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Canário R, Ribeiro AS, Morgado I, Peixoto A, Barbosa A, Santos C, Mendes N, Lopes P, Monteiro P, Coelho R, Jacob F, Heinzelmann-Schwarz V, Ricardo S, Teixeira MR, Bartosch C, Paredes J. P-cadherin overexpression is associated with early transformation of the Fallopian tube epithelium and aggressiveness of tubo-ovarian high-grade serous carcinoma. Virchows Arch 2025:10.1007/s00428-025-04104-7. [PMID: 40320493 DOI: 10.1007/s00428-025-04104-7] [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: 02/13/2025] [Revised: 03/26/2025] [Accepted: 04/05/2025] [Indexed: 05/20/2025]
Abstract
Tubo-ovarian high-grade serous carcinoma (HGSC) with proficient homologous recombination (HR) DNA repair (HRP) accounts for approximately 50% of cases and is associated with platinum-resistance and poor prognosis. We hypothesize that the acquisition of hybrid phenotypes displaying both epithelial and mesenchymal (E/M) features may be involved in the malignant transformation and tumour dissemination in this subgroup. Therefore, we analysed, by digital pathology, the expression and prognostic significance of 3 classic cadherins (E-cadherin, epithelial marker; N-cadherin, mesenchymal marker; and P-cadherin, candidate marker of hybrid E/M) in 577 formalin-fixed paraffin-embedded human samples representing the putative stepwise serous carcinogenesis in the Fallopian tube epithelium (FTE). We observed a non-canonical N-to-P-cadherin switch along the carcinogenic progression, with a statistically significant overexpression of P-cadherin in pre-malignant and malignant samples, compared to the control FTE. Interestingly, this overexpression was most pronounced in precursor lesions and HGSC cells from malignant ascites. Tumours with high P-cadherin expression were significantly associated with worse overall survival, especially in the subgroup without BRCA1/2 mutations. Transient P-cadherin knock-down resulted in in vitro significant reduction of functional hybrid E/M hallmarks, namely decreased anoikis resistance, reduced collective migration and invasion in a representative platinum-resistant HRP cell line. Taken together, our results suggest that P-cadherin overexpression is an early event in the serous carcinogenesis and may be involved in hybrid E/M activation in HRP-HGSC, further supporting this adhesion molecule as a promising biomarker for this poor prognostic subgroup.
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Affiliation(s)
- Rita Canário
- Graduate Program in Areas of Basic and Applied Biology (GABBA), School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
- Cancer Metastasis, i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
- Cancer Biology and Epigenetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Cancer Genetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
| | - Ana Sofia Ribeiro
- Cancer Metastasis, i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Inês Morgado
- Cancer Metastasis, i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Ana Peixoto
- Cancer Genetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
| | - Ana Barbosa
- Cancer Genetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
| | - Catarina Santos
- Cancer Genetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
| | - Nuno Mendes
- Histology and Electron Microscopy, i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal
| | - Paula Lopes
- Cancer Biology and Epigenetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Pathology Department, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca) , Porto, Portugal
| | - Paula Monteiro
- Cancer Biology and Epigenetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Pathology Department, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca) , Porto, Portugal
| | - Ricardo Coelho
- Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031, Basel, Switzerland
| | - Francis Jacob
- Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031, Basel, Switzerland
| | - Viola Heinzelmann-Schwarz
- Ovarian Cancer Research, Department of Biomedicine, University Hospital Basel and University of Basel, 4031, Basel, Switzerland
| | - Sara Ricardo
- Ageing and Stress Group, i3S-Institute for Research and Innovation in Health,, University of Porto, Porto, Portugal
- Associate Laboratory I4HB, Institute for Health and Bioeconomy, University Institute of Health Sciences-CESPU, Gandra, Portugal
- UCIBIO-Applied Molecular Biosciences Unit, Toxicologic Pathology Research Laboratory, University Institute of Health Sciences (1H-TOXRUN, IUCS-CESPU), Gandra, Portugal
| | - Manuel R Teixeira
- Cancer Genetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Pathology and Molecular Immunology Department, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Carla Bartosch
- Cancer Biology and Epigenetics Group, Research Center-Portuguese Oncology Institute of Porto (CI-IPO-Porto)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca), Porto, Portugal
- Pathology Department, Portuguese Oncology Institute of Porto (IPO-Porto)/Porto. Comprehensive Cancer Center Raquel Seruca (P.CCC Raquel Seruca) , Porto, Portugal
- Pathology and Molecular Immunology Department, School of Medicine and Biomedical Sciences (ICBAS), University of Porto, Porto, Portugal
| | - Joana Paredes
- Cancer Metastasis, i3S-Institute for Research and Innovation in Health, University of Porto, Porto, Portugal.
- FMUP-Faculty of Medicine, University of Porto, Porto, Portugal.
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Zhu Y, Abedini A, Rodriguez GM, McCloskey CW, Abou-Hamad J, Salah OS, Larocque J, Tsoi MF, Boerboom D, Cook D, Vanderhyden B. Loss of LATS1 and LATS2 promotes ovarian tumor formation by enhancing AKT activity and PD-L1 expression. Oncogene 2025:10.1038/s41388-025-03387-z. [PMID: 40221530 DOI: 10.1038/s41388-025-03387-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 03/14/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025]
Abstract
High-grade serous ovarian cancer (HGSOC) is the deadliest and most common subtype of ovarian cancer. Unfortunately, most patients develop recurrence and, ultimately, resistance to standard platinum chemotherapy. Large tumor suppressors LATS1 and LATS2, the core Hippo signaling kinases, have been implicated in various cancer types, including ovarian cancer. The mechanism by which LATS1/2 suppresses ovarian cancer progression is currently elusive, but the expression of LATS1/2 is frequently reduced or lost in these cancers. In this study, we demonstrate that the inactivation of LATS1/2 is sufficient to transform normal mouse ovarian epithelium into tumorigenic cells associated with increased cell proliferation, invasion, and stemness and epithelial-mesenchymal transition (EMT) characteristics. The knockout of Lats1/2 in the epithelial cells also leads to higher expression levels of the immune checkpoint molecule PD-L1, suggesting a regulatory role of LATS1/2 in modulating immune responses and immune evasion. In addition to the loss of LATS1/2 activating the downstream transcriptional coactivators YAP and TAZ, PI3K-AKT activity was also increased, likely contributing to enhanced tumor proliferation and survival. The stimulatory effect of Lats1/2 knockout on cell proliferation can be partially reversed by treatment with the AKT inhibitor MK2206. Treatment with verteporfin, a potent inhibitor of YAP/TAZ, decreases ovarian tumor progression and reduces the activated AKT in the tumors. In summary, this study uncovers several biological mechanisms for the initiation of HGSOC and identifies LATS1/2 as potential prognostic indicators and therapeutic targets.
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Affiliation(s)
- Yalun Zhu
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Atefeh Abedini
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Galaxia M Rodriguez
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Curtis W McCloskey
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - John Abou-Hamad
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Omar Salah Salah
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Janie Larocque
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Mayra F Tsoi
- Centre de Recherche en Reproduction et Fertilité (CRRF), Université de Montréal, Saint-Hyacinthe, QC, Canada
| | - Derek Boerboom
- Centre de Recherche en Reproduction et Fertilité (CRRF), Université de Montréal, Saint-Hyacinthe, QC, Canada
| | - David Cook
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Barbara Vanderhyden
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
- Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada.
