Microenvironmental Regulation of Ovarian Cancer Metastasis (original) (raw)
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Journal of Ovarian Research, 2013
Background: While metastasis ranks among the most lethal of all cancer-associated processes, on the molecular level, it remains one of the least well understood. One model that has gained credibility in recent years is that metastasizing cells at least partially recapitulate the developmental process of epithelial-to-mesenchymal transition (EMT) in their transit from primary to metastatic sites. While experimentally supported by cell culture and animal model studies, the lack of unambiguous confirmatory evidence in cancer patients has led to persistent challenges to the model's relevance in humans. Methods: Gene expression profiling (Affymetrix, U133) was carried out on 14 matched sets of primary (ovary) and metastatic (omentum) ovarian cancer (serous adenocarcinoma) patient samples. Hierarchical clustering and functional pathway algorithms were used in the data analysis. Results: While histological examination reveled no morphological distinction between the matched sets of primary and metastatic samples, gene expression profiling clearly distinguished two classes of metastatic samples. One class displayed expression patterns statistically indistinguishable from primary samples isolated from the same patients while a second class displayed expression patterns significantly different from primary samples. Further analyses focusing on genes previously associated with EMT clearly distinguished the primary from metastatic samples in all but one patient. Conclusion: Our results are consistent with a role of EMT in most if not all ovarian cancer metastases and demonstrate that identical morphologies between primary and metastatic cancer samples is insufficient evidence to negate a role of EMT in the metastatic process.
Role of tumor microenvironment in ovarian cancer pathobiology
Oncotarget, 2018
Ovarian cancer is the fifth most common cancer affecting the female population and at present, stands as the most lethal gynecologic malignancy. Poor prognosis and low five-year survival rate are attributed to nonspecific symptoms and below par diagnostic criteria at early phases along with a lack of effective treatment at advanced stages. It is thus of utmost importance to understand ovarian carcinoma through several lenses including its molecular pathogenesis, epidemiology, histological subtypes, hereditary factors, diagnostic approaches and methods of treatment. Above all, it is crucial to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several important aspects of ovarian cancer pathobiology as a means to provide the necessary background to approach ovarian malignancies in the future.
Productive Cross-Talk with the Microenvironment: A Critical Step in Ovarian Cancer Metastasis
Cancers
Most ovarian cancer patients present with disseminated disease at the time of their diagnosis, which is one of the main reasons for their poor prognosis. Metastasis is a multi-step process and a clear understanding of the mechanism of regulation of these steps remains elusive. Productive reciprocal interactions between the metastasizing ovarian cancer cells and the microenvironment of the metastatic site or the tumor microenvironment play an important role in the successful establishment of metastasis. Much progress has been made in the recent past in our understanding of such interactions and the role of the cellular and acellular components of the microenvironment in establishing the metastatic tumors. This review will outline the role of the microenvironmental components of the ovarian cancer metastatic niche and their role in helping establish the metastatic tumors. Special emphasis will be given to the mesothelial cells, which are the first cells encountered by the cancer cells...
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.
Cancer medicine, 2018
Ovarian cancer is the fifth most common cancer affecting women and at present, stands as the most lethal gynecologic malignancy. The poor disease outcome is due to the nonspecific symptoms and the lack of effective treatment at advanced stages. Thus, it is of utmost importance to understand ovarian carcinoma through several lenses and to dissect the role that the unique peritoneal tumor microenvironment plays in ovarian cancer progression and metastasis. This review seeks to highlight several determinants of this unique tumor microenvironment, their influence on disease outcome and ongoing clinical trials targeting these determinants.
Journal of Cellular Physiology, 2007
Cancer that arises from the ovarian surface epithelium (OSE) accounts for approximately 90% of human ovarian cancer, and is the fourth leading cause of cancer-related deaths among women in developed countries. The pathophysiology of epithelial ovarian cancer is still unclear because of the poor understanding of the complex nature of its development and the unusual mechanism(s) of disease progression. Recent studies have reported epithelial-mesenchymal transition (EMT) in cultured OSE and ovarian cancer cell lines in response to various stimuli, but our understanding of the importance of these observations for normal ovarian physiology and cancer progression is not well established. This review highlights the current literature on EMT-associated events in normal OSE and ovarian cancer cell lines, and discusses its implication for normal ovarian function as well as acquisition of neoplastic phenotypes. The pathological changes in OSE in response to EMT during neoplastic transformation and the contribution of hormones, growth factors, and cytokines that initiate and drive EMT to sustain normal ovarian function, as well as cancer development and progression are also discussed. Finally, emphasis is placed on the clinical implications of EMT and potential therapeutic opportunities that may arise from these observations have been proposed.
