Biological Significance of Focal Adhesion Kinase in Ovarian Cancer

Abstract

Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is activated by integrin clustering. There are limited data regarding the functional role of FAK in ovarian cancer migration and invasion. In the current study, FAK expression was evaluated in ovarian cell lines (nontransformed and cancer), 12 benign ovarian samples, and in 79 invasive epithelial ovarian cancers. All three ovarian cancer cell lines overexpressed FAK compared to the nontransformed cells. The dominant-negative construct called FAK-related nonkinase (FRNK) was introduced into two ovarian cancer cell lines (SKOV3 and 222). FRNK promoted FAK dephosphorylation without changing total FAK levels in these cell lines. Furthermore, FRNK decreased the in vitro invasive ability of ovarian cancer cells by 56 to 85% and decreased migration by 52 to 68%. FRNK-transfected cells also displayed poor cell spreading. Immunohistochemical analysis revealed that the surface epithelium from all benign ovarian samples had weak FAK expression. In contrast, 68% of invasive ovarian cancers overexpressed FAK. FAK overexpression was significantly associated with high tumor stage, high tumor grade, positive lymph nodes and presence of distant metastasis (all P values <0.05). FAK overexpression was also associated with shorter overall survival (P = 0.008). Multivariate analysis revealed that FAK overexpression and residual disease >1 cm were independent predictors of poor survival. These data indicate that FAK is overexpressed in most invasive ovarian cancers and plays a functionally significant role in ovarian cancer migration and invasion. Thus, FAK may be an important therapeutic target in ovarian carcinoma.

Intrinsic focal adhesion kinase activity controls orthotopic breast carcinoma metastasis via the regulation of urokinase plasminogen activator expression in a syngeneic tumor model

“…Finally, analyses of FAK expression levels in esophageal squamous cell carcinoma (Miyazaki et al, 2003), hepatocellular carcinoma (Itoh et al, 2004), acute myeloid leukemia (Recher et al, 2004) and ovarian cancer (Sood et al, 2004) tissue samples have found that FAK expression levels are inversely correlated with patient survival. As many cancer-related deaths are associated with elevated metastatic tumor burden, it is of interest to note that injection of malignant 4T1 cells expressing high levels of FAK led to the early death of 90% of injected animals within 21 days.…”

Differential FAK phosphorylation at Ser-910, Ser-843 and Tyr-397 induced by angiotensin II, LPA and EGF in intestinal epithelial cells

“…The biological importance of FAK-mediated signal transduction is underscored by the fact that this tyrosine kinase plays a fundamental role in embryonic development [11,12] and in the control of cell migration [9,[12][13][14][15][16][17][18][19], cell cycle progression [20] and apoptosis [21][22][23][24]. Furthermore, there is increasing evidence linking overexpression of FAK to the invasive properties of cancer cells [25][26][27][28][29][30][31].…”

Involvement of focal adhesion kinase in cellular invasion of head and neck squamous cell carcinomas via regulation of MMP-2 expression

“…A large number of reports describe an enhanced expression of FAK protein in a variety of human cancers, including sarcomas, astrocytomas and carcinomas of the breast, colon, thyroid, prostate, oral cavity, liver, stomach and ovary (see (McLean et al, 2005) and references herein). Furthermore, FAK overexpression has been correlated with the invasive potential of a tumour and poor patient prognosis Miyazaki et al, 2003;Recher et al, 2004;Sood et al, 2004). In a study of 106 matched pairs of larynx carcinomas and corresponding normal tissue, using immunohistochemistry, we have previously shown a significantly increased expression of FAK at the protein level in both the tumour tissues and the corresponding metastasis (Canel et al, 2006).…”