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3
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Tugizov S. HIV-1 Tat-induced disruption of epithelial junctions and epithelial-mesenchymal transition of oral and genital epithelial cells lead to increased invasiveness of neoplastic cells and the spread of herpes simplex virus and cytomegalovirus. Front Immunol 2025; 16:1541532. [PMID: 40018040 PMCID: PMC11866325 DOI: 10.3389/fimmu.2025.1541532] [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: 12/08/2024] [Accepted: 01/28/2025] [Indexed: 03/01/2025] Open
Abstract
Human immunodeficiency virus (HIV-1) transactivator Tat is a unique multi-functional viral protein secreted by infected cells. Although its primary function is to promote HIV-1 transcription, secreted Tat interacts with neighboring cells and induces numerous disease-associated pathological changes. Despite the substantial reduction of viral load and disease burden, Tat expression and secretion persist in people living with HIV who are undergoing treatment with highly effective combination antiretroviral therapy (cART). Tat interacts with both oral and genital epithelial cells and impairs their mucosal barrier functions, which facilitates the entry of other pathogenic viruses. Tat-mediated interactions with both human papillomavirus (HPV) -infected and HPV-negative neoplastic epithelial cells lead to epithelial-mesenchymal transition and increased invasiveness of malignant cells. Likewise, Tat-induced disruption of oral epithelial cell junctions leads to herpes simplex virus-1 (HSV-1) infection and spread via exposure of its receptor, nectin-1. HIV-1 Tat facilitates infection and spread of human cytomegalovirus (HCMV) by activating mitogen-activated protein kinases (MAPK) and promoting NF-κB signaling, both critical for the replication and production of progeny virions. HIV extracellular Tat also plays a critical role in human herpesvirus 8 (HHV8) -caused Kaposi sarcoma (KS) pathogenesis by synergizing with HHV-8 lytic proteins and promoting the proliferation, angiogenesis, and migration of endothelial cells. Collectively, these findings emphasize the critical impact of HIV-1 Tat on HIV/AIDS pathogenesis during the cART era and highlight the need for further research on the molecular mechanisms underlying Tat-mediated interactions with oral and genital mucosal epithelial cells.
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Affiliation(s)
- Sharof Tugizov
- Department of Medicine, School of Medicine, University of California, San Francisco, San Francisco, CA, United States
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4
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Mehta G, Horst E, Cotter L, Bonini M, Novak C, Treacher N, Zhang Y, Jackson Z, Narayanan IV, Wuchu F, Nenwani M, Fischer Z, Sunshine A, Lin Z, Tran L, Nagrath D, Ljungman M, Maturen K, DiFeo A, Nordsletten D. Ascitic Shear Stress Activates GPCRs and Downregulates Mucin 15 to Promote Ovarian Cancer Malignancy. RESEARCH SQUARE 2024:rs.3.rs-5160301. [PMID: 39483899 PMCID: PMC11527234 DOI: 10.21203/rs.3.rs-5160301/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
The accumulation of ascites in patients with ovarian cancer increases their risk of transcoelomic metastasis. Although common routes of peritoneal dissemination are known to follow distinct paths of circulating ascites, the mechanisms that initiate these currents and subsequent fluid shear stresses are not well understood. Here, we developed a patient-based, boundary-driven computational fluid dynamics model to predict an upper range of fluid shear stress generated by the accumulation of ascites. We show that ovarian cancer cells exposed to ascitic shear stresses display heightened G protein-coupled receptor mechanosignaling and the induction of an epithelial to mesenchymal-like transition through p38α mitogen-activated protein kinase and mucin 15 modulation. These findings along with a shear-induced immunomodulatory secretome position elevated shear stress as a protumoural signal. Together, this study suggests inhibition of the Gαq protein and restriction of ascites accumulation as maintenance strategies for overcoming mechanotransduction-mediated metastasis within the peritoneal cavity.
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5
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Naciri I, Liang M, Yang Y, Karner H, Lin B, De Lourdes Andrade Ludena M, Hanse EA, Lebron A, Razorenova OV, Nicholas D, Kong M, Sun S. Loss of XIST lncRNA unlocks stemness and cellular plasticity in ovarian cancer. Proc Natl Acad Sci U S A 2024; 121:e2418096121. [PMID: 39546568 PMCID: PMC11588085 DOI: 10.1073/pnas.2418096121] [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: 09/04/2024] [Accepted: 10/16/2024] [Indexed: 11/17/2024] Open
Abstract
Plasticity, a key hallmark of cancer, enables cells to transition into different states, driving tumor heterogeneity. This cellular plasticity is associated with cancer progression, treatment resistance, and relapse. Cancer stem cells (CSCs) play a central role in this process, yet the molecular factors underlying cancer cell stemness remain poorly understood. In this study, we explored the role of XIST (X-inactive specific transcript) long noncoding RNA in ovarian cancer stemness and plasticity through in silico and in vitro analyses. We found that XIST is significantly down-regulated in ovarian tumors, with low XIST expression linked to a higher stemness index and lower overall survival. Knocking down XIST in ovarian cancer cells enhanced stemness, particularly increasing mesenchymal-like CSCs, and under hypoxic conditions, it promoted epithelial-like CSC markers. Our findings suggest that XIST loss leads to CSC enrichment and cellular plasticity in ovarian cancer, pointing to potential therapeutic targets for patients with low XIST expression.
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Affiliation(s)
- Ikrame Naciri
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Minzhi Liang
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Ying Yang
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Heather Karner
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Benjamin Lin
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Maria De Lourdes Andrade Ludena
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Eric A. Hanse
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Alfredo Lebron
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Olga V. Razorenova
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Dequina Nicholas
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Mei Kong
- Department of Molecular Biology and Biochemistry, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
| | - Sha Sun
- Department of Developmental and Cell Biology, Charlie Dunlop School of Biological Sciences, University of California, Irvine, CA92697
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Gu X, Wei S, Lv X. Circulating tumor cells: from new biological insights to clinical practice. Signal Transduct Target Ther 2024; 9:226. [PMID: 39218931 PMCID: PMC11366768 DOI: 10.1038/s41392-024-01938-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/31/2024] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
The primary reason for high mortality rates among cancer patients is metastasis, where tumor cells migrate through the bloodstream from the original site to other parts of the body. Recent advancements in technology have significantly enhanced our comprehension of the mechanisms behind the bloodborne spread of circulating tumor cells (CTCs). One critical process, DNA methylation, regulates gene expression and chromosome stability, thus maintaining dynamic equilibrium in the body. Global hypomethylation and locus-specific hypermethylation are examples of changes in DNA methylation patterns that are pivotal to carcinogenesis. This comprehensive review first provides an overview of the various processes that contribute to the formation of CTCs, including epithelial-mesenchymal transition (EMT), immune surveillance, and colonization. We then conduct an in-depth analysis of how modifications in DNA methylation within CTCs impact each of these critical stages during CTC dissemination. Furthermore, we explored potential clinical implications of changes in DNA methylation in CTCs for patients with cancer. By understanding these epigenetic modifications, we can gain insights into the metastatic process and identify new biomarkers for early detection, prognosis, and targeted therapies. This review aims to bridge the gap between basic research and clinical application, highlighting the significance of DNA methylation in the context of cancer metastasis and offering new avenues for improving patient outcomes.
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Affiliation(s)
- Xuyu Gu
- Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shiyou Wei
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xin Lv
- Department of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.
