherapy and chemotherapy and constructed a nomogram suitable for efficient prognosis prediction. Mechanistic exploration of anti-tumor immunity and mutational perspectives are also included. We also analyzed the correlation between the model and immune checkpoint inhibitors (ICIs)-related, N6-methyadenosine (m6A)-related, and multidrug resistance genes. RESULTS We used a total of 20 pairs of PR-DE-irlncRNAs to create a prognosis model. Quantitative real-time polymerase chain reaction experiments further verified the abnormal expression of 11 lncRNAs in HNSCC cells. Various methods have confirmed the excellent performance of the model in predicting patient prognosis. We reasoned that lncRNAs/TP53 mutation might play a positive/negative anti-tumor role through the immune system by multi-perspective analyses. Finally, it was found that the prognostic model was closely related to immunotherapy and chemotherapy as well as the expression of ICIs/m6A/multidrug resistance-related genes. CONCLUSION The prognostic model performs excellently in predicting the prognosis of patients and provides the potential value of practical guidance for treatment.
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Affiliation(s)
- Xin Fan
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yuhan Huang
- Yunnan University of Chinese Medicine, Kunming, Yunnan Province, China
| | - Yun Zhong
- The First Clinical Medical College of Nanchang University, Nanchang, Jiangxi Province, China
| | - Yujie Yan
- School of Stomatology, Nanchang University, Nanchang, Jiangxi Province, China
| | - Jiaqi Li
- School of Stomatology, Nanchang University, Nanchang, Jiangxi Province, China
| | - Yanting Fan
- The First Clinical Medical College of Nanchang University, Nanchang, Jiangxi Province, China
| | - Fei Xie
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Qing Luo
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Zhiyuan Zhang
- Department of Otolaryngology Head and Neck Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.
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22
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Kommineni N, Chaudhari R, Conde J, Tamburaci S, Cecen B, Chandra P, Prasad R. Engineered Liposomes in Interventional Theranostics of Solid Tumors. ACS Biomater Sci Eng 2023; 9:4527-4557. [PMID: 37450683 DOI: 10.1021/acsbiomaterials.3c00510] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Engineered liposomal nanoparticles have unique characteristics as cargo carriers in cancer care and therapeutics. Liposomal theranostics have shown significant progress in preclinical and clinical cancer models in the past few years. Liposomal hybrid systems have not only been approved by the FDA but have also reached the market level. Nanosized liposomes are clinically proven systems for delivering multiple therapeutic as well as imaging agents to the target sites in (i) cancer theranostics of solid tumors, (ii) image-guided therapeutics, and (iii) combination therapeutic applications. The choice of diagnostics and therapeutics can intervene in the theranostics property of the engineered system. However, integrating imaging and therapeutics probes within lipid self-assembly "liposome" may compromise their overall theranostics performance. On the other hand, liposomal systems suffer from their fragile nature, site-selective tumor targeting, specific biodistribution and premature leakage of loaded cargo molecules before reaching the target site. Various engineering approaches, viz., grafting, conjugation, encapsulations, etc., have been investigated to overcome the aforementioned issues. It has been studied that surface-engineered liposomes demonstrate better tumor selectivity and improved therapeutic activity and retention in cells/or solid tumors. It should be noted that several other parameters like reproducibility, stability, smooth circulation, toxicity of vital organs, patient compliance, etc. must be addressed before using liposomal theranostics agents in solid tumors or clinical models. Herein, we have reviewed the importance and challenges of liposomal medicines in targeted cancer theranostics with their preclinical and clinical progress and a translational overview.
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Affiliation(s)
- Nagavendra Kommineni
- Center for Biomedical Research, Population Council, New York, New York 10065, United States
| | - Ruchita Chaudhari
- School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - João Conde
- ToxOmics, NOVA Medical School, Faculdade de Ciências Médicas, NMS|FCM, Universidade NOVA de Lisboa; Lisboa 1169-056, Portugal
| | - Sedef Tamburaci
- Department of Chemical Engineering, Izmir Institute of Technology, Gulbahce Campus, Izmir 35430, Turkey
| | - Berivan Cecen
- Department of Biomedical Engineering, Rowan University, Glassboro, New Jersey 08028, United States
- Department of Mechanical Engineering, Rowan University, Glassboro, New Jersey 08028, United States
| | - Pranjal Chandra
- School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, India
| | - Rajendra Prasad
- School of Biochemical Engineering, Indian Institute of Technology (BHU), Varanasi 221005, India
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23
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Suzuki H, Goto N, Tanaka T, Ouchida T, Kaneko MK, Kato Y. Development of a Novel Anti-CD44 Variant 8 Monoclonal Antibody C 44Mab-94 against Gastric Carcinomas. Antibodies (Basel) 2023; 12:45. [PMID: 37489367 PMCID: PMC10366929 DOI: 10.3390/antib12030045] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/28/2023] [Accepted: 07/03/2023] [Indexed: 07/26/2023] Open
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related deaths worldwide. GC with peritoneal metastasis exhibits a poor prognosis due to the lack of effective therapy. A comprehensive analysis of malignant ascites identified the genomic alterations and significant amplifications of cancer driver genes, including CD44. CD44 and its splicing variants are overexpressed in tumors, and play crucial roles in the acquisition of invasiveness, stemness, and resistance to treatments. Therefore, the development of CD44-targeted monoclonal antibodies (mAbs) is important for GC diagnosis and therapy. In this study, we immunized mice with CD44v3-10-overexpressed PANC-1 cells and established several dozens of clones that produce anti-CD44v3-10 mAbs. One of the clones (C44Mab-94; IgG1, kappa) recognized the variant-8-encoded region and peptide, indicating that C44Mab-94 is a specific mAb for CD44v8. Furthermore, C44Mab-94 could recognize CHO/CD44v3-10 cells, oral squamous cell carcinoma cell line (HSC-3), or GC cell lines (MKN45 and NUGC-4) in flow cytometric analyses. C44Mab-94 could detect the exogenous CD44v3-10 and endogenous CD44v8 in western blotting and stained the formalin-fixed paraffin-embedded gastric cancer cells. These results indicate that C44Mab-94 is useful for detecting CD44v8 in a variety of experimental methods and is expected to become usefully applied to GC diagnosis and therapy.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tsunenori Ouchida
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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24
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Ishikawa K, Suzuki H, Kaneko MK, Kato Y. Establishment of a Novel Anti-CD44 Variant 10 Monoclonal Antibody C 44Mab-18 for Immunohistochemical Analysis against Oral Squamous Cell Carcinomas. Curr Issues Mol Biol 2023; 45:5248-5262. [PMID: 37504249 PMCID: PMC10378409 DOI: 10.3390/cimb45070333] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/14/2023] [Accepted: 06/19/2023] [Indexed: 07/29/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer, and has been revealed as the second-highest expression of CD44 in cancers. CD44 has been investigated as a cancer stem cell marker of HNSCC and plays a critical role in tumor malignant progression. Especially, splicing variant isoforms of CD44 (CD44v) are overexpressed in cancers and considered a promising target for cancer diagnosis and therapy. We developed monoclonal antibodies (mAbs) against CD44 by immunizing mice with CD44v3-10-overexpressed PANC-1 cells. Among the established clones, C44Mab-18 (IgM, kappa) reacted with CHO/CD44v3-10, but not with CHO/CD44s and parental CHO-K1 using flow cytometry. The epitope mapping using peptides that cover variant exon-encoded regions revealed that C44Mab-18 recognized the border sequence between variant 10 and the constant exon 16-encoded sequence. These results suggest that C44Mab-18 recognizes variant 10-containing CD44v, but not CD44s. Furthermore, C44Mab-18 could recognize the human oral squamous cell carcinoma (OSCC) cell line, HSC-3, in flow cytometry. The apparent dissociation constant (KD) of C44Mab-18 for CHO/CD44v3-10 and HSC-3 was 1.6 × 10-7 M and 1.7 × 10-7 M, respectively. Furthermore, C44Mab-18 detected CD44v3-10 but not CHO/CD44s in Western blotting, and endogenous CD44v10 in immunohistochemistry using OSCC tissues. These results indicate that C44Mab-18 is useful for detecting CD44v10 in flow cytometry and immunohistochemistry.
