Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer (original) (raw)
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Expression profiling of epithelial plasticity in tumor progression
Oncogene, 2003
Epithelial-to-mesenchymal transition (EMT), a switch of polarized epithelial cells to a migratory, fibroblastoid phenotype, is increasingly considered as an important event during malignant tumor progression and metastasis. To identify molecular players involved in EMT and metastasis, we performed expression profiling of a set of combined in vitro/in vivo cellular models, based on clonal, fully polarized mammary epithelial cells. Seven closely related cell pairs were used, which were modified by defined oncogenes and/or external factors and showed specific aspects of epithelial plasticity relevant to cell migration, local invasion and metastasis. Since mRNA levels do not necessarily reflect protein levels in cells, we used an improved expression profiling method based on polysome-bound RNA, suitable to analyse global gene expression on Affymetrix chips. A substantial fraction of all regulated genes was found to be exclusively controlled at the translational level. Furthermore, profiling of the above multiple cell pairs allowed one to identify small numbers of genes by cluster analysis, specifically correlating gene expression with EMT, metastasis, scattering and/or oncogene function. A small set of genes specifically regulated during EMT was identified, including key regulators and signaling pathways involved in cell proliferation, epithelial polarity, survival and transdifferentiation to mesenchymal-like cells with invasive behavior.
Mutation Research/Reviews in Mutation Research, 2004
Carcinomas arising from epithelial cells represent the most prevalent malignancies in humans, and metastasis is the major cause for the death of carcinoma patients. The breakdown of epithelial cell homeostasis leading to aggressive cancer progression has been correlated with the loss of epithelial characteristics and the acquisition of a migratory phenotype. This phenomenon, referred to as epithelial to mesenchymal transition (EMT), is considered as a crucial event in late stage tumorigenesis. Here we summarize the multitude of EMT models derived from different tissues, and review the diversity of molecular mechanisms contributing to the plasticity of epithelial cells. In particular, the synergism between activation of Ras, provided by the aberrant stimulation of receptor tyrosine kinases, and transforming growth factor (TGF)- signaling plays a pivotal role in inducing EMT of various epithelial cell types. Cytokines such as TGF- and extracellular matrix molecules are thought to fundamentally contribute to the microenvironmental interaction between stromal and malignant cells, and provide the basis for a broad repertoire of epithelial differentiation. Investigations of EMT tumor models, which represent in vitro correlates to local invasion and metastasis in vivo, facilitate the identification of diagnostic markers for a more accurate and faithful clinical and pathological assessment of epithelial tumors. In addition, the analysis of molecular mechanisms involved in EMT might yield novel therapeutic targets for the specific treatment of aggressive carcinomas.
PloS one, 2011
In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherin(low)/cytoplasmic E-cadherin(high)/CD133(high), CD44(high), Tie2(low)) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is a...
Epithelial–mesenchymal transition in ovarian cancer
Cancer Letters, 2010
Ovarian cancer is a highly metastatic disease and the leading cause of death from gynecologic malignancy. Hence, and understanding of the molecular changes associated with ovarian cancer metastasis could lead to the identification of targets for novel therapeutic interventions.
Neoplasia, 2013
Epithelial-to-mesenchymal transition (EMT) facilitates the escape of epithelial cancer cells from the primary tumor site, which is a key event early in metastasis. Here, we explore how extrinsic, tumor microenvironmental cytokines cooperate with intrinsic, genetic changes to promote EMT in human mammary epithelial cells (HMECs). Viral transduction of transforming genetic events into HMECs routinely generated two distinct cell populations. One population retained epithelial characteristics, while an emergent population spontaneously acquired a mesenchymal morphology and properties associated with cancer stem cells (CSCs). Interestingly, the spontaneous mesenchymal/ CSCs were unable to differentiate and lacked epithelial-mesenchymal plasticity. In contrast, exposure of the transformed HMECs retaining epithelial characteristics to exogenous transforming growth factor-β (TGF-β) generated a mesenchymal/CSC population with remarkable plasticity. The TGF-β-induced mesenchymal/CSC population was dependent on the continued presence of TGF-β. Removal of TGF-β or pharmacologic or genetic inhibition of TGF-β/ SMAD signaling led to the reversion of mesenchymal/CSC to epithelial/non-CSC. Our results demonstrate that targeting exogenous cytokine signaling disrupts epithelial-mesenchymal plasticity and may be an effective strategy to inhibit the emergence of circulating tumor cells. The model of epithelial-mesenchymal plasticity we describe here can be used to identify novel tumor microenvironmental factors and downstream signaling that cooperate with intrinsic genetic changes to drive metastasis. Understanding the interaction between extrinsic and intrinsic factors that regulate epithelial-mesenchymal plasticity will allow the development of new therapies that target tumor microenvironmental signals to reduce metastasis.