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Wang F, Zhou C, Zhu Y, Keshavarzi M. The microRNA Let-7 and its exosomal form: Epigenetic regulators of gynecological cancers. Cell Biol Toxicol 2024; 40:42. [PMID: 38836981 PMCID: PMC11153289 DOI: 10.1007/s10565-024-09884-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/15/2024] [Indexed: 06/06/2024]
Abstract
Many types of gynecological cancer (GC) are often silent until they reach an advanced stage, and are therefore often diagnosed too late for effective treatment. Hence, there is a real need for more efficient diagnosis and treatment for patients with GC. During recent years, researchers have increasingly studied the impact of microRNAs cancer development, leading to a number of applications in detection and treatment. MicroRNAs are a particular group of tiny RNA molecules that regulate regular gene expression by affecting the translation process. The downregulation of numerous miRNAs has been observed in human malignancies. Let-7 is an example of a miRNA that controls cellular processes as well as signaling cascades to affect post-transcriptional gene expression. Recent research supports the hypothesis that enhancing let-7 expression in those cancers where it is downregulated may be a potential treatment option. Exosomes are tiny vesicles that move through body fluids and can include components like miRNAs (including let-7) that are important for communication between cells. Studies proved that exosomes are able to enhance tumor growth, angiogenesis, chemoresistance, metastasis, and immune evasion, thus suggesting their importance in GC management.
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Affiliation(s)
- Fei Wang
- Haiyan People's Hospital, Zhejiang Province, Jiaxing, 314300, Zhejiang, China
| | - Chundi Zhou
- Haiyan People's Hospital, Zhejiang Province, Jiaxing, 314300, Zhejiang, China
| | - Yanping Zhu
- Haiyan People's Hospital, Zhejiang Province, Jiaxing, 314300, Zhejiang, China.
| | - Maryam Keshavarzi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Tehran, Iran.
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8
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Fontana R, Mestre-Farrera A, Yang J. Update on Epithelial-Mesenchymal Plasticity in Cancer Progression. ANNUAL REVIEW OF PATHOLOGY 2024; 19:133-156. [PMID: 37758242 PMCID: PMC10872224 DOI: 10.1146/annurev-pathmechdis-051222-122423] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/03/2023]
Abstract
Epithelial-mesenchymal transition (EMT) is a cellular process by which epithelial cells lose their characteristics and acquire mesenchymal traits to promote cell movement. This program is aberrantly activated in human cancers and endows tumor cells with increased abilities in tumor initiation, cell migration, invasion, metastasis, and therapy resistance. The EMT program in tumors is rarely binary and often leads to a series of gradual or intermediate epithelial-mesenchymal states. Functionally, epithelial-mesenchymal plasticity (EMP) improves the fitness of cancer cells during tumor progression and in response to therapies. Here, we discuss the most recent advances in our understanding of the diverse roles of EMP in tumor initiation, progression, metastasis, and therapy resistance and address major clinical challenges due to EMP-driven phenotypic heterogeneity in cancer. Uncovering novel molecular markers and key regulators of EMP in cancer will aid the development of new therapeutic strategies to prevent cancer recurrence and overcome therapy resistance.
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Affiliation(s)
- Rosa Fontana
- Department of Pharmacology, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, California, USA;
| | - Aida Mestre-Farrera
- Department of Pharmacology, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, California, USA;
| | - Jing Yang
- Department of Pharmacology, Moores Cancer Center, University of California San Diego School of Medicine, La Jolla, California, USA;
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA
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9
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Nakagawa M, Matsumoto T, Yokoi A, Hashimura M, Oguri Y, Konno R, Ishibashi Y, Ito T, Ohhigata K, Harada Y, Fukagawa N, Kodera Y, Saegusa M. Interaction between membranous EBP50 and myosin 9 as a favorable prognostic factor in ovarian clear cell carcinoma. Mol Oncol 2023; 17:2168-2182. [PMID: 37539980 PMCID: PMC10552901 DOI: 10.1002/1878-0261.13503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/05/2023] Open
Abstract
Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is a scaffold protein that is required for epithelial polarity. Knockout (KO) of membranous EBP50 (Me-EBP50) in ovarian clear cell carcinoma (OCCC) cells induced an epithelial-mesenchymal transition (EMT)-like phenotype, along with decreased proliferation, accelerated migration capability, and induction of cancer stem cell (CSC)-like properties. Shotgun proteomics analysis of proteins that co-immunoprecipitated with EBP50 revealed that Me-EBP50 strongly interacts with myosin 9 (MYH9). Specific inhibition of MYH9 with blebbistatin phenocopied Me-EBP50 KO, and blebbistatin treatment potentiated the effects of Me-EBP50 KO. In OCCC cells from clinical samples, Me-EBP50 and MYH9 were co-localized at the apical plasma membrane. Patients with a combination of Me-EBP50-high and MYH9-high scores had the best prognosis for overall and progression-free survival. Our data suggest that Me-EBP50 has tumor-suppressive effects through the establishment and maintenance of epithelial polarization. By contrast, loss of Me-EBP50 expression induces EMT-like phenotypes, probably due to MYH9 dysfunction; this results in increased cell mobility and enhanced CSC-like properties, which in turn promote OCCC progression.
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Affiliation(s)
- Mayu Nakagawa
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Toshihide Matsumoto
- Department of PathologyKitasato University School of Allied Health ScienceSagamiharaJapan
| | - Ako Yokoi
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Miki Hashimura
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Yasuko Oguri
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Ryo Konno
- Center for Disease Proteomics, School of ScienceKitasato UniversitySagamiharaJapan
| | - Yu Ishibashi
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Takashi Ito
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Kensuke Ohhigata
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Yohei Harada
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Naomi Fukagawa
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
| | - Yoshio Kodera
- Center for Disease Proteomics, School of ScienceKitasato UniversitySagamiharaJapan
| | - Makoto Saegusa
- Department of PathologyKitasato University School of MedicineSagamiharaJapan
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10
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Suzuki T, Conant A, Curow C, Alexander A, Ioffe Y, Unternaehrer JJ. Role of epithelial-mesenchymal transition factor SNAI1 and its targets in ovarian cancer aggressiveness. JOURNAL OF CANCER METASTASIS AND TREATMENT 2023; 9:25. [PMID: 38009093 PMCID: PMC10673625 DOI: 10.20517/2394-4722.2023.34] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/28/2023]
Abstract
Ovarian cancer remains the most lethal gynecologic malignancy in the USA. For over twenty years, epithelial-mesenchymal transition (EMT) has been characterized extensively in development and disease. The dysregulation of this process in cancer has been identified as a mechanism by which epithelial tumors become more aggressive, allowing them to survive and invade distant tissues. This occurs in part due to the increased expression of the EMT transcription factor, SNAI1 (Snail). In the case of epithelial ovarian cancer, Snail has been shown to contribute to cancer invasion, stemness, chemoresistance, and metabolic changes. Thus, in this review, we focus on summarizing current findings on the role of EMT (specifically, factors downstream of Snail) in determining ovarian cancer aggressiveness.