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Affiliation(s)
- Kenichiro Ishikawa
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Joshi P, Waghmare S. Molecular signaling in cancer stem cells of tongue squamous cell carcinoma: Therapeutic implications and challenges. World J Stem Cells 2023; 15:438-452. [PMID: 37342225 PMCID: PMC10277967 DOI: 10.4252/wjsc.v15.i5.438] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 02/21/2023] [Accepted: 04/07/2023] [Indexed: 05/26/2023] Open
Abstract
Head and neck squamous cell carcinoma is the seventh most common cancer worldwide with high mortality rates. Amongst oral cavity cancers, tongue carcinoma is a very common and aggressive oral cavity carcinoma. Despite the implementation of a multimodality treatment regime including surgical intervention, chemo-radiation as well as targeted therapy, tongue carcinoma shows a poor overall 5-year survival pattern, which is attributed to therapy resistance and recurrence of the disease. The presence of a rare population, i.e., cancer stem cells (CSCs) within the tumor, are involved in therapy resistance, recurrence, and distant metastasis that results in poor survival patterns. Therapeutic agents targeting CSCs have been in clinical trials, although they are unable to reach into therapy stage which is due to their failure in trials. A more detailed understanding of the CSCs is essential for identifying efficient targets. Molecular signaling pathways, which are differentially regulated in the CSCs, are one of the promising targets to manipulate the CSCs that would provide an improved outcome. In this review, we summarize the current understanding of molecular signaling associated with the maintenance and regulation of CSCs in tongue squamous cell carcinoma in order to emphasize the need of the hour to get a deeper understanding to unravel novel targets.
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Affiliation(s)
- Priyanka Joshi
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
| | - Sanjeev Waghmare
- Stem Cell Biology Group, Cancer Research Institute, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai 410210, India
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Almagro J, Messal HA. Volume imaging to interrogate cancer cell-tumor microenvironment interactions in space and time. Front Immunol 2023; 14:1176594. [PMID: 37261345 PMCID: PMC10228654 DOI: 10.3389/fimmu.2023.1176594] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 04/26/2023] [Indexed: 06/02/2023] Open
Abstract
Volume imaging visualizes the three-dimensional (3D) complexity of tumors to unravel the dynamic crosstalk between cancer cells and the heterogeneous landscape of the tumor microenvironment (TME). Tissue clearing and intravital microscopy (IVM) constitute rapidly progressing technologies to study the architectural context of such interactions. Tissue clearing enables high-resolution imaging of large samples, allowing for the characterization of entire tumors and even organs and organisms with tumors. With IVM, the dynamic engagement between cancer cells and the TME can be visualized in 3D over time, allowing for acquisition of 4D data. Together, tissue clearing and IVM have been critical in the examination of cancer-TME interactions and have drastically advanced our knowledge in fundamental cancer research and clinical oncology. This review provides an overview of the current technical repertoire of fluorescence volume imaging technologies to study cancer and the TME, and discusses how their recent applications have been utilized to advance our fundamental understanding of tumor architecture, stromal and immune infiltration, vascularization and innervation, and to explore avenues for immunotherapy and optimized chemotherapy delivery.
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Affiliation(s)
- Jorge Almagro
- Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, United States
| | - Hendrik A. Messal
- Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan, Amsterdam, Netherlands
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27
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Suzuki H, Kitamura K, Goto N, Ishikawa K, Ouchida T, Tanaka T, Kaneko MK, Kato Y. A Novel Anti-CD44 Variant 3 Monoclonal Antibody C 44Mab-6 Was Established for Multiple Applications. Int J Mol Sci 2023; 24:8411. [PMID: 37176118 PMCID: PMC10179237 DOI: 10.3390/ijms24098411] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 05/04/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023] Open
Abstract
Cluster of differentiation 44 (CD44) promotes tumor progression through the recruitment of growth factors and the acquisition of stemness, invasiveness, and drug resistance. CD44 has multiple isoforms including CD44 standard (CD44s) and CD44 variants (CD44v), which have common and unique functions in tumor development. Therefore, elucidating the function of each CD44 isoform in a tumor is essential for the establishment of CD44-targeting tumor therapy. We have established various anti-CD44s and anti-CD44v monoclonal antibodies (mAbs) through the immunization of CD44v3-10-overexpressed cells. In this study, we established C44Mab-6 (IgG1, kappa), which recognized the CD44 variant 3-encoded region (CD44v3), as determined via an enzyme-linked immunosorbent assay. C44Mab-6 reacted with CD44v3-10-overexpressed Chinese hamster ovary (CHO)-K1 cells (CHO/CD44v3-10) or some cancer cell lines (COLO205 and HSC-3) via flow cytometry. The apparent KD of C44Mab-6 for CHO/CD44v3-10, COLO205, and HSC-3 was 1.5 × 10-9 M, 6.3 × 10-9 M, and 1.9 × 10-9 M, respectively. C44Mab-6 could detect the CD44v3-10 in Western blotting and stained the formalin-fixed paraffin-embedded tumor sections in immunohistochemistry. These results indicate that C44Mab-6 is useful for detecting CD44v3 in various experiments and is expected for the application of tumor diagnosis and therapy.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Kaishi Kitamura
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
| | - Kenichiro Ishikawa
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
| | - Tsunenori Ouchida
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Mika K. Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (K.K.); (N.G.); (K.I.); (T.O.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Puzzo L, Bianco MR, Salvatorelli L, Tinnirello G, Occhiuzzi F, Latella D, Allegra E. CD44, PDL1, and ATG7 Expression in Laryngeal Squamous Cell Carcinomas with Tissue Microarray (TMA) Technique: Evaluation of the Potential Prognostic and Predictive Roles. Cancers (Basel) 2023; 15:cancers15092461. [PMID: 37173926 PMCID: PMC10177409 DOI: 10.3390/cancers15092461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/10/2023] [Accepted: 04/17/2023] [Indexed: 05/15/2023] Open
Abstract
We focus on the new prognostic and predictive factors CD44, PDL1, and ATG7 in our study of surgical samples of patients with laryngeal squamous cell carcinoma (LSCC) using tissue microarray (TMA). Thirty-nine previously untreated patients affected by laryngeal carcinoma who then underwent surgical treatment were considered in this retrospective study. All surgical specimens were sampled, embedded in paraffin blocks, and stained with hematoxylin and eosin. A representative sample of the tumor was chosen and transferred into a new block of paraffin, the recipient block, to perform immunohistochemical analysis with the primary antibodies anti-CD44, PD-L1, and ATG7. At follow-up, 5-year disease-free survival (DFS) for negative and positive tumors was determined as 85.71% and 36% for CD44, 60% and 33.33% for PDL1, and 58.06% and 37.50% for ATG7, respectively. Multivariate analysis revealed that CD44 expression is an independent predictive factor of low-grade tumors (p = 0.008), lymph node metastasis at the time of diagnosis, and AGT7 negativity. Thus, CD44 expression is a potential marker for more aggressive forms of laryngeal cancer.
