Integrins play an important role in cellular matrix interactions requisite for
cancer cell adhesion, growth, migration and invasion. In this study, we have investigated the expression of
integrin subunits alpha3, alpha6, alphav and beta1 in normal ovaries, benign ovarian
tumors and ovarian
carcinomas of different pathological grades. The expression of these
integrins in
ovarian cancer cell lines was also investigated, and their role in sustaining proliferation, adhesion, migration and invasion in cohort with the activation of signaling pathways in response to extracellular matrices (ECM) was evaluated. We demonstrate a differential expression pattern of alpha3, alpha6, alphav and
beta1 integrin subunits in ovarian
carcinomas compared to normal ovaries and benign ovarian
tumors.
Ovarian cancer cell lines (Hey, Ovcar3 and Peo.36) demonstrated significantly high expression of alpha3, alpha6, alphav and
beta1 integrin subunits. A significant increase in proliferation and adhesion (P<0.05) in response to
collagen 1 (Coll) and
laminin (LM),
ligands for
integrin receptor alpha3beta1 and alpha6beta1 was observed in
ovarian cancer cell lines. On the other hand,
fibronectin (FN), a receptor for
alphavbeta1 integrin, increased proliferation in all
ovarian cancer cell lines studied but only enhanced adhesion in Hey cell line (P<0.05).
Neutralizing antibodies against alpha3, alpha6, alphav and
beta1 integrin subunits inhibited ECM-induced proliferation, but increased adhesion to ECM was inhibited by
beta1 integrin subunit antibody. No suppression of Coll, LM and FN-induced (Hey cells only) adhesion was observed in the presence of alpha3 or alphav subunit
antibodies but LM-induced adhesion was inhibited by blocking alpha6 subunit functions. LM, FN and Coll enhanced chemotactic migration in Hey cells, but direct invasion across ECM was observed only in the presence of LM and Coll.
Blocking antibodies against alpha3, alpha6 and
beta1 integrin subunits inhibited both chemotactic migration and invasion of Hey cells in response to respective ECM. Adhesion of
ovarian cancer cells to FN, Coll and LM activated Ras, Erk and Akt pathways. Neutralizing alphav and beta1 functions did not inhibit FN-induced activation of Ras and Erk pathways but inhibited the Akt pathway. On the other hand,
antibodies against alpha6 and beta1 subunits, but not alpha3 subunit, inhibited LM-induced activation of Ras but did not inhibit the downstream Akt pathway. Neutralizing beta1 subunit function however, inhibited LM-induced Erk activation. Coll-induced activation of Ras, Erk and Akt pathways was inhibited by alpha3 and
beta1 integrin subunit
antibodies. These results indicate that alpha3beta1, alphavbeta1 and
alpha6beta1 integrin mediate proliferation, adhesion, migration and invasion of
ovarian cancer cells in response to ECM and targeting these
integrins to modulate
integrin-ECM interactions in
tumor cells may be a promising tool to reduce the dissemination of ovarian
carcinoma in vivo.