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Affiliation(s)
- Tise Suzuki
- Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
| | - Ashlyn Conant
- Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
| | - Casey Curow
- Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
- University of Redlands, Department of Biology, Redlands, CA 92373, USA
| | - Audrey Alexander
- Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
- Division of Natural and Mathematical Sciences, Department of Biological Sciences, California Baptist University, Riverside, CA 92504, USA
| | - Yevgeniya Ioffe
- Department of Gynecology and Obstetrics, Division of Gynecologic Oncology, Loma Linda University Medical Center, Loma Linda, CA 92354, USA
| | - Juli J Unternaehrer
- Division of Biochemistry, Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
- Department of Gynecology and Obstetrics, Loma Linda University, Loma Linda, CA 92354, USA
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11
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Kralj J, Pernar Kovač M, Dabelić S, Polančec DS, Wachtmeister T, Köhrer K, Brozovic A. Transcriptome analysis of newly established carboplatin-resistant ovarian cancer cell model reveals genes shared by drug resistance and drug-induced EMT. Br J Cancer 2023; 128:1344-1359. [PMID: 36717670 PMCID: PMC10050213 DOI: 10.1038/s41416-023-02140-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 12/20/2022] [Accepted: 01/04/2023] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND In ovarian cancer (OC) therapy, even initially responsive patients develop drug resistance. METHODS Here, we present an OC cell model composed of variants with differing degrees of acquired resistance to carboplatin (CBP), cross-resistance to paclitaxel, and CBP-induced metastatic properties (migration and invasion). Transcriptome data were analysed by two approaches identifying differentially expressed genes and CBP sensitivity-correlating genes. The impact of selected genes and signalling pathways on drug resistance and metastatic potential, along with their clinical relevance, was examined by in vitro and in silico approaches. RESULTS TMEM200A and PRKAR1B were recognised as potentially involved in both phenomena, also having high predictive and prognostic values for OC patients. CBP-resistant MES-OV CBP8 cells were more sensitive to PI3K/Akt/mTOR pathway inhibitors Rapamycin, Wortmannin, SB216763, and transcription inhibitor Triptolide compared with parental MES-OV cells. When combined with CBP, Rapamycin decreased the sensitivity of parental cells while Triptolide sensitised drug-resistant cells to CBP. Four PI3K/Akt/mTOR inhibitors reduced migration in both cell lines. CONCLUSIONS A newly established research model and two distinct transcriptome analysis approaches identified novel candidate genes enrolled in CBP resistance development and/or CBP-induced EMT and implied that one-gene targeting could be a better approach than signalling pathway inhibition for influencing both phenomena.
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Affiliation(s)
- Juran Kralj
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
| | - Margareta Pernar Kovač
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia
| | - Sanja Dabelić
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy and Biochemistry, University of Zagreb, Ante Kovačića 1, Zagreb, Croatia
| | | | - Thorsten Wachtmeister
- Genomics and Transcriptomics Laboratory at the Biological and Medical Research Center (BMFZ), Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf, Germany
| | - Karl Köhrer
- Genomics and Transcriptomics Laboratory at the Biological and Medical Research Center (BMFZ), Heinrich-Heine-University Düsseldorf, Universitätsstraße 1, Düsseldorf, Germany
| | - Anamaria Brozovic
- Division of Molecular Biology, Ruđer Bošković Institute, Bijenička cesta 54, Zagreb, Croatia.
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12
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Ring A, Nguyen-Sträuli BD, Wicki A, Aceto N. Biology, vulnerabilities and clinical applications of circulating tumour cells. Nat Rev Cancer 2023; 23:95-111. [PMID: 36494603 PMCID: PMC9734934 DOI: 10.1038/s41568-022-00536-4] [Citation(s) in RCA: 155] [Impact Index Per Article: 77.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2022] [Indexed: 12/13/2022]
Abstract
In recent years, exceptional technological advances have enabled the identification and interrogation of rare circulating tumour cells (CTCs) from blood samples of patients, leading to new fields of research and fostering the promise for paradigm-changing, liquid biopsy-based clinical applications. Analysis of CTCs has revealed distinct biological phenotypes, including the presence of CTC clusters and the interaction between CTCs and immune or stromal cells, impacting metastasis formation and providing new insights into cancer vulnerabilities. Here we review the progress made in understanding biological features of CTCs and provide insight into exploiting these developments to design future clinical tools for improving the diagnosis and treatment of cancer.
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Affiliation(s)
- Alexander Ring
- Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Bich Doan Nguyen-Sträuli
- Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
- Department of Gynecology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Andreas Wicki
- Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Nicola Aceto
- Department of Biology, Institute for Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
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13
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Escalona RM, Chu S, Kadife E, Kelly JK, Kannourakis G, Findlay JK, Ahmed N. Knock down of TIMP-2 by siRNA and CRISPR/Cas9 mediates diverse cellular reprogramming of metastasis and chemosensitivity in ovarian cancer. Cancer Cell Int 2022; 22:422. [PMID: 36585738 PMCID: PMC9805260 DOI: 10.1186/s12935-022-02838-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 12/21/2022] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2), through its homeostatic action on certain metalloproteinases, plays a vital role in remodelling extracellular matrix (ECM) to facilitate cancer progression. This study investigated the role of TIMP-2 in an ovarian cancer cell line in which the expression of TIMP-2 was reduced by either siRNA or CRISPR/Cas9. METHODS OVCAR5 cells were transiently and stably transfected with either single or pooled TIMP-2 siRNAs (T2-KD cells) or by CRISPR/Cas9 under the influence of two distinct guide RNAs (gRNA1 and gRNA2 cell lines). The expression of different genes was analysed at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence (IF) and western blot. Proliferation of cells was investigated by 5-Ethynyl-2'-deoxyuridine (EdU) assay or staining with Ki67. Cell migration/invasion was determined by xCELLigence. Cell growth in vitro was determined by 3D spheroid cultures and in vivo by a mouse xenograft model. RESULTS Approximately 70-90% knock down of TIMP-2 expression were confirmed in T2-KD, gRNA1 and gRNA2 OVCAR5 ovarian cancer cells at the protein level. T2-KD, gRNA1 and gRNA2 cells exhibited a significant downregulation of MMP-2 expression, but concurrently a significant upregulation in the expression of membrane bound MMP-14 compared to control and parental cells. Enhanced proliferation and invasion were exhibited in all TIMP-2 knocked down cells but differences in sensitivity to paclitaxel (PTX) treatment were observed, with T2-KD cells and gRNA2 cell line being sensitive, while the gRNA1 cell line was resistant to PTX treatment. In addition, significant differences in the growth of gRNA1 and gRNA2 cell lines were observed in in vitro 3D cultures as well as in an in vivo mouse xenograft model. CONCLUSIONS Our results suggest that the inhibition of TIMP-2 by siRNA and CRISPR/Cas-9 modulate the expression of MMP-2 and MMP-14 and reprogram ovarian cancer cells to facilitate proliferation and invasion. Distinct disparities in in vitro chemosensitivity and growth in 3D culture, and differences in tumour burden and invasion to proximal organs in a mouse model imply that selective suppression of TIMP-2 expression by siRNA or CRISPR/Cas-9 alters important aspects of metastasis and chemosensitivity in ovarian cancer.