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Affiliation(s)
- Lidia Puzzo
- Department "G.F. Ingrassia", Section of Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Maria Rita Bianco
- Department of Medical and Surgical Sciences, Otolaryngology, University of Catanzaro, 88100 Catanzaro, Italy
| | - Lucia Salvatorelli
- Department "G.F. Ingrassia", Section of Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Giordana Tinnirello
- Department "G.F. Ingrassia", Section of Anatomic Pathology, University of Catania, 95123 Catania, Italy
| | - Federico Occhiuzzi
- Department of Health Science, Otolaryngology, University of Catanzaro, 88100 Catanzaro, Italy
| | - Daniele Latella
- Department of Health Science, Otolaryngology, University of Catanzaro, 88100 Catanzaro, Italy
| | - Eugenia Allegra
- Department of Health Science, Otolaryngology, University of Catanzaro, 88100 Catanzaro, Italy
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Tawara M, Suzuki H, Goto N, Tanaka T, Kaneko MK, Kato Y. A Novel Anti-CD44 Variant 9 Monoclonal Antibody C 44Mab-1 Was Developed for Immunohistochemical Analyses against Colorectal Cancers. Curr Issues Mol Biol 2023; 45:3658-3673. [PMID: 37185762 PMCID: PMC10137259 DOI: 10.3390/cimb45040238] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Cluster of differentiation 44 (CD44) is a type I transmembrane glycoprotein and has been shown to be a cell surface marker of cancer stem-like cells in various cancers. In particular, the splicing variants of CD44 (CD44v) are overexpressed in cancers and play critical roles in cancer stemness, invasiveness, and resistance to chemotherapy and radiotherapy. Therefore, the understanding of the function of each CD44v is indispensable for CD44-targeting therapy. CD44v9 contains the variant 9-encoded region, and its expression predicts poor prognosis in patients with various cancers. CD44v9 plays critical roles in the malignant progression of tumors. Therefore, CD44v9 is a promising target for cancer diagnosis and therapy. Here, we developed sensitive and specific monoclonal antibodies (mAbs) against CD44 by immunizing mice with CD44v3-10-overexpressed Chinese hamster ovary-K1 (CHO/CD44v3-10) cells. We first determined their critical epitopes using enzyme-linked immunosorbent assay and characterized their applications as flow cytometry, western blotting, and immunohistochemistry. One of the established clones, C44Mab-1 (IgG1, kappa), reacted with a peptide of the variant 9-encoded region, indicating that C44Mab-1 recognizes CD44v9. C44Mab-1 could recognize CHO/CD44v3-10 cells or colorectal cancer cell lines (COLO201 and COLO205) in flow cytometric analysis. The apparent dissociation constant (KD) of C44Mab-1 for CHO/CD44v3-10, COLO201, and COLO205 was 2.5 × 10-8 M, 3.3 × 10-8 M, and 6.5 × 10-8 M, respectively. Furthermore, C44Mab-1 was able to detect the CD44v3-10 in western blotting and the endogenous CD44v9 in immunohistochemistry using colorectal cancer tissues. These results indicated that C44Mab-1 is useful for detecting CD44v9 not only in flow cytometry or western blotting but also in immunohistochemistry against colorectal cancers.
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Affiliation(s)
- Mayuki Tawara
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Hiroyuki Suzuki
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Nohara Goto
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Tomohiro Tanaka
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
| | - Mika K. Kaneko
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yukinari Kato
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan; (M.T.); (N.G.); (T.T.); (M.K.K.)
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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30
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Suzuki H, Ozawa K, Tanaka T, Kaneko MK, Kato Y. Development of a Novel Anti-CD44 Variant 7/8 Monoclonal Antibody, C44Mab-34, for Multiple Applications against Oral Carcinomas. Biomedicines 2023; 11:biomedicines11041099. [PMID: 37189717 DOI: 10.3390/biomedicines11041099] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Cluster of differentiation 44 (CD44) has been investigated as a cancer stem cell (CSC) marker as it plays critical roles in tumor malignant progression. The splicing variants are overexpressed in many carcinomas, especially squamous cell carcinomas, and play critical roles in the promotion of tumor metastasis, the acquisition of CSC properties, and resistance to treatments. Therefore, each CD44 variant (CD44v) function and distribution in carcinomas should be clarified for the establishment of novel tumor diagnosis and therapy. In this study, we immunized mouse with a CD44 variant (CD44v3–10) ectodomain and established various anti-CD44 monoclonal antibodies (mAbs). One of the established clones (C44Mab-34; IgG1, kappa) recognized a peptide that covers both variant 7- and variant 8-encoded regions, indicating that C44Mab-34 is a specific mAb for CD44v7/8. Moreover, C44Mab-34 reacted with CD44v3–10-overexpressed Chinese hamster ovary-K1 (CHO) cells or the oral squamous cell carcinoma (OSCC) cell line (HSC-3) by flow cytometry. The apparent KD of C44Mab-34 for CHO/CD44v3–10 and HSC-3 was 1.4 × 10−9 and 3.2 × 10−9 M, respectively. C44Mab-34 could detect CD44v3–10 in Western blotting and stained the formalin-fixed paraffin-embedded OSCC in immunohistochemistry. These results indicate that C44Mab-34 is useful for detecting CD44v7/8 in various applications and is expected to be useful in the application of OSCC diagnosis and therapy.