Frontiers in Oncology, 2021
Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs via a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but a...
Cancers
Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effect...
The Epithelial-Mesenchymal Transition and the Estrogen-Signaling in Ovarian Cancer
Current Drug Targets, 2010
Epithelial ovarian cancer is the leading cause of death for gynecological cancer in most of the Western world; lethality ensues from the occurrence of occult metastasis within the peritoneal cavity, a process requiring the acquisition of capacity for migration and invasiveness by ovarian tumor cells (metastatic phenotype), and characterized by a complex series of interrelated cellular events. Unlike most carcinomas that dedifferentiate during neoplastic progression with loss of epithelial E-cadherin (epithelial to mesenchymal transition, EMT), ovarian carcinomas undergo transition to a more epithelial phenotype, early in tumor progression, with increased E-cadherin expression. Subsequent reacquisition of mesenchymal features is observed in late-stage tumors, and loss of E-cadherin expression or function is a factor in ovarian cancer progression. Changes in E-cadherin expression are indicative of the phenotypic plasticity that occurs in ovarian cancer, with a variety of signal transduction pathways impinging on the regulation of E-cadherin levels or subcellular distribution. Among them, the Snail transcription family, consisting of members SNAIL and SLUG, is thought to be mainly involved in the repression of E-cadherin expression, leading to EMT. E-cadherin, SNAIL, and SLUG also represent crucial targets of estrogen signaling. In this review, we discuss recent advances in the understanding of the role of estrogen signaling in the complex network underlying the phenotypic plasticity in ovarian cancer. Insight into the mechanisms involved will allow rational drug designs, aimed at the molecules critical to cellular signaling.
2020
High Grade Serous Ovarian Cancer (HGSOC) is one of the deadliest gynecological diseases in the United States ranking fifth in cancer deaths among women. Approximately 22 thousand new cases are expected to occur in the year 2020, and unfortunately, it is estimated that 14 thousand women will succumb to the disease; the incidence to death ratio, 64%, remains high despite current research. Current treatment includes debulking surgery followed by combinatorial chemotherapeutics with platinum-based and taxol-based compounds. But despite aggressive surgery and standard-of-care chemotherapeutics, 80% of patients will experience a recurrence and only 15-30% of those with recurring disease will respond to further treatment. Tumors consist of a heterogeneous population of cell types. A small minority of tumor cells, called cancer stem cells (CSCs), can self-renew and differentiate and are thought to be responsible for recurrent, chemoresistant disease. A cancer cell's ability to migrate and invade other tissues is a hallmark of metastatic disease. To invade, cells must undergo a process called an epithelial-mesenchymal transition (EMT) in which epithelial genes such as CDH1, which codes for E-Cadherin (E-CAD), a cell-cell adhesion molecule, are repressed by the transcription factor SNAI1 (Snail) and genes associated with a mesenchymal phenotype, such as CDH2, which codes for N-Cadherin (N-CAD) are upregulated. This switch from epithelial to mesenchymal gene expression leads vi ACKNOWLEDGEMENTS I would like to extend my gratitude to Dr. Juli Unternaehrer who, so graciously, allowed me to perform this research in her lab as well as provide me continual guidance and support throughout this process. A special thank you to Evgeny Chirshev from Dr. Unternaehrer's lab whose hard work and dedication contributed to my thesis. In addition, I would like to thank the other members of Dr. Unternaehrer's lab, Antonella Bertucci, Nozomi Hojo, Alyse Hill & Hanmin Wang, who were always available for guidance and support. Furthermore, to Dr. Nicole Bournias-Vardiabasis and Dr. Daniel Nickerson, thank you for taking the time to serve on my thesis committee. I would also like to thank CIRM Bridges program,