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Affiliation(s)
- Ruth M. Escalona
- grid.1008.90000 0001 2179 088XDepartment of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052 Australia ,grid.1002.30000 0004 1936 7857Centre for Reproductive Health, Hudson Institute of Medical Research and Department of Translational Medicine, Monash University, Clayton, VIC 3168 Australia ,Fiona Elsey Cancer Research Institute, Suites 23, 106-110 Lydiard Street South, Ballarat Technology Park Central, Ballarat, VIC 3350 Australia
| | - Simon Chu
- grid.1002.30000 0004 1936 7857Centre for Endocrinology and Metabolism, Hudson Institute of Medical Research and Department of Translational Medicine, Monash University, Clayton, VIC 3168 Australia
| | - Elif Kadife
- Fiona Elsey Cancer Research Institute, Suites 23, 106-110 Lydiard Street South, Ballarat Technology Park Central, Ballarat, VIC 3350 Australia
| | - Jason K. Kelly
- Fiona Elsey Cancer Research Institute, Suites 23, 106-110 Lydiard Street South, Ballarat Technology Park Central, Ballarat, VIC 3350 Australia
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Suites 23, 106-110 Lydiard Street South, Ballarat Technology Park Central, Ballarat, VIC 3350 Australia ,grid.1040.50000 0001 1091 4859School of Science, Psychology and Sport, Federation University, Mt Helen, VIC 3350 Australia
| | - Jock K. Findlay
- grid.1008.90000 0001 2179 088XDepartment of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052 Australia ,grid.1002.30000 0004 1936 7857Centre for Reproductive Health, Hudson Institute of Medical Research and Department of Translational Medicine, Monash University, Clayton, VIC 3168 Australia
| | - Nuzhat Ahmed
- grid.1008.90000 0001 2179 088XDepartment of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052 Australia ,grid.1002.30000 0004 1936 7857Centre for Reproductive Health, Hudson Institute of Medical Research and Department of Translational Medicine, Monash University, Clayton, VIC 3168 Australia ,Fiona Elsey Cancer Research Institute, Suites 23, 106-110 Lydiard Street South, Ballarat Technology Park Central, Ballarat, VIC 3350 Australia ,grid.1040.50000 0001 1091 4859School of Science, Psychology and Sport, Federation University, Mt Helen, VIC 3350 Australia
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14
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Lien K, Mayer W, Herrera R, Padilla NT, Cai X, Lin V, Pholcharoenchit R, Palefsky J, Tugizov SM. HIV-1 Proteins gp120 and Tat Promote Epithelial-Mesenchymal Transition and Invasiveness of HPV-Positive and HPV-Negative Neoplastic Genital and Oral Epithelial Cells. Microbiol Spectr 2022; 10:e0362222. [PMID: 36314970 PMCID: PMC9770004 DOI: 10.1128/spectrum.03622-22] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/11/2022] [Indexed: 11/06/2022] Open
Abstract
The incidence of human papillomavirus (HPV)-associated anogenital and oropharyngeal cancer in human immunodeficiency virus (HIV)-infected individuals is substantially higher than in HIV-uninfected individuals. HIV may also be a risk factor for the development of HPV-negative head and neck, liver, lung, and kidney cancer. However, the molecular mechanisms underlying HIV-1-associated increase of epithelial malignancies are not fully understood. Here, we showed that HPV-16-immortalized anal AKC-2 and cervical CaSki epithelial cells that undergo prolonged exposure to cell-free HIV-1 virions or HIV-1 viral proteins gp120 and tat respond with the epithelial-mesenchymal transition (EMT) and increased invasiveness. Similar responses were observed in HPV-16-infected SCC-47 and HPV-16-negative HSC-3 oral epithelial cancer cells that were cultured with these viral proteins. EMT induced by gp120 and tat led to detachment of poorly adherent cells from the culture substratum; these cells remained capable of reattachment, upon which they coexpressed both E-cadherin and vimentin, indicative of an intermediate stage of EMT. The reattached cells also expressed stem cell markers CD133 and CD44, which may play a critical role in cancer cell invasion and metastasis. Inhibition of transforming growth factor (TGF)-β1 and MAPK signaling and vimentin expression, and restoration of E-cadherin expression reduced HIV-induced EMT and the invasive activity of HPV-16-immortalized anal and cervical epithelial cells. Collectively, our results suggest that these approaches along with HIV viral suppression with antiretroviral therapy (ART) might be useful to limit the role of HIV-1 infection in the acceleration of HPV-associated or HPV-independent epithelial neoplasia. IMPORTANCE HPV-16-immortalized genital and oral epithelial cells and HPV-negative oral cancer cells that undergo prolonged contact with cell-free HIV-1 virions or with viral proteins gp120 and tat respond by becoming more invasive. EMT cells induced by HIV-1 in cultures of HPV-16-immortalized anal and cervical epithelial cells express the stem cell markers CD133 and CD44. These results suggest that the interaction of HIV-1 with neoplastic epithelial cells may lead to their de-differentiation into cancer stem cells that are resistant to apoptosis and anti-cancer drugs. Thus, this pathway may play a critical role in the development of invasive cancer. Inhibition of TGF-β1 and MAPK signaling and vimentin expression, and restoration of E-cadherin expression reduced HIV-induced EMT and the invasiveness of HPV-16-immortalized anal and cervical epithelial cells. Taken together, these results suggest that these approaches might be exploited to limit the role of HIV-1 infection in the acceleration of HPV-associated or HPV-independent epithelial neoplasia.
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Affiliation(s)
- Kathy Lien
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Wasima Mayer
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Rossana Herrera
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Nicole T. Padilla
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Xiaodan Cai
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Vicky Lin
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | | | - Joel Palefsky
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
| | - Sharof M. Tugizov
- Department of Medicine, University of California-San Francisco, San Francisco, California, USA
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15
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Chen C, Ibrahim Z, Marchand MF, Piolot T, Kamboj S, Carreiras F, Yamada A, Schanne-Klein MC, Chen Y, Lambert A, Aimé C. Three-Dimensional Collagen Topology Shapes Cell Morphology, beyond Stiffness. ACS Biomater Sci Eng 2022; 8:5284-5294. [PMID: 36342082 DOI: 10.1021/acsbiomaterials.2c00879] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Cellular heterogeneity is associated with many physiological processes, including pathological ones, such as morphogenesis and tumorigenesis. The extracellular matrix (ECM) is a key player in the generation of cellular heterogeneity. Advances in our understanding rely on our ability to provide relevant in vitro models. This requires obtainment of the characteristics of the tissues that are essential for controlling cell fate. To do this, we must consider the diversity of tissues, the diversity of physiological contexts, and the constant remodeling of the ECM along these processes. To this aim, we have fabricated a library of ECM models for reproducing the scaffold of connective tissues and the basement membrane by using different biofabrication routes based on the electrospinning and drop casting of biopolymers from the ECM. Using a combination of electron microscopy, multiphoton imaging, and AFM nanoindentation, we show that we can vary independently protein composition, topology, and stiffness of ECM models. This in turns allows one to generate the in vivo complexity of the phenotypic landscape of ovarian cancer cells. We show that, while this phenotypic shift cannot be directly correlated with a unique ECM feature, the three-dimensional collagen fibril topology patterns cell shape, beyond protein composition and stiffness of the ECM. On this line, this work is a further step toward the development of ECM models recapitulating the constantly remodeled environment that cells face and thus provides new insights for cancer model engineering and drug testing.