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Affiliation(s)
- Hiroyuki Suzuki
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Kazuki Ozawa
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Mika K. Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan
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Wei Y, Cheng X, Deng L, Dong H, Wei H, Xie C, Tuo Y, Li G, Yu D, Cao Y. Expression signature and molecular basis of CDH11 in OSCC detected by a combination of multiple methods. BMC Med Genomics 2023; 16:70. [PMID: 37013637 PMCID: PMC10069064 DOI: 10.1186/s12920-023-01499-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 03/25/2023] [Indexed: 04/05/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignancy in the oral cancer threatening human health and the survival rate of OSCC has not been effectively improved in recent decades, so more effective biomarkers for the targeted therapy of OSCC are needed. Moreover, the role of CDH11 in OSCC has not been intensively investigated. We here show that the CDH11 protein and mRNA expression levels in the OSCC tissues were all significantly higher than in the non-cancerous tissues using RT-qPCR and western blot. This study also revealed that patients with higher CDH11 levels showed a higher incidence of perineural invasion and lymph node metastasis. By using data available from the Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and ArrayExpress databases, overexpressed CDH11 in OSCC that associated with patients'history of alcohol, negative Human Papilloma Virus (HPV) status, perineural invasion, infiltration of multiple immune cells, and Single-cell functional states including quiescence and angiogenesis, possessed an excellent discriminatory capability in the OSCC patients. Moreover, the majority of the biological processes or pathways were significantly clustered by co-expressed genes, including extracellular matrix organization, the epithelial to mesenchymal transition, carbon metabolism, and the PI3K-Akt signaling pathway, and the upstream transcriptional regulation mechanism of CDH11 in OSCC was showed on a transcription factor/miRNA-mRNA network with the online tool NetworkAnalyst. Finally, frequent mutation of CDH11 was observed on a mouse OSCC model through whole-genome sequencing. CDH11 might serve as a valuable biomarker in OSCC, as it was identified to be overexpressed in OSCC and related to its clinical progression.
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Affiliation(s)
- Yuxing Wei
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Xujie Cheng
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Limei Deng
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Hao Dong
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Huiping Wei
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Cheng Xie
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Yangjuan Tuo
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China
| | - Guangyu Li
- Department of Stomatology, People's hospital of Yongning District, Nanning, 530200, China
| | - Dahai Yu
- Department of Stomatology, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, China
| | - Yong Cao
- Department of Oral and Maxillofacial Surgery, Guangxi Academy of Medical Sciences, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530021, China.
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Urriola-Muñoz P, Pattison LA, Smith ESJ. Dysregulation of ADAM10 shedding activity in naked mole-rat fibroblasts is due to deficient phosphatidylserine externalization. J Cell Physiol 2023; 238:761-775. [PMID: 36790936 DOI: 10.1002/jcp.30972] [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: 10/02/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 02/16/2023]
Abstract
The naked mole-rat (NMR, Heterocephalus glaber) is of significant interest to biogerontological research, rarely developing age-associated diseases, such as cancer. The transmembrane glycoprotein CD44 is upregulated in certain cancers and CD44 cleavage by a disintegrin and metalloproteinase 10 (ADAM10) regulates cellular migration. Here we provide evidence that mature ADAM10 is expressed in NMR primary skin fibroblasts (NPSF), and that ionomycin increases cell surface ADAM10 localization. However, we observed an absence of ADAM10 mediated CD44 cleavage, as well as shedding of exogenous and overexpressed betacellulin in NPSF, whereas in mouse primary skin fibroblasts ionomycin induced ADAM10-dependent cleavage of both CD44 and betacellulin. Overexpressing a hyperactive form of the Ca2+ -dependent phospholipid scramblase ANO6 in NPSF increased phosphatidylserine (PS) externalization, which rescued the ADAM10 sheddase activity and promoted cell migration in NPSF in an ADAM10-dependent manner. These findings suggest that dysregulation of ADAM10 shedding activity is due to a deficient PS externalization in NMR.
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Affiliation(s)
| | - Luke A Pattison
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - Ewan St J Smith
- Department of Pharmacology, University of Cambridge, Cambridge, UK
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Identity matters: cancer stem cells and tumour plasticity in head and neck squamous cell carcinoma. Expert Rev Mol Med 2023; 25:e8. [PMID: 36740973 DOI: 10.1017/erm.2023.4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents frequent yet aggressive tumours that encompass complex ecosystems of stromal and neoplastic components including a dynamic population of cancer stem cells (CSCs). Recently, research in the field of CSCs has gained increased momentum owing in part to their role in tumourigenicity, metastasis, therapy resistance and relapse. We provide herein a comprehensive assessment of the latest progress in comprehending CSC plasticity, including newly discovered influencing factors and their possible application in HNSCC. We further discuss the dynamic interplay of CSCs within tumour microenvironment considering our evolving appreciation of the contribution of oral microbiota and the pressing need for relevant models depicting their features. In sum, CSCs and tumour plasticity represent an exciting and expanding battleground with great implications for cancer therapy that are only beginning to be appreciated in head and neck oncology.
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Polverini PJ, Nör F, Nör JE. Crosstalk between cancer stem cells and the tumor microenvironment drives progression of premalignant oral epithelium. FRONTIERS IN ORAL HEALTH 2023; 3:1095842. [PMID: 36704239 PMCID: PMC9872128 DOI: 10.3389/froh.2022.1095842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
Cancer stem cells (CSC) are a subpopulation of cancer cells that exhibit properties of self-renewal and differentiation and have been implicated in metastasis and treatment failures. There is mounting evidence that carcinogen-initiated mucosal epithelial stem cells acquire the CSC phenotype following exposure to environmental or infectious mutagens and are responsible for promoting the malignant transformation of premalignant (dysplastic) epithelium. CSC further contribute to the progression of dysplasia by activating signaling pathways through crosstalk with various cell populations in the tumor microenvironment. Two cell types, tumor-associated macrophages (TAM) and vascular endothelial cells (EC) nurture CSC development, support CSC stemness, and contribute to tumor progression. Despite mounting evidence implicating CSC in the initiation and progression of dysplastic oral epithelium to squamous cell carcinoma (SCC), the molecular mechanisms underlying these synergistic biological processes remain unclear. This review will examine the mechanisms that underlie the transformation of normal epithelial stem cells into CSC and the mechanistic link between CSC, TAM, and EC in the growth and the malignant conversation of dysplastic oral epithelium.
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Affiliation(s)
- Peter J. Polverini
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States,Correspondence: Peter J. Polverini
| | - Felipe Nör
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Jacques E. Nör
- Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
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Afshari K, Sohal KS. Potential Alternative Therapeutic Modalities for Management Head and Neck Squamous Cell Carcinoma: A Review. Cancer Control 2023; 30:10732748231185003. [PMID: 37328298 DOI: 10.1177/10732748231185003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/18/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) includes malignancies of the lip and oral cavity, oropharynx, nasopharynx, larynx, and hypopharynx. It is among the most common malignancy worldwide, affecting nearly 1 million people annually. The traditional treatment options for HNSCC include surgery, radiotherapy, and conventional chemotherapy. However, these treatment options have their specific sequelae, which produce high rates of recurrence and severe treatment-related disabilities. Recent technological advancements have led to tremendous progress in understanding tumor biology, and hence the emergence of several alternative therapeutic modalities for managing cancers (including HNSCC). These treatment options are stem cell targeted therapy, gene therapy, and immunotherapy. Therefore, this review article aims to provide an overview of these alternative treatments of HNSCC.
