Requirement for Focal Adhesion Kinase in the Early Phase of Mammary Adenocarcinoma Lung Metastasis Formation

Abstract

An increased expression of focal adhesion kinase (FAK) in a variety of cancers is associated with a poor disease prognosis. To study the role of FAK in breast tumor growth and metastasis formation, we used conditional doxycycline-regulated expression of a dominant-negative acting splice variant of FAK, FAK-related non-kinase (FRNK), in MTLn3 mammary adenocarcinoma cells in a syngeneic Fischer 344 rat tumor and metastasis model. In cell culture, doxycycline-mediated expression of FRNK inhibited MTLn3 cell spreading and migration in association with reduced formation of focal adhesions and phosphorylation of FAK on Tyr 397 , but FRNK did not cause apoptosis. Continuous expression of FRNK decreased the primary tumor growth in the mammary fat pad by 60%, which was not due to induction of apoptosis. Lung metastasis formation was almost completely prevented when FRNK was already expressed 1 day before tumor cell injection, whereas expression of FRNK 11 days after injection did not affect lung metastasis formation. FRNK expression during the first 5 days was sufficient to block metastasis formation, excluding the possibility of FRNK-induced dormancy of tumor cells. Together, these data fit with a model wherein FAK is required for breast tumor cell invasion/migration processes that take place in the early phase of metastasis formation. Our findings suggest that FAK is a good candidate for therapeutic intervention of metastasis formation. (Cancer Res 2005; 65(11): 4698-706)

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

“…Several studies have indicated that FAK may have a direct role in tumour growth and cell survival (Xu et al, 1996(Xu et al, , 1998Sonoda et al, 1999Sonoda et al, , 2000Aguirre Ghiso, 2002;Hecker et al, 2002Hecker et al, , 2004van Nimwegen et al, 2005). However, there are also published data showing that FRNK expression induces defects on migration and/or invasion without effects on cell survival or proliferation (Han et al, 2004;.…”

“…However, there are also published data showing that FRNK expression induces defects on migration and/or invasion without effects on cell survival or proliferation (Han et al, 2004;. Indeed, impairment of cell proliferation and survival after FRNK expression in carcinoma cells has been associated with high levels of overexpression Golubovskaya et al, 2002;van Nimwegen et al, 2005). Therefore, the contradictory effects on cell growth or survival may be due to the levels of functional FAK in the presence of FRNK or FAK siRNA.…”

“…In addition, FAK has been directly implicated in the promotion of tumour growth and cell cycle progression in some tumour cells (Aguirre Ghiso, 2002;Hecker et al, 2002Hecker et al, , 2004van Nimwegen et al, 2005). To investigate the possible role of FAK on cell proliferation of HNSCC cells, MTS assays and cell counting were performed in SCC40 and SCC38 cells expressing FRNK, siRNA against FAK, and in their corresponding control cells.…”

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

“…In experimental metastasis assays after tail vein injection, FRNK expression in v-Src-transformed fibroblasts (Hauck et al, 2002b), B16-F10 (AbdelGhany et al, 2002) and MTLn3 breast carcinoma cells (van Nimwegen et al, 2005) blocked tumor cell colonization of lungs. In various tumor cells, exogenous FRNK expression is correlated with reduced levels of protease secretion (Hauck et al, 2002b;Hess et al, 2005) or slower growth (van Nimwegen et al, 2005). Although FRNK acts to inhibit FAK activity, it also encompasses multiple protein binding sites and may act to sequester signaling proteins away from FAK.…”

“…Whereas high levels of FRNK can promote cell apoptosis (Xu et al, 2000;Golubovskaya et al, 2002), FRNK expression can also reduce tumor growth by promoting tumor dormancy and by inhibiting cell proliferation (Aguirre Ghiso, 2002;van Nimwegen et al, 2005). Low levels of FRNK expression have revealed the importance of FAK activity in promoting tumor cell migration (Slack et al, 2001) and in generating an invasive cell phenotype (Hauck et al, 2001(Hauck et al, , 2002bHsia et al, 2003;.…”