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Affiliation(s)
- Changchong Chen
- PASTEUR, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, Paris 75005, France
| | - Zeinab Ibrahim
- PASTEUR, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, Paris 75005, France
| | - Marion F Marchand
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, PSL Research University, 11 Place Marcelin Berthelot, Paris 75231, France
| | - Tristan Piolot
- Center for Interdisciplinary Research in Biology (CIRB), Collège de France, CNRS, INSERM, PSL Research University, 11 Place Marcelin Berthelot, Paris 75231, France
| | - Sahil Kamboj
- Equipe de Recherche sur les Relations Matrice Extracellulaire-Cellules, ERRMECe, (EA1391), Groupe Matrice Extracellulaire et Physiopathologie (MECuP), Institut des Matériaux, I-MAT (FD4122), CY Cergy Paris Université, Maison Internationale de la Recherche, Rue Descartes, Neuville sur Oise Cedex 95031, France
| | - Franck Carreiras
- Equipe de Recherche sur les Relations Matrice Extracellulaire-Cellules, ERRMECe, (EA1391), Groupe Matrice Extracellulaire et Physiopathologie (MECuP), Institut des Matériaux, I-MAT (FD4122), CY Cergy Paris Université, Maison Internationale de la Recherche, Rue Descartes, Neuville sur Oise Cedex 95031, France
| | - Ayako Yamada
- PASTEUR, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, Paris 75005, France
| | - Marie-Claire Schanne-Klein
- Laboratoire d'Optique et Biosciences (LOB), École Polytechnique, CNRS, INSERM, Institut Polytechnique de Paris, Route de Saclay, Palaiseau Cedex 91128, France
| | - Yong Chen
- PASTEUR, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, Paris 75005, France
| | - Ambroise Lambert
- Equipe de Recherche sur les Relations Matrice Extracellulaire-Cellules, ERRMECe, (EA1391), Groupe Matrice Extracellulaire et Physiopathologie (MECuP), Institut des Matériaux, I-MAT (FD4122), CY Cergy Paris Université, Maison Internationale de la Recherche, Rue Descartes, Neuville sur Oise Cedex 95031, France
| | - Carole Aimé
- PASTEUR, Département de Chimie, École Normale Supérieure, PSL University, Sorbonne Université, CNRS, 24 rue Lhomond, Paris 75005, France
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16
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Kielbik M, Szulc-Kielbik I, Klink M. E-Cadherin Expression in Relation to Clinicopathological Parameters and Survival of Patients with Epithelial Ovarian Cancer. Int J Mol Sci 2022; 23:ijms232214383. [PMID: 36430858 PMCID: PMC9695266 DOI: 10.3390/ijms232214383] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 11/15/2022] [Accepted: 11/17/2022] [Indexed: 11/22/2022] Open
Abstract
It is generally accepted that loss/reduction of E-cadherin expression on tumor cells promotes their migration, invasiveness, and metastasis. It is also an indicator of cancer cells' aggressiveness. The aim of this study was to assess how the expression of E-cadherin varies in primary ovarian cancer tissue in regard to overall survival of patients; FIGO stage; grade; histopathological type of tumor; and potential factors discriminating malignant and nonmalignant ovarian tumors. Our analysis was based on literature research (1 January 2000-8 November 2021) conducted according to the PRISMA guidelines. Most studies support the assumption that loss/reduced expression of E-cadherin results in shorter overall survival of EOC patients. Moreover, most research has shown that there is a correlation between the low level of E-cadherin and the advancement stage of disease, especially in high-grade serous ovarian carcinoma type. However, E-cadherin expression seems to not be helpful to distinguish malignant and nonmalignant tumors. In conclusion, reduced E-cadherin expression in primary ovarian cancer tissue may indicate a less favorable disease outcome and is associated with high advancement of the disease.
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17
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Network topology metrics explaining enrichment of hybrid epithelial mesenchymal phenotypes in metastasis. PLoS Comput Biol 2022; 18:e1010687. [DOI: 10.1371/journal.pcbi.1010687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 11/18/2022] [Accepted: 10/26/2022] [Indexed: 11/10/2022] Open
Abstract
Epithelial to Mesenchymal Transition (EMT) and its reverse—Mesenchymal to Epithelial Transition (MET) are hallmarks of metastasis. Cancer cells use this reversible cellular programming to switch among Epithelial (E), Mesenchymal (M), and hybrid Epithelial/Mesenchymal (hybrid E/M) state(s) and seed tumors at distant sites. Hybrid E/M cells are often more aggressive and metastatic than the “pure” E and M cells. Thus, identifying mechanisms to inhibit hybrid E/M cells can be promising in curtailing metastasis. While multiple gene regulatory networks (GRNs) based mathematical models for EMT/MET have been developed recently, identifying topological signatures enriching hybrid E/M phenotypes remains to be done. Here, we investigate the dynamics of 13 different GRNs and report an interesting association between “hybridness” and the number of negative/positive feedback loops across the networks. While networks having more negative feedback loops favor hybrid phenotype(s), networks having more positive feedback loops (PFLs) or many HiLoops–specific combinations of PFLs, support terminal (E and M) phenotypes. We also establish a connection between “hybridness” and network-frustration by showing that hybrid phenotypes likely result from non-reinforcing interactions among network nodes (genes) and therefore tend to be more frustrated (less stable). Our analysis, thus, identifies network topology-based signatures that can give rise to, as well as prevent, the emergence of hybrid E/M phenotype in GRNs underlying EMP. Our results can have implications in terms of targeting specific interactions in GRNs as a potent way to restrict switching to the hybrid E/M phenotype(s) to curtail metastasis.
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18
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Marles H, Biddle A. Cancer stem cell plasticity and its implications in the development of new clinical approaches for oral squamous cell carcinoma. Biochem Pharmacol 2022; 204:115212. [PMID: 35985402 DOI: 10.1016/j.bcp.2022.115212] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/10/2022] [Accepted: 08/10/2022] [Indexed: 11/25/2022]
Abstract
Oral squamous cell carcinoma (SCC) represents a major worldwide disease burden, with high rates of recurrence and metastatic spread following existing treatment methods. Populations of treatment resistant cancer stem cells (CSCs) are well characterised in oral SCC. These populations of CSCs engage the cellular programme known as epithelial mesenchymal transition (EMT) to enhance metastatic spread and therapeutic resistance. EMT is characterised by specific morphological changes and the expression of certain cell surface markers that represent a transition from an epithelial phenotype to a mesenchymal phenotype. This process is regulated by several cellular pathways that interact both horizontally and hierarchically. The cellular changes in EMT occur along a spectrum, with sub-populations of cells displaying both epithelial and mesenchymal features. The unique features of these CSCs in terms of their EMT state, cell surface markers and metabolism may offer new druggable targets. In addition, these features could be used to identify more aggressive disease states and the opportunity to personalise therapy depending on the presence of certain CSC sub-populations.
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Affiliation(s)
- Henry Marles
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Adrian Biddle
- Centre for Cell Biology and Cutaneous Research, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.
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19
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Huang Y, Hong W, Wei X. The molecular mechanisms and therapeutic strategies of EMT in tumor progression and metastasis. J Hematol Oncol 2022; 15:129. [PMID: 36076302 PMCID: PMC9461252 DOI: 10.1186/s13045-022-01347-8] [Citation(s) in RCA: 435] [Impact Index Per Article: 145.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/30/2022] [Indexed: 11/10/2022] Open
Abstract
Epithelial–mesenchymal transition (EMT) is an essential process in normal embryonic development and tissue regeneration. However, aberrant reactivation of EMT is associated with malignant properties of tumor cells during cancer progression and metastasis, including promoted migration and invasiveness, increased tumor stemness, and enhanced resistance to chemotherapy and immunotherapy. EMT is tightly regulated by a complex network which is orchestrated with several intrinsic and extrinsic factors, including multiple transcription factors, post-translational control, epigenetic modifications, and noncoding RNA-mediated regulation. In this review, we described the molecular mechanisms, signaling pathways, and the stages of tumorigenesis involved in the EMT process and discussed the dynamic non-binary process of EMT and its role in tumor metastasis. Finally, we summarized the challenges of chemotherapy and immunotherapy in EMT and proposed strategies for tumor therapy targeting EMT.
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Affiliation(s)
- Yuhe Huang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Weiqi Hong
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
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20
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Shah HK, Banerjee BD, Thakur GK, Guleria K. Organochlorine pesticides induce epithelial as well as inflammatory mediators following exposure to human ovarian surface epithelial cells: An in vitro study. J Biochem Mol Toxicol 2022; 36:e23191. [PMID: 35946146 DOI: 10.1002/jbt.23191] [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: 09/29/2021] [Revised: 05/12/2022] [Accepted: 07/25/2022] [Indexed: 11/10/2022]
Abstract
Although studies have suggested organochlorine pesticides (OCPs) exposure increased the risk of epithelial ovarian cancer, the mechanisms underlying its potential tumorigenic effects in the human ovary are not well understood. In this study, we investigated the impact of dichlorodiphenyldichloroethylene (DDE), endosulfan, and heptachlor exposure on epithelial cadherin (E-cadherin) and proinflammatory mediators in human ovary surface epithelial (HOSE) cells. We found that DDE, endosulfan, and heptachlor exposure resulted in epithelial differentiation accompanied by upregulation of E-cadherin expression and overexpression of proinflammatory cytokines (TNFα, IL-1β, and IL-6) in HOSE cells. The epithelial differentiation may accelerate HOSE cells to inclusion body formation, a common site for ovarian cancer initiation and persistent exposure to OCPs creates a chronic inflammatory microenvironment that may promote the neoplastic transformation of HOSE cells within the inclusion cyst.