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Affiliation(s)
- Keihan Afshari
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
| | - Karpal Singh Sohal
- Department of Oral and Maxillofacial Surgery, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania
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Zhang Q, Chen L, Huang L, Cheng H, Wang L, Xu L, Hu D, He C, Fu C, Wei Q. CD44 promotes angiogenesis in myocardial infarction through regulating plasma exosome uptake and further enhancing FGFR2 signaling transduction. Mol Med 2022; 28:145. [PMID: 36463112 PMCID: PMC9719212 DOI: 10.1186/s10020-022-00575-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 11/14/2022] [Indexed: 12/05/2022] Open
Abstract
BACKGROUND Since angiogenesis occurs as the pathological process following myocardial infarction to alleviate ischemia, therapeutic angiogenesis has been proposed to be a cardioprotective strategy. CD44 has been implicated in endothelial cell functions and its role has been well established in angiogenesis for years. Although recent studies indicate the close correlation between CD44 and exosome, as well as the two being implicated in myocardial ischemia pathological processes, the effect and the underlying mechanism of CD44 and its regulated plasma exosome in pathological angiogenesis post-myocardial infarction have not been fully elucidated. METHODS In this study, we used CD44 knockout mice to study the in vivo impacts of CD44 on ischemic angiogenesis in myocardial infarction. Mouse cardiac function was measured by echocardiography, histological changes were observed by Evans Blue and TTC-double staining and Masson's trichrome staining, and molecular changes were detected by immunofluorescence. In the in vitro study, CD44 knockout HUVECs were generated and CD44 inhibitor was used to study the mechanism of CD44 on angiogenesis. We performed the immunoprecipitation, proximity ligation assay, and super-resolution imaging to study the mechanistic regulation of FGFR2 signaling transduction by CD44. Importantly, we also isolated plasma exosomes from myocardial infarction model mice and studied the effect of plasma exosomes on the activation of the FGFR2 signaling pathway and the related phenotypic alterations, including exosomes uptake and angiogenic function in primary mouse microvascular endothelial cells, and further discovered the regulation mechanism of exosomal miRNAs. RESULTS We observed that the expression of CD44 in the border zone of the infarcted heart was tightly related to pathological angiogenesis following myocardial ischemia. The depletion of CD44 impaired angiogenesis and impacts biogenesis and proangiogenic function of plasma exosomes. Subsequently, we found that CD44 mediated the activation of the FGFR2 signaling pathway as well as the caveolin 1-dependent uptake of exosomes in vascular endothelial cells. Most importantly, the proangiogenic therapeutic effect of plasma exosomal miRNAs depended upon the participation of CD44/FGFR2 signaling transduction in vascular endothelial cells. CONCLUSION CD44 and its regulated plasma exosomes have crucial potent angiogenic activity. Our studies elucidate that CD44 plays a key role in plasma exosomal miRNA-enhanced angiogenic FGFR2 singling transduction and ischemic angiogenesis in the early stage of myocardial infarction.
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Affiliation(s)
- Qing Zhang
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Li Chen
- grid.415440.0Department of Rehabilitation Medicine, The Fifth Affiliated People’s Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan People’s Republic of China
| | - Liyi Huang
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Hongxin Cheng
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Lu Wang
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Lin Xu
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Danrong Hu
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Chengqi He
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
| | - Chenying Fu
- grid.13291.380000 0001 0807 1581National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,grid.13291.380000 0001 0807 1581Aging and Geriatric Mechanism Laboratory, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China
| | - Quan Wei
- grid.13291.380000 0001 0807 1581Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan People’s Republic of China ,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan People’s Republic of China
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Zhang XP, Pei JP, Zhang CD, Yusupu M, Han MH, Dai DQ. Exosomal circRNAs: A key factor of tumor angiogenesis and therapeutic intervention. Biomed Pharmacother 2022; 156:113921. [DOI: 10.1016/j.biopha.2022.113921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/16/2022] [Accepted: 10/24/2022] [Indexed: 11/02/2022] Open
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Zheng Y, Wang L, Yin L, Yao Z, Tong R, Xue J, Lu Y. Lung Cancer Stem Cell Markers as Therapeutic Targets: An Update on Signaling Pathways and Therapies. Front Oncol 2022; 12:873994. [PMID: 35719973 PMCID: PMC9204354 DOI: 10.3389/fonc.2022.873994] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 04/25/2022] [Indexed: 02/05/2023] Open
Abstract
Cancer stem cells, a relatively small group of self-renewing cancer cells, were first isolated from acute myeloid leukemia. These cells can play a crucial role in tumor metastasis, relapse, and therapy resistance. The cancer stem cell theory may be applied to lung cancer and explain the inefficiency of traditional treatments and eventual recurrence. However, because of the unclear accuracy and illusive biological function of cancer stem cells, some researchers remain cautious about this theory. Despite the ongoing controversy, cancer stem cells are still being investigated, and their biomarkers are being discovered for application in cancer diagnosis, targeted therapy, and prognosis prediction. Potential lung cancer stem cell markers mainly include surface biomarkers such as CD44, CD133, epithelial cell adhesion molecule, and ATP-binding cassette subfamily G member 2, along with intracellular biomarkers such as aldehyde dehydrogenase, sex-determining region Y-box 2, NANOG, and octamer-binding transcription factor 4. These markers have different structures and functions but are closely associated with the stem potential and uncontrollable proliferation of tumor cells. The aberrant activation of major signaling pathways, such as Notch, Hedgehog, and Wnt, may be associated with the expression and regulation of certain lung cancer stem cell markers, thus leading to lung cancer stem cell maintenance, chemotherapy resistance, and cancer promotion. Treatments targeting lung cancer stem cell markers, including antibody drugs, nanoparticle drugs, chimeric antigen receptor T-cell therapy, and other natural or synthetic specific inhibitors, may provide new hope for patients who are resistant to conventional lung cancer therapies. This review provides comprehensive and updated data on lung cancer stem cell markers with regard to their structures, functions, signaling pathways, and promising therapeutic target approaches, aiming to elucidate potential new therapies for lung cancer.
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Affiliation(s)
- Yue Zheng
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Laduona Wang
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Limei Yin
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zhuoran Yao
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ruizhan Tong
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jianxin Xue
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China
| | - You Lu
- Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.,Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, China
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Żurek M, Rzepakowska A, Kotuła I, Demkow U, Niemczyk K. Serum expression of Vascular Endothelial-Cadherin, CD44, Human High mobility group B1, Kallikrein 6 proteins in different stages of laryngeal intraepithelial lesions and early glottis cancer. PeerJ 2022; 10:e13104. [PMID: 35462765 PMCID: PMC9029362 DOI: 10.7717/peerj.13104] [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: 12/02/2021] [Accepted: 02/22/2022] [Indexed: 01/12/2023] Open
Abstract
Background The study was designed to evaluate the potential validity and utility of selected molecular markers in serum samples from patients with specific stages of laryngeal intraepithelial lesions that could serve as diagnostic tools in differentiation of benign and dysplastic lesions from invasive pathologies. Methods Prospective study included 80 consecutive patients with vocal fold lesions treated at the single otorhinolaryngology centre. All participants had surgical resection of the lesion. Blood samples were collected from each patient before the surgery. Final diagnosis was confirmed on histopathological examination and included 39 (48.75%) non-dysplastic lesions, eight (10%) low-grade dysplasia, six (7.5%) high-grade dysplasia and 27 (33.75%) invasive cancers. The ELISA procedures were performed according to the manufacturer's instruction. Individual serum concentration of selected proteins was reported in ng/ml: Vascular Endothelial-Cadherin Complex (VE-cad), CD44, Human High mobility group protein B1(HMGB1), Kallikrein 6. Results The highest mean levels of HMGB1, KLK6 and VE-cad were detected in sera of patients with low-grade dysplasia (81.14, 24.33, 14.17 respectively). Soluble CD44 was the most elevated in patients with non-dysplastic lesions (2.49). The HMGB1, KLK6 and VE-cad serum levels were increasing from non-dysplastic to low-grade dysplasia and followed by the decrease for high-grade dysplasia and invasive cancer, however the differences were not significant (p-values 0.897, 0.354, 0.1 respectively). Patients' serum had the highest CD44 concentration in non-dysplastic and low-grade dysplasia with the following decrease through high-grade dysplasia and invasive cancer. GERD symptomatic patients had higher levels of KLK6 and CD44 than other patients (p-value 0.06 and 0.084 respectively). There were no significant differences of biomarkers levels related to patients' gender (p-value from 0.243 to 1) or smoking status (p-value from 0.22 to 0.706). Conclusions VE-cad, HMGB1, CD44 and KLK6 did not prove to be reliable biomarkers implicating malignant potential within vocal fold hypertrophic intraepithelial lesions.
