1. Kallikrein-related peptidase 7 promotes multicellular aggregation via the alpha(5)beta(1) integrin pathway and paclitaxel chemoresistance in serous epithelial ovarian carcinoma
- Author
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Olivia L. Tan, Peter G. Parsons, Carson Stephens, Daniela Loessner, Glen M. Boyle, Carina Walpole, Ying Dong, and Judith A. Clements
- Subjects
Cancer Research ,endocrine system diseases ,Paclitaxel ,Serous carcinoma ,Integrin ,Epithelium ,Mice ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,RNA, Messenger ,Vitronectin ,Cell adhesion ,Cell Aggregation ,Ovarian Neoplasms ,biology ,medicine.disease ,female genital diseases and pregnancy complications ,Cell aggregation ,Cystadenocarcinoma, Serous ,Fibronectins ,Fibronectin ,Serous fluid ,Oncology ,Drug Resistance, Neoplasm ,Immunology ,Cancer cell ,Cancer research ,biology.protein ,Female ,Kallikreins ,Integrin alpha5beta1 - Abstract
Kallikrein-related peptidase 7 (KLK7) is upregulated in epithelial ovarian carcinoma (EOC) with high levels correlated with poor prognosis. However, the mechanisms underlying this relationship and the role of KLK7 in EOC progression are unknown. We report that two different KLK7 transcripts, KLK7-253 and KLK7-181, are simultaneously expressed in high-grade serous EOC. Multicellular aggregates (MCA), which promote cell survival and chemoresistance, were observed in SKOV-3 cells stably overexpressing KLK7-253 in particular. Importantly, these MCAs invade into a monolayer of mesothelial cells and form cancer cell foci. Blocking MCA using antibodies against KLK7 and α5β1 and β1 integrins confirmed the involvement of KLK7 and integrin-regulated cell adhesion. Increased levels of α5/β1 integrins and enhanced attachment to fibronectin and vitronectin, which was blocked with an anti–β1 integrin antibody, were also observed. Finally, Western blot and immunohistochemistry showed higher KLK7 and α5/β1 integrin levels in serous EOC cells from ascites and tumor samples from chemotherapy nonresponders with short postsurvival times. Additionally, both KLK7-253 and KLK7-181 clones were more resistant to paclitaxel treatment in vitro. These findings suggest a mechanism for the association of high KLK7 levels with chemoresistance and poor prognosis for serous EOC patients by promotion of peritoneal dissemination and reinvasion via increased MCA and α5β1 integrin–dependent cell adhesion. Cancer Res; 70(7); 2624–33
- Published
- 2010