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Affiliation(s)
- Harendra K Shah
- Department of Biochemistry, Environmental Biochemistry and Molecular Biology Laboratory, University College of Medical Sciences and G.T.B. Hospital (University of Delhi), Delhi, India
| | - Basu D Banerjee
- Department of Biochemistry, Environmental Biochemistry and Molecular Biology Laboratory, University College of Medical Sciences and G.T.B. Hospital (University of Delhi), Delhi, India
| | - Gaurav K Thakur
- Department of Biochemistry, Environmental Biochemistry and Molecular Biology Laboratory, University College of Medical Sciences and G.T.B. Hospital (University of Delhi), Delhi, India
| | - Kiran Guleria
- Department of Obstetrics and Gynecology, University College of Medical Sciences and G.T.B. Hospital (University of Delhi), Delhi, India
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21
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Role of CD44 isoforms in epithelial-mesenchymal plasticity and metastasis. Clin Exp Metastasis 2022; 39:391-406. [PMID: 35023031 PMCID: PMC10042269 DOI: 10.1007/s10585-022-10146-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 01/03/2022] [Indexed: 01/21/2023]
Abstract
Cellular plasticity lies at the core of cancer progression, metastasis, and resistance to treatment. Stemness and epithelial-mesenchymal plasticity in cancer are concepts that represent a cancer cell's ability to coopt and adapt normal developmental programs to promote survival and expansion. The cancer stem cell model states that a small subset of cancer cells with stem cell-like properties are responsible for driving tumorigenesis and metastasis while remaining especially resistant to common chemotherapeutic drugs. Epithelial-mesenchymal plasticity describes a cancer cell's ability to transition between epithelial and mesenchymal phenotypes which drives invasion and metastasis. Recent research supports the existence of stable epithelial/mesenchymal hybrid phenotypes which represent highly plastic states with cancer stem cell characteristics. The cell adhesion molecule CD44 is a widely accepted marker for cancer stem cells, and it lies at a functional intersection between signaling networks regulating both stemness and epithelial-mesenchymal plasticity. CD44 expression is complex, with alternative splicing producing many isoforms. Interestingly, not only does the pattern of isoform expression change during transitions between epithelial and mesenchymal phenotypes in cancer, but these isoforms have distinct effects on cell behavior including the promotion of metastasis and stemness. The role of CD44 both downstream and upstream of signaling pathways regulating epithelial-mesenchymal plasticity and stemness make this protein a valuable target for further research and therapeutic intervention.
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22
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Generation of Cancer Stem/Initiating Cells by Cell-Cell Fusion. Int J Mol Sci 2022; 23:ijms23094514. [PMID: 35562905 PMCID: PMC9101717 DOI: 10.3390/ijms23094514] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/10/2022] [Accepted: 04/17/2022] [Indexed: 02/04/2023] Open
Abstract
CS/ICs have raised great expectations in cancer research and therapy, as eradication of this key cancer cell type is expected to lead to a complete cure. Unfortunately, the biology of CS/ICs is rather complex, since no common CS/IC marker has yet been identified. Certain surface markers or ALDH1 expression can be used for detection, but some studies indicated that cancer cells exhibit a certain plasticity, so CS/ICs can also arise from non-CS/ICs. Another problem is intratumoral heterogeneity, from which it can be inferred that different CS/IC subclones must be present in the tumor. Cell–cell fusion between cancer cells and normal cells, such as macrophages and stem cells, has been associated with the generation of tumor hybrids that can exhibit novel properties, such as an enhanced metastatic capacity and even CS/IC properties. Moreover, cell–cell fusion is a complex process in which parental chromosomes are mixed and randomly distributed among daughter cells, resulting in multiple, unique tumor hybrids. These, if they have CS/IC properties, may contribute to the heterogeneity of the CS/IC pool. In this review, we will discuss whether cell–cell fusion could also lead to the origin of different CS/ICs that may expand the overall CS/IC pool in a primary tumor.
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23
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Harryman WL, Marr KD, Nagle RB, Cress AE. Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers. Front Cell Dev Biol 2022; 10:837585. [PMID: 35300411 PMCID: PMC8921537 DOI: 10.3389/fcell.2022.837585] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 02/04/2022] [Indexed: 11/18/2022] Open
Abstract
Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.
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Affiliation(s)
- William L Harryman
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States
| | - Kendra D Marr
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, United States.,Medical Scientist Training Program, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Ray B Nagle
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Department of Pathology, College of Medicine, University of Arizona, Tucson, AZ, United States
| | - Anne E Cress
- Cancer Biology Graduate Interdisciplinary Program, University of Arizona Cancer Center, Tucson, AZ, United States.,Department of Cellular and Molecular Medicine and Department of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ, United States
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24
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Chu X, Wang J. Deciphering the molecular mechanism of the cancer formation by chromosome structural dynamics. PLoS Comput Biol 2021; 17:e1009596. [PMID: 34752443 PMCID: PMC8631624 DOI: 10.1371/journal.pcbi.1009596] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 11/30/2021] [Accepted: 10/28/2021] [Indexed: 12/15/2022] Open
Abstract
Cancer reflects the dysregulation of the underlying gene network, which is strongly related to the 3D genome organization. Numerous efforts have been spent on experimental characterizations of the structural alterations in cancer genomes. However, there is still a lack of genomic structural-level understanding of the temporal dynamics for cancer initiation and progression. Here, we use a landscape-switching model to investigate the chromosome structural transition during the cancerization and reversion processes. We find that the chromosome undergoes a non-monotonic structural shape-changing pathway with initial expansion followed by compaction during both of these processes. Furthermore, our analysis reveals that the chromosome with a more expanding structure than those at both the normal and cancer cell during cancerization exhibits a sparse contact pattern, which shows significant structural similarity to the one at the embryonic stem cell in many aspects, including the trend of contact probability declining with the genomic distance, the global structural shape geometry and the spatial distribution of loci on the chromosome. In light of the intimate structure-function relationship at the chromosomal level, we further describe the cell state transition processes by the chromosome structural changes, suggesting an elevated cell stemness during the formation of the cancer cells. We show that cell cancerization and reversion are highly irreversible processes in terms of the chromosome structural transition pathways, spatial repositioning of chromosomal loci and hysteresis loop of contact evolution analysis. Our model draws a molecular-scale picture of cell cancerization from the chromosome structural perspective. The process contains initial reprogramming towards the stem cell followed by the differentiation towards the cancer cell, accompanied by an initial increase and subsequent decrease of the cell stemness.
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Affiliation(s)
- Xiakun Chu
- Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York, United States of America
| | - Jin Wang
- Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York, United States of America
- Department of Physics and Astronomy, State University of New York at Stony Brook, Stony Brook, New York, United States of America
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25
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Wu F, Wu B, Zhang X, Yang C, Zhou C, Ren S, Wang J, Yang Y, Wang G. Screening of MicroRNA Related to Irradiation Response and the Regulation Mechanism of miRNA-96-5p in Rectal Cancer Cells. Front Oncol 2021; 11:699475. [PMID: 34458143 PMCID: PMC8386172 DOI: 10.3389/fonc.2021.699475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 07/13/2021] [Indexed: 01/03/2023] Open
Abstract
Neoadjuvant chemoradiotherapy has been widely used in the treatment of locally advanced rectal cancer due to the excellent advantages of irradiation in cancer therapy. Unfortunately, not every patient can benefit from this treatment, therefore, it is of great significance to explore biomarkers that can predict irradiation sensitivity. In this study, we screened microRNAs (miRNAs) which were positively correlated with irradiation resistance and found that miRNA-552 and miRNA-183 families were positively correlated with the irradiation resistance of rectal cancer, and found that high expression of miRNA-96-5p enhanced the irradiation resistance of rectal cancer cells through direct regulation of the GPC3 gene and abnormal activation of the canonical Wnt signal transduction pathway. Based on the radioreactivity results of patient-derived xenograft models, this is the first screening report for radio-resistant biomarkers in rectal cancer. Our results suggest that miRNA-96-5p expression is an important factor affecting the radiation response of colorectal cancer cells.