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Affiliation(s)
- Michał Żurek
- Department of Otorhinolaryngology Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland,Doctoral School, Medical University of Warsaw, Warsaw, Poland
| | - Anna Rzepakowska
- Department of Otorhinolaryngology Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Iwona Kotuła
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland
| | - Urszula Demkow
- Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland
| | - Kazimierz Niemczyk
- Department of Otorhinolaryngology Head and Neck Surgery, Medical University of Warsaw, Warsaw, Poland
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Shahoumi LA. Oral Cancer Stem Cells: Therapeutic Implications and Challenges. FRONTIERS IN ORAL HEALTH 2022; 2:685236. [PMID: 35048028 PMCID: PMC8757826 DOI: 10.3389/froh.2021.685236] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 06/25/2021] [Indexed: 12/12/2022] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is currently one of the 10 most common malignancies worldwide, characterized by a biologically highly diverse group of tumors with non-specific biomarkers and poor prognosis. The incidence rate of HNSCC varies widely throughout the world, with an evident prevalence in developing countries such as those in Southeast Asia and Southern Africa. Tumor relapse and metastasis following traditional treatment remain major clinical problems in oral cancer management. Current evidence suggests that therapeutic resistance and metastasis of cancer are mainly driven by a unique subpopulation of tumor cells, termed cancer stem cells (CSCs), or cancer-initiating cells (CICs), which are characterized by their capacity for self-renewal, maintenance of stemness and increased tumorigenicity. Thus, more understanding of the molecular mechanisms of CSCs and their behavior may help in developing effective therapeutic interventions that inhibit tumor growth and progression. This review provides an overview of the main signaling cascades in CSCs that drive tumor repropagation and metastasis in oral cancer, with a focus on squamous cell carcinoma. Other oral non-SCC tumors, including melanoma and malignant salivary gland tumors, will also be considered. In addition, this review discusses some of the CSC-targeted therapeutic strategies that have been employed to combat disease progression, and the challenges of targeting CSCs, with the aim of improving the clinical outcomes for patients with oral malignancies. Targeting of CSCs in head and neck cancer (HNC) represents a promising approach to improve disease outcome. Some CSC-targeted therapies have already been proven to be successful in pre-clinical studies and they are now being tested in clinical trials, mainly in combination with conventional treatment regimens. However, some studies revealed that CSCs may not be the only players that control disease relapse and progression of HNC. Further, clinical research studying a combination of therapies targeted against head and neck CSCs may provide significant advances.
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Affiliation(s)
- Linah A Shahoumi
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA, United States
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41
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Essa AAM, Deraz EM. Expression of CD44 (NKI-P1) in oral squamous cell carcinoma associated vascular endothelial cells: A relationship to tumor angiogenesis. Saudi Dent J 2022; 34:21-26. [PMID: 35068895 PMCID: PMC8767246 DOI: 10.1016/j.sdentj.2021.09.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 11/01/2022] Open
Abstract
Background Aim Materials and methods
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Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A Multifunctional Mediator of Cancer Progression. Biomolecules 2021; 11:1850. [PMID: 34944493 PMCID: PMC8699317 DOI: 10.3390/biom11121850] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/23/2021] [Accepted: 11/02/2021] [Indexed: 12/15/2022] Open
Abstract
CD44, a non-kinase cell surface transmembrane glycoprotein, has been widely implicated as a cancer stem cell (CSC) marker in several cancers. Cells overexpressing CD44 possess several CSC traits, such as self-renewal and epithelial-mesenchymal transition (EMT) capability, as well as a resistance to chemo- and radiotherapy. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The interaction of such isoforms with ligands, particularly hyaluronic acid (HA), osteopontin (OPN) and matrix metalloproteinases (MMPs), drive numerous cancer-associated signalling. However, there are contradictory results regarding whether high or low CD44 expression is associated with worsening clinicopathological features, such as a higher tumour histological grade, advanced tumour stage and poorer survival rates. Nonetheless, high CD44 expression significantly contributes to enhanced tumourigenic mechanisms, such as cell proliferation, metastasis, invasion, migration and stemness; hence, CD44 is an important clinical target. This review summarises current research regarding the different CD44 isoform structures and their roles and functions in supporting tumourigenesis and discusses CD44 expression regulation, CD44-signalling pathways and interactions involved in cancer development. The clinical significance and prognostic value of CD44 and the potential of CD44 as a therapeutic target in cancer are also addressed.
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Affiliation(s)
- Malak Hassn Mesrati
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
| | - Saiful Effendi Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - M. Aiman Mohtar
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia; (S.E.S.); (M.A.M.)
| | - Amir Syahir
- Nanobiotechnology Research Group, Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia;
- UPM-MAKNA Cancer Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, Serdang 43400 UPM, Selangor, Malaysia
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Characterization of Cancer Stem Cell Characteristics and Development of a Prognostic Stemness Index Cell-Related Signature in Oral Squamous Cell Carcinoma. DISEASE MARKERS 2021; 2021:1571421. [PMID: 34840626 PMCID: PMC8617564 DOI: 10.1155/2021/1571421] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 10/06/2021] [Indexed: 01/27/2023]
Abstract
Objective Cancer stem cells (CSCs) with self-renewal and plasticity contribute to tumor initiation and progression. This study developed an mRNA expression-based stemness index- (mRNAsi-) associated signature and validated biological functions of stem cell-related genes in oral squamous cell carcinoma (OSCC). Methods Here, mRNAsi was measured for OSCC samples from TCGA cohort, and prognosis and tumor microenvironment (stromal/immune scores, tumor purity) in high- and low-mRNAsi samples were evaluated with survival analyses and ESTIMATE algorithm. Based on prognostic mRNAsi-related genes, a risk score model was constructed by the LASSO method. The predictive accuracy was evaluated by uni- and multivariate Cox analyses and ROC curves. Among the genes in the model, the functions of H2AFZ on proliferation, apoptosis, invasion, and EMT were investigated in OSCC cells. Results High mRNAsi was distinctly associated with undesirable prognosis, increased stromal and immune scores, and lowered tumor purity. The mRNAsi-associated signature containing 11 genes was developed, and high-risk score was distinctly related to poor survival outcomes. Moreover, this signature was an independent and robust risk factor. H2AFZ upregulation significantly enhanced proliferative and invasive capacities and facilitated EMT as well as lowered apoptotic levels in Cal-27 and HSC-3 cells. Conclusion Our study characterized cancer stem cell characteristics that were closely related to tumor microenvironment and developed a stemness index cell-related signature that could assist prognosis prediction and risk stratification for OSCC. H2AFZ could become a potential therapeutic target against OSCC.
