Kumamoto University, Japan
Takeshi Motohara is Assistant Professor in Department of Obstetrics and Gynecology, Kumamoto University, Japan. He is now engaged in research on molecular biology of ovarian cancer in Ovarian Cancer Cell Laboratory, Weatherall Institute of Molecular Medicine, Nuffield Department of Obstetrics and Gynaecology, University of Oxford as a Visiting Postdoctoral Research Scientist. He is distinguished gynecologic oncologist in Japan. His research is focused on understanding the molecular mechanisms of evolution of ovarian cancer, especially cancer stem cell, and on the development of novel therapeutic strategies for ovarian cancer.
The cancer stem cell hypothesis considers cancer stem cells as the main culprits of driving tumor initiation, metastasis, and resistance to conventional chemotherapy. Several previous studies have supported the premise that EpCAM proves to be a useful marker for the isolation of subsets enriched for cancer stem cells in many solid cancers, including ovarian cancer. We investigated the role of EpCAM in the resistance to platinum-based chemotherapy and the potential relevance of EpCAM to the clinical outcomes of patients with epithelial ovarian cancer. Here, we have showed that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line platinum-based chemotherapy. Furthermore, multivariate analysis demonstrated that EpCAM expression in primary tumors is an independent risk factor for tumor resistance to chemotherapy, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in in vitro assays, we also found that treatment with chemotherapeutic agents enhances the cell surface expression of EpCAM in ovarian cancer cells. In association with anti-apoptotic mechanisms, the subpopulation of EpCAM-positive cancer cells showed a significantly higher viability than EpCAM-negative cells in response to chemotherapy. In an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, indicating that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we revealed that an increased expression of EpCAM in primary tumors was involved in a shortened overall- and progression-free survival in ovarian cancer patients. Our findings highlight the clinical significance of EpCAM in the resistance to chemotherapy and provide a rationale for EpCAM-targeted therapy to improve chemoresistance in ovarian cancer patients. Targeting EpCAM should be a promising approach to effectively eradicate the cancer stem cells as the putative root of ovarian cancer.