Abstract
Epithelial ovarian cancer is a highly lethal gynecological malignancy that is characterized by the early development of disseminated metastasis. Though ovarian cancer has been generally considered to preferentially metastasize via direct transcoelomic dissemination instead of the hematogenous route, emerging evidence has indicated that the hematogenous spread of cancer cells plays a larger role in ovarian cancer metastasis than previously thought. Considering the distinctive biology of ovarian cancer, an in-depth understanding of the biological and molecular mechanisms that drive metastasis is critical for developing effective therapeutic strategies against this fatal disease. The recent “cancer stem cell theory” postulates that cancer stem cells are principally responsible for tumor initiation, metastasis, and chemotherapy resistance. Even though the hallmarks of ovarian cancer stem cells have not yet been completely elucidated, metastasized ovarian cancer cells, which have a high degree of chemoresistance, seem to manifest cancer stem cell properties and play a key role during relapse at metastatic sites. Herein, we review our current understanding of the cell-biological mechanisms that regulate ovarian cancer metastasis and chemotherapy resistance, with a pivotal focus on ovarian cancer stem cells, and discuss the potential clinical implications of evolving cancer stem cell research and resultant novel therapeutic approaches.
Highlights
Epithelial ovarian cancer is the most lethal cause of death among gynecological malignancies and is characterized by an early metastatic spread throughout the peritoneal cavity, along with extensive disseminated tumors, omental caking, and accumulation of malignant ascites [1,2]
Though most patients with the advanced stage of the disease may respond to a combination of taxane and platinum-based chemotherapy, chemoresistant residual cancer cells can persist in metastatic sites, where they remain dormant for prolonged periods after initial therapy and eventually lead to a relapse [6,7,8]
Consistent with clinical data, we found that a subpopulation of epithelial cell adhesion molecule (EpCAM)-positive cancer cells manifests significantly a higher viability after cisplatin treatment by preventing chemotherapy induced-apoptosis, which is regulated by the EpCAM-Bcl-2 signaling axis, in in vitro assays
Summary
Epithelial ovarian cancer is the most lethal cause of death among gynecological malignancies and is characterized by an early metastatic spread throughout the peritoneal cavity, along with extensive disseminated tumors, omental caking, and accumulation of malignant ascites [1,2]. With respect to the differentiation capacity of EpCAM-positive cancer cells, we showed that these cells can give rise to less tumorigenic EpCAM-negative cancer cells, attesting to the multi-lineage differentiation potential of these cells [36] Taken together, it appears that there are currently a significant number of markers that can be used to isolate a specific ovarian cancer stem cell population; these markers have not proven to be ubiquitously expressed in a given tumor, and it remains challenging to identify bona fide ovarian cancer stem cells. Multi-differentiation, sphere formation, chemoresistance, prevention of chemotherapy induced-apoptosis [27,36,45,48]
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