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Zhang Q, Cheng S, Wang Y, Wang M, Lu Y, Wen Z, Ge Y, Ma Q, Chen Y, Zhang Y, Cao R, Li M, Liu W, Wang B, Wu Q, Jia W, Wang X. Interrogation of the microenvironmental landscape in spinal ependymomas reveals dual functions of tumor-associated macrophages. Nat Commun 2021; 12:6867. [PMID: 34824203 PMCID: PMC8617028 DOI: 10.1038/s41467-021-27018-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 11/01/2021] [Indexed: 02/01/2023] Open
Abstract
Spinal ependymomas are the most common spinal cord tumors in adults, but their intratumoral cellular heterogeneity has been less studied, and how spinal microglia are involved in tumor progression is still unknown. Here, our single-cell RNA-sequencing analyses of three spinal ependymoma subtypes dissect the microenvironmental landscape of spinal ependymomas and reveal tumor-associated macrophage (TAM) subsets with distinct functional phenotypes. CCL2+ TAMs are related to the immune response and exhibit a high capacity for apoptosis, while CD44+ TAMs are associated with tumor angiogenesis. By combining these results with those of single-cell ATAC-sequencing data analysis, we reveal that TEAD1 and EGR3 play roles in regulating the functional diversity of TAMs. We further identify diverse characteristics of both malignant cells and TAMs that might underlie the different malignant degrees of each subtype. Finally, assessment of cell-cell interactions reveal that stromal cells act as extracellular factors that mediate TAM diversity. Overall, our results reveal dual functions of TAMs in tumor progression, providing valuable insights for TAM-targeting immunotherapy.
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Affiliation(s)
- Qianqian Zhang
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Sijin Cheng
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yongzhi Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
- China National Clinical Research Center for Neurological Diseases, 100070, Beijing, China
| | - Mengdi Wang
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yufeng Lu
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Zengqi Wen
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
| | - Yuxin Ge
- State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, 100875, Beijing, China
| | - Qiang Ma
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Youqiao Chen
- State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, 100875, Beijing, China
| | - Yaowu Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
- China National Clinical Research Center for Neurological Diseases, 100070, Beijing, China
| | - Ren Cao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
- China National Clinical Research Center for Neurological Diseases, 100070, Beijing, China
| | - Min Li
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China
- University of Chinese Academy of Sciences, 100049, Beijing, China
| | - Weihao Liu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
- China National Clinical Research Center for Neurological Diseases, 100070, Beijing, China
| | - Bo Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China
- China National Clinical Research Center for Neurological Diseases, 100070, Beijing, China
| | - Qian Wu
- State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, 100875, Beijing, China.
- Chinese Institute for Brain Research, 102206, Beijing, China.
| | - Wenqing Jia
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, 100070, Beijing, China.
- China National Clinical Research Center for Neurological Diseases, 100070, Beijing, China.
| | - Xiaoqun Wang
- State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Bioland Laboratory (Guangzhou), Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China.
- University of Chinese Academy of Sciences, 100049, Beijing, China.
- Chinese Institute for Brain Research, 102206, Beijing, China.
- Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University & Capital Medical University, 100069, Beijing, China.
- Advanced Innovation Center for Human Brain Protection, Beijing Institute for Brain Disorders, Capital Medical University, 100069, Beijing, China.
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Grambow E, Sorg H, Sorg CGG, Strüder D. Experimental Models to Study Skin Wound Healing with a Focus on Angiogenesis. Med Sci (Basel) 2021; 9:medsci9030055. [PMID: 34449673 PMCID: PMC8395822 DOI: 10.3390/medsci9030055] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 12/11/2022] Open
Abstract
A large number of models are now available for the investigation of skin wound healing. These can be used to study the processes that take place in a phase-specific manner under both physiological and pathological conditions. Most models focus on wound closure, which is a crucial parameter for wound healing. However, vascular supply plays an equally important role and corresponding models for selective or parallel investigation of microcirculation regeneration and angiogenesis are also described. In this review article, we therefore focus on the different levels of investigation of skin wound healing (in vivo to in virtuo) and the investigation of angiogenesis and its parameters.
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Affiliation(s)
- Eberhard Grambow
- Department of General, Visceral, Thoracic, Vascular and Transplantation Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Correspondence:
| | - Heiko Sorg
- Department of Health, University of Witten/Herdecke, Alfred-Herrhausen-Str. 50, 58455 Witten, Germany;
- Department of Plastic, Reconstructive, Aesthetic and Hand Surgery, Klinikum Westfalen, Am Knappschaftskrankenhaus 1, 44309 Dortmund, Germany
| | - Christian G. G. Sorg
- Chair of Management and Innovation in Health Care, Department of Management and Entrepreneurship, Faculty of Management, Economics and Society, Witten/Herdecke University, Alfred-Herrhausen-Straße 50, 58455 Witten, Germany;
| | - Daniel Strüder
- Department of Oto-Rhino-Laryngology, Head and Neck Surgery “Otto Körner”, Rostock University Medical Center, 18057 Rostock, Germany;
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Cancer Stem Cells in Oropharyngeal Cancer. Cancers (Basel) 2021; 13:cancers13153878. [PMID: 34359786 PMCID: PMC8345685 DOI: 10.3390/cancers13153878] [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: 05/25/2021] [Revised: 07/17/2021] [Accepted: 07/20/2021] [Indexed: 12/16/2022] Open
Abstract
Oropharyngeal cancer (OPC), which is a common type of head and neck squamous cell carcinoma (HNSCC), is associated with tobacco and alcohol use, and human papillomavirus (HPV) infection. Underlying mechanisms and as a result prognosis of the HPV-positive and HPV-negative OPC patients are different. Like stem cells, the ability of self-renewal and differentiate, cancer stem cells (CSCs) have roles in tumor invasion, metastasis, drug resistance, and recurrence after therapy. Research revealed their roles to some extent in all of these processes but there are still many unresolved points to connect to CSC-targeted therapy. In this review, we will focus on what we currently know about CSCs of OPC and limitations of our current knowledge. We will present perspectives that will broaden our understanding and recent literature which may connect to therapy.