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Affiliation(s)
- Fengpeng Wu
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Bingyue Wu
- Department of Oncology, Hebei Provincial People's Hospital, Graduate School of Hebei Medical University, Shijiazhuang, China
| | - Xiaoxiao Zhang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Congrong Yang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Chaoxi Zhou
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Shuguang Ren
- Laboratory Animal Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Wang
- Department of Radiation Oncology, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Yafan Yang
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Guiying Wang
- Department of General Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Department of General Surgery, Third Hospital of Hebei Medical University, Shijiazhuang, China
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26
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Hansen MB, Postol M, Tvingsholm S, Nielsen IØ, Dietrich TN, Puustinen P, Maeda K, Dinant C, Strauss R, Egan D, Jäättelä M, Kallunki T. Identification of lysosome-targeting drugs with anti-inflammatory activity as potential invasion inhibitors of treatment resistant HER2 positive cancers. Cell Oncol (Dordr) 2021; 44:805-820. [PMID: 33939112 PMCID: PMC8090911 DOI: 10.1007/s13402-021-00603-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/10/2021] [Indexed: 10/26/2022] Open
Abstract
PURPOSE Most HER2 positive invasive cancers are either intrinsic non-responsive or develop resistance when treated with 1st line HER2 targeting drugs. Both 1st and 2nd line treatments of HER2 positive cancers are aimed at targeting the HER2 receptor directly, thereby strongly limiting the treatment options of HER2/ErbB2 inhibition resistant invasive cancers. METHODS We used phenotypic high throughput microscopy screening to identify efficient inhibitors of ErbB2-induced invasion using 1st line HER2 inhibitor trastuzumab- and pertuzumab-resistant, p95-ErbB2 expressing breast cancer cells in conjunction with the Prestwick Chemical Library®. The screening entailed a drug's ability to inhibit ErbB2-induced, invasion-promoting positioning of lysosomes at the cellular periphery, a phenotype that defines their invasiveness. In addition, we used high throughput microscopy and biochemical assays to assess the effects of the drugs on lysosomal membrane permeabilization (LMP) and autophagy, two features connected to cancer treatment. Using 2nd line HER2 inhibitor lapatinib resistant 3-dimensional model systems, we assessed the effects of the drugs on ErbB2 positive breast cancer spheroids and developed a high-throughput invasion assay for HER2 positive ovarian cancer organoids for further evaluation. RESULTS We identified Auranofin, Colchicine, Monensin, Niclosamide, Podophyllotoxin, Quinacrine and Thiostrepton as efficient inhibitors of invasive growth of 2nd line HER2 inhibitor lapatinib resistant breast cancer spheroids and ovarian cancer organoids. We classified these drugs into four groups based on their ability to target lysosomes by inducing autophagy and/or LMP, i.e., drugs inducing early LMP, early autophagy with late LMP, late LMP, or neither. CONCLUSIONS Our results indicate that targetable lysosome-engaging cellular pathways downstream of ErbB2 contribute to invasion. They support lysosomal trafficking as an attractive target for therapy aiming at preventing the spreading of cancer cells. Since these drugs additionally possess anti-inflammatory activities, they could serve as multipurpose drugs simultaneously targeting infection/inflammation and cancer spreading.
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Affiliation(s)
- Malene Bredahl Hansen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Maria Postol
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Siri Tvingsholm
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Inger Ødum Nielsen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Tiina Naumanen Dietrich
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Pietri Puustinen
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Kenji Maeda
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Christoffel Dinant
- Genome Integrity Group, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
- Core Facility for Bioimaging, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - Robert Strauss
- Genome Integrity Group, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
| | - David Egan
- Department of Cell Biology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands
- Core Life Analytics, Padualaan, 83584 CH, Utrecht, The Netherlands
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark
| | - Tuula Kallunki
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Strandboulevarden 49, 2100, Copenhagen, Denmark.
- Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.
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27
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Partial EMT in head and neck cancer biology: a spectrum instead of a switch. Oncogene 2021; 40:5049-5065. [PMID: 34239045 PMCID: PMC8934590 DOI: 10.1038/s41388-021-01868-5] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 05/03/2021] [Accepted: 05/25/2021] [Indexed: 12/14/2022]
Abstract
Our understanding of epithelial-to-mesenchymal transition (EMT) has slowly evolved from a simple two state, binary model to a multi-step, dynamic continuum of epithelial-to-mesenchymal plasticity, with metastable intermediate transition states that may drive cancer metastasis. Head and neck cancer is no exception, and in this review, we use head and neck as a case study for how partial-EMT (p-EMT) cell states may play an important role in cancer progression. In particular, we summarize recent in vitro and in vivo studies that uncover these intermediate transition states, which exhibit both epithelial and mesenchymal properties and appear to have distinct advantages in migration, survival in the bloodstream, and seeding and propagation within secondary metastatic sites. We then summarize the common and distinct regulators of p-EMT as well as methodologies for identifying this unique cellular subpopulation, with a specific emphasis on the role of cutting-edge technologies, such as single cell approaches. Finally, we propose strategies to target p-EMT cells, highlighting potential opportunities for therapeutic intervention to specifically target the process of metastasis. Thus, although significant challenges remain, including numerous gaps in current knowledge, a deeper understanding of EMT plasticity and a genuine identification of EMT as spectrum rather than a switch will be critical for improving patient diagnosis and treatment across oncology.
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28
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Wesley T, Berzins S, Kannourakis G, Ahmed N. The attributes of plakins in cancer and disease: perspectives on ovarian cancer progression, chemoresistance and recurrence. Cell Commun Signal 2021; 19:55. [PMID: 34001250 PMCID: PMC8127266 DOI: 10.1186/s12964-021-00726-x] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 02/20/2021] [Indexed: 02/06/2023] Open
Abstract
The plakin family of cytoskeletal proteins play an important role in cancer progression yet are under-studied in cancer, especially ovarian cancer. These large cytoskeletal proteins have primary roles in the maintenance of cytoskeletal integrity but are also associated with scaffolds of intermediate filaments and hemidesmosomal adhesion complexes mediating signalling pathways that regulate cellular growth, migration, invasion and differentiation as well as stress response. Abnormalities of plakins, and the closely related spectraplakins, result in diseases of the skin, striated muscle and nervous tissue. Their prevalence in epithelial cells suggests that plakins may play a role in epithelial ovarian cancer progression and recurrence. In this review article, we explore the roles of plakins, particularly plectin, periplakin and envoplakin in disease-states and cancers with emphasis on ovarian cancer. We discuss the potential role the plakin family of proteins play in regulating cancer cell growth, survival, migration, invasion and drug resistance. We highlight potential relationships between plakins, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) and discuss how interaction of these processes may affect ovarian cancer progression, chemoresistance and ultimately recurrence. We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease. In this review, attempts have been made to understand the crucial changes in plakin expression in relation to progression and recurrence of ovarian cancer.
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