Kallikrein-Related Peptidase 7 Promotes Multicellular Aggregation via the α5β1 Integrin Pathway and Paclitaxel Chemoresistance in Serous Epithelial Ovarian Carcinoma

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 α 5 β 1 and β 1 integrins confirmed the involvement of KLK7 and integrinregulated cell adhesion. Increased levels of α 5 /β 1 integrins and enhanced attachment to fibronectin and vitronectin, which was blocked with an anti-β 1 integrin antibody, were also observed. Finally, Western blot and immunohistochemistry showed higher KLK7 and α 5 /β 1 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 α 5 β 1 integrin-dependent cell adhesion. Cancer Res; 70(7); 2624-33. ©2010 AACR.

Kallikrein-related peptidases in prostate, breast, and ovarian cancers: from pathobiology to clinical relevance

“…More precisely, the stable overexpression of KLK7 in serous epithelial ovarian carcinoma SKOV-3 cells was found to promote the formation of multicellular aggregates, facilitating, in this way, the cancer cells ' survival and resistance to paclitaxel in vitro . A positive association between the expression levels of the α 5 / β 1 integrins and KLK7, in SKOV-3 transformed cells and epithelial ovarian carcinoma tissues, was observed (Dong et al , 2010 ). Moreover, the formation of multicellular aggregates was inhibited by the antibody-mediated blockage of KLK7 and α 5 / β 1 integrins.…”

“…Additionally, enhanced KLK4 ovarian cancer tissue staining has been correlated with paclitaxel resistance (Xi et al , 2004 ), whereas elevated KLK11 and KLK13 tissue protein levels are correlated with improved clinical response to chemotherapy (Zheng et al , 2007 ). Moreover, the latest data show that KLK7 levels in ovarian tissues are indicative of unfavorable outcome for ovarian cancer patients and are associated with paclitaxel chemoresistance (Dong et al , 2010 ). Finally, recently published data propose that measurements of level differentials (between metastasis and primary tumor) of KLK5 -8, KLK10, KLK11, and uPA are correlated signifi cantly with the disease outcome of ovarian cancer patients (Dorn et al , 2011a ).…”

Transforming the Future of Treatment for Ovarian Cancer

“…Conventional pathology has divided epithelial ovarian cancer into endometrioid, serous, clear cell and mucinous subtypes according to its histological phenotypes with many different immunohistochemical markers for the different subtypes being described (Figure 1) [7]. Traditionally, epithelial ovarian cancer is believed to derive from a single layer of flat or cuboidal mesothelial cells covering the ovary.…”

The tumor suppressor geneARHI(DIRAS3)inhibits ovarian cancer cell migration through multiple mechanisms

“…Integrin β1 has a well-established role in cell adhesion and motility in various types of cancers, including ovarian cancer. [19][20][21][22][23][24] In ovarian cancer, overexpression of integrin β1 has been found to be associated with higher clinical stage and poor survival. 23,25 Upregulation of integrin β1 expression promotes ovarian cancer cell migration and matrix cell invasion.…”

“…[19][20][21][22][23][24] In ovarian cancer, overexpression of integrin β1 has been found to be associated with higher clinical stage and poor survival. 23,25 Upregulation of integrin β1 expression promotes ovarian cancer cell migration and matrix cell invasion. [26][27][28] Moreover, the integrin β1 subunit has been shown to mediate ovarian cancer adhesion to peritoneal mesothelial cells and to increase peritoneal metastasis.…”