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Cardiovascular Effects Mediated by HMMR and CD44. Mediators Inflamm 2021; 2021:4977209. [PMID: 34335086 PMCID: PMC8286199 DOI: 10.1155/2021/4977209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 06/07/2021] [Indexed: 01/01/2023] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. The most dangerous life-threatening symptoms of CVD are myocardial infarction and stroke. The causes of CVD are not entirely clear, and new therapeutic targets are still being sought. One of the factors involved in CVD development among vascular damage and oxidative stress is chronic inflammation. It is known that hyaluronic acid plays an important role in inflammation and is regulated by numerous stimuli, including proinflammatory cytokines. The main receptors for hyaluronic acid are CD44 and RHAMM. These receptors are membrane proteins that differ in structure, but it seems that they can perform similar or synergistic functions in many diseases. Both RHAMM and CD44 are involved in cell migration and wound healing. However, their close association with CVD is not fully understood. In this review, we describe the role of both receptors in CVD.
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48
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Patil S. CD44 Sorted Cells Have an Augmented Potential for Proliferation, Epithelial-Mesenchymal Transition, Stemness, and a Predominantly Inflammatory Cytokine and Angiogenic Secretome. Curr Issues Mol Biol 2021; 43:423-433. [PMID: 34205649 PMCID: PMC8929035 DOI: 10.3390/cimb43010034] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 11/16/2022] Open
Abstract
Cancer stem cells (CSCs) have garnered attention with their potential for early diagnosis and prognosis of oral squamous cell carcinoma (OSCC). It is still indistinct whether CSCs are recognized with a specific set of characteristics. The present study aimed to assess the association of CD44 with stemness-related, Epithelial Mesenchymal Transition EMT-related genes and the secretome of the CSCs. The single-cell suspension from primary OSCC tumors was prepared by enzymatic digestion and the cells were cultured in-vitro. The cancer stem cells were isolated by CD44+ selection using magnetic cell-sorting. The expression of CD44, proliferation rate, gene expression of EMT-related transcription factors, stemness markers, cytokine levels and angiogenic factors in both cell population was assessed. The sorted CD44+ cells showed significantly higher proliferation rate than heterogenous population. The CD44 expression was >90% in the sorted cells which was higher than the heterogenous cells. The CD44+ CSCs cells demonstrated significant increased levels of EMT-related genes TWIST1 and CDH2 (N-cadherin), CSC-related genes CD44 and CD133 (PROM1), stemness-related genes OCT4, SOX2, inflammatory cytokines IL-1ß, IL-12, IL-18 and TNF-α and angiogenic factors Angiopoietin-1, Angiopoietin-2, bFGF and VEGF while levels of epithelial gene CDH1 (E-cadherin) decreased in comparison to mixed cell population. The genetic and secretome profiling of the CD44+ CSCs could serve as diagnostic and prognostic tools in the treatment of oral cancers.
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Affiliation(s)
- Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan 45142, Saudi Arabia
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Wang G, Zhang M, Cheng M, Wang X, Li K, Chen J, Chen Z, Chen S, Chen J, Xiong G, Xu X, Wang C, Chen D. Tumor microenvironment in head and neck squamous cell carcinoma: Functions and regulatory mechanisms. Cancer Lett 2021; 507:55-69. [PMID: 33741424 DOI: 10.1016/j.canlet.2021.03.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023]
Abstract
The tumor microenvironment has been recently reported to play a pivotal role in sustaining tumor cells survival and protecting them from immunotherapy and chemotherapy-induced death. It remains largely unknown how the specific signaling pathway exerts the tumor microenvironment in head and neck squamous cell carcinoma though previous studies have elucidated the regulatory mechanisms involve in tumor immune microenvironment, stromal cells, tumor angiogenesis and cancer stem cell. These components are responsible for tumor progression as well as anti-cancer therapy resistance, leading to rapid tumor growth and treatment failure. In this review, we focus on discussing the interaction between tumor cells and the surrounding components for better understanding of anti-cancer treatment ineffectiveness and its underlying molecular mechanisms.
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Affiliation(s)
- Ganping Wang
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Ming Zhang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Maosheng Cheng
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Xiaochen Wang
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Kang Li
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jianwen Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Zhi Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Shuang Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Jie Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China
| | - Gan Xiong
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Xiuyun Xu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Cheng Wang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, 510030, China
| | - Demeng Chen
- Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510080, China.
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50
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Sasaki Y, Takagane K, Konno T, Itoh G, Kuriyama S, Yanagihara K, Yashiro M, Yamada S, Murakami S, Tanaka M. Expression of asporin reprograms cancer cells to acquire resistance to oxidative stress. Cancer Sci 2021; 112:1251-1261. [PMID: 33393151 PMCID: PMC7935789 DOI: 10.1111/cas.14794] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 12/21/2022] Open
Abstract
Asporin (ASPN), a small leucine‐rich proteoglycan expressed predominantly by cancer associated fibroblasts (CAFs), plays a pivotal role in tumor progression. ASPN is also expressed by some cancer cells, but its biological significance is unclear. Here, we investigated the effects of ASPN expression in gastric cancer cells. Overexpression of ASPN in 2 gastric cancer cell lines, HSC‐43 and 44As3, led to increased migration and invasion capacity, accompanied by induction of CD44 expression and activation of Rac1 and MMP9. ASPN expression increased resistance of HSC‐43 cells to oxidative stress by reducing the amount of mitochondrial reactive oxygen species. ASPN induced expression of the transcription factor HIF1α and upregulated lactate dehydrogenase A (LDHA) and PDH‐E1α, suggesting that ASPN reprograms HSC‐43 cells to undergo anaerobic glycolysis and suppresses ROS generation in mitochondria, which has been observed in another cell line HSC‐44PE. By contrast, 44As3 cells expressed high levels of HIF1α in response to oxidant stress and escaped apoptosis regardless of ASPN expression. Examination of xenografts in the gastric wall of ASPN–/– mice revealed that growth of HSC‐43 tumors with increased micro blood vessel density was significantly accelerated by ASPN; however, ASPN increased the invasion depth of both HSC‐43 and 44As3 tumors. These results suggest that ASPN has 2 distinct effects on cancer cells: HIF1α‐mediated resistance to oxidative stress via reprogramming of glucose metabolism, and activation of CD44‐Rac1 and MMP9 to promote cell migration and invasion. Therefore, ASPN may be a new therapeutic target in tumor fibroblasts and cancer cells in some gastric carcinomas.
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Affiliation(s)
- Yuto Sasaki
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.,Department of Life Science, Faculty and Graduate School of Engineering and Resource Science, Akita University, Akita, Japan
| | - Kurara Takagane
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan
| | - Takumi Konno
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.,Department of Life Science, Faculty and Graduate School of Engineering and Resource Science, Akita University, Akita, Japan
| | - Go Itoh
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan
| | - Sei Kuriyama
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan
| | - Kazuyoshi Yanagihara
- Division of Biomarker Discovery, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Chiba, Japan
| | - Masakazu Yashiro
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Satoru Yamada
- Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, Sendai, Japan.,Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Shinya Murakami
- Department of Periodontology, Osaka University Graduate School of Dentistry, Osaka, Japan
| | - Masamitsu Tanaka
- Department of Molecular Medicine and Biochemistry, Akita University Graduate School of Medicine, Akita, Japan
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