Current insights into the metastasis of epithelial ovarian cancer - hopes and hurdles
Cellular Oncology, 2020
Background Ovarian cancer is the most lethal gynecologic cancer and the fifth leading cause of cancer-related mortality in women worldwide. Despite various attempts to improve the diagnosis and therapy of ovarian cancer patients, the survival rate for these patients is still dismal, mainly because most of them are diagnosed at a late stage. Up to 90% of ovarian cancers arise from neoplastic transformation of ovarian surface epithelial cells, and are usually referred to as epithelial ovarian cancer (EOC). Unlike most human cancers, which are disseminated through blood-borne metastatic routes, EOC has traditionally been thought to be disseminated through direct migration of ovarian tumor cells to the peritoneal cavity and omentum via peritoneal fluid. It has recently been shown, however, that EOC can also be disseminated through blood-borne metastatic routes, challenging previous thoughts about ovarian cancer metastasis. Conclusions Here, we review our current understanding of the most updated cellular and molecular mechanisms underlying EOC metastasis and discuss in more detail two main metastatic routes of EOC, i.e., transcoelomic metastasis and hematogenous metastasis. The emerging concept of blood-borne EOC metastasis has led to exploration of the significance of circulating tumor cells (CTCs) as novel and non-invasive prognostic markers in this daunting cancer. We also evaluate the role of tumor stroma, including cancer associated fibroblasts (CAFs), tumor associated macrophages (TAMs), endothelial cells, adipocytes, dendritic cells and extracellular matrix (ECM) components in EOC growth and metastasis. Lastly, we discuss therapeutic approaches for targeting EOC. Unraveling the mechanisms underlying EOC metastasis will open up avenues to the design of new therapeutic options. For instance, understanding the molecular mechanisms involved in the hematogenous metastasis of EOC, the biology of CTCs, and the detailed mechanisms through which EOC cells take advantage of stromal cells may help to find new opportunities for targeting EOC metastasis.
Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression
Cancers
Ovarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. Recent findings have revealed that the tumor microenvironment plays an essential role in promoting cancer progression and metastasis. The tumor microenvironment consists of cancer cells and several different types of normal cells recruited and reprogrammed by the cancer cells to produce factors beneficial to tumor growth and spread. These normal cells present within the tumor, along with the various extracellular matrix proteins and secreted factors, constitute the tumor stroma and can compose 10–60% of the tumor volume. Cancer associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, and play a critical role in promoting many aspects of tumor function. This revie...
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...
Epithelial ovarian cancer experimental models
Oncogene, 2014
Epithelial ovarian cancer (OvCa) is associated with high mortality and, as the majority (>75%) of women with OvCa have metastatic disease at the time of diagnosis, rates of survival have not changed appreciably over 30 years. A mechanistic understanding of OvCa initiation and progression is hindered by the complexity of genetic and/or environmental initiating events and lack of clarity regarding the cell(s) or tissue(s) of origin. Metastasis of OvCa involves direct extension or exfoliation of cells and cellular aggregates into the peritoneal cavity, survival of matrix-detached cells in a complex ascites fluid phase, and subsequent adhesion to the mesothelium lining covering abdominal organs to establish secondary lesions containing host stromal and inflammatory components. Development of experimental models to recapitulate this unique mechanism of metastasis presents a remarkable scientific challenge and many approaches used to study other solid tumors (lung, colon, and breast, for example) are not transferable to OvCa research given the distinct metastasis pattern and unique tumor microenvironment. This review will discuss recent progress in the development and refinement of experimental models to study OvCa. Novel cellular, three-dimensional organotypic, and ex vivo models are considered and the current in vivo models summarized. The review critically evaluates currently available genetic mouse models of OvCa, the emergence of xenopatients, and the utility of the hen model to study OvCa prevention, tumorigenesis, metastasis, and chemoresistance. As these new approaches more accurately recapitulate the complex tumor microenvironment, it is predicted that new opportunities for enhanced understanding of disease progression, metastasis and therapeutic response will emerge.