The impact of EpCAM expression on response to chemotherapy and clinical outcomes in patients with epithelial ovarian cancer

Autor: Osamu Nagano, Isao Sakaguchi, Hironori Tashiro, Koichi Fujimoto, Chenyan Li, Hidetaka Katabuchi, Takeshi Motohara, Hideyuki Saya, Dashdemberel Narantuya, Shingo Tayama
Rok vydání: 2017
Předmět:
0301 basic medicine
medicine.medical_treatment
Gene Expression
Apoptosis
Tumor initiation
Carcinoma
Ovarian Epithelial
Metastasis
Mice
0302 clinical medicine
Risk Factors
Antineoplastic Combined Chemotherapy Protocols
Odds Ratio
Neoplasms
Glandular and Epithelial
Aged
80 and over
Ovarian Neoplasms
chemoresistance
Middle Aged
Epithelial Cell Adhesion Molecule
Prognosis
Treatment Outcome
ovarian cancer
Oncology
030220 oncology & carcinogenesis
Retreatment
Female
Research Paper
medicine.drug
Adult
cancer stem cell
Malignancy
Young Adult
03 medical and health sciences
Cancer stem cell
Biomarkers
Tumor
medicine
Animals
Humans
Clinical significance
Aged
Neoplasm Staging
Cisplatin
Chemotherapy
business.industry
medicine.disease
Xenograft Model Antitumor Assays
Disease Models
Animal
030104 developmental biology
Drug Resistance
Neoplasm
EpCAM
Immunology
Cancer research
Neoplasm Grading
business
Ovarian cancer
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: // Shingo Tayama 1, * , Takeshi Motohara 1, * , Dashdemberel Narantuya 1 , Chenyan Li 1 , Koichi Fujimoto 1 , Isao Sakaguchi 1 , Hironori Tashiro 2 , Hideyuki Saya 3 , Osamu Nagano 3 and Hidetaka Katabuchi 1 1 Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Chuo-Ku, Kumamoto 860-8556, Japan 2 Department of Maternal-Newborn Nursing, Kumamoto University, Chuo-Ku, Kumamoto 860-0976, Japan 3 Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Shinjuku-Ku, Tokyo 160-8582, Japan * These authors contributed equally to this work Correspondence to: Takeshi Motohara, email: kan@kumamoto-u.ac.jp Keywords: ovarian cancer, cancer stem cell, EpCAM, chemoresistance, prognosis Received: October 09, 2016 Accepted: April 29, 2017 Published: May 15, 2017 ABSTRACT Epithelial ovarian cancer is a highly lethal malignancy; moreover, overcoming chemoresistance is the major challenging in treating ovarian cancer patients. The cancer stem cell (CSC) hypothesis considers CSCs to be the main culprits in driving tumor initiation, metastasis, and resistance to conventional therapy. Although growing evidence suggest that CSCs are responsible for chemoresistance, the contribution of CSC marker EpCAM to resistance to chemotherapy remains unresolved. Here we have demonstrated that ovarian cancers containing high levels of EpCAM have a significantly much lower probability of achieving overall responsive rates after first-line chemotherapy. In addition, multivariate analysis revealed that EpCAM expression is an independent risk factor for chemoresistance, indicating that EpCAM expression is a predictive biomarker of chemotherapeutic response. Consistent with these clinical observations, in vitro assays, we found that the subpopulation of EpCAM-positive ovarian cancer cells shows a significantly higher viability compared with EpCAM-negative cells in response to cisplatin treatment by preventing chemotherapy-induced apoptosis, which is regulated by EpCAM-Bcl-2 axis. Furthermore, in an in vivo mouse model, platinum agents preferentially eliminated EpCAM-negative cells in comparison with EpCAM-positive cells, suggesting that the remaining subpopulation of EpCAM-positive cells contributes to tumor recurrence after chemotherapy. Finally, we also found that an increased expression of EpCAM is associated with poor prognosis 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. Targeting EpCAM should be a promising approach to effectively extirpate the CSCs as the putative root of ovarian cancer.
Databáze: OpenAIRE
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