Focal adhesion kinase and its potential involvement in tumor invasion and metastasis

Abstract

Background Integrins are cell surface receptors which, in part, mediate the adhesion of cells to the extracelluar matrix. In addition to providing a molecular “glue” essential for tissue organization and survival, integrins are dynamic signaling molecules. Integrins allow normal, nontransformed cells to sense that they are adhered to the extracellular matrix, thus providing a cell survival signal. This signal allows cells to proliferate in the presence of growth factors and in some instances prevents apoptosis. Integrins also mediate cell migration as it occurs in normal processes such as angiogenesis, wound healing, immune system function, and development. Aberrances in the expression and function of integrins contribute to many disease states including cancer. Results Focal adhesion kinase (FAK) becomes phosphorylated and activated during integrin‐mediated cell adhesion. Focal adhesion kinase is a signal transducer of integrins (and certain soluble growth factors). Cells derived from FAK −/− mouse embryos exhibit reduced migration relative to wild‐type cells. Cells which overexpress FAK show increased migration relative to wild‐type cells. Focal adhesion kinase promotes cell survival under certain in vitro conditions. Focal adhesion kinase is overexpressed in invasive and metastatic colon, breast, thyroid, and prostate cancers. Enhanced FAK immunostaining is detected in small populations of preinvasive (carcinoma in situ) oral cancers and in large populations of cells in invasive oral cancers. Conclusions Focal adhesion kinase is probably not a classical oncogene but may be involved in the progression of cancer to invasion and metastasis. It is hypothesized that overexpression of FAK in subpopulations of tumor cells leads to populations of cells with a high propensity toward invasion and metastasis. Focal adhesion kinase would have a dual role in this regard: Overexpression of FAK leads to (1) increased cell migration and (2) increased cell survival under anchorage‐independent conditions. Further work is needed to test this model and to determine whether FAK represents a viable target for anticancer therapy. © 1998 John Wiley & Sons, Inc. Head Neck 20: 745–752, 1998.

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…Additionally, aberrant trafficking of integrins to the leading edge has been documented to activate the matrix-degrading proteases such as matrix metalloproteinases (MMPs) and plasmin, required for degradation of the ECM and subsequent cell invasion [38,40]. Moreover, stimulation of cells with the growth factor heregulin (HRG), has been shown to affect the expression and serine phosphorylation status of the focal adhesion protein paxillin, resulting in both the induction of morphological changes in cell shape as well as the stimulation of cell scattering in the breast cancer epithelial cell line, MCF-7 [41][42][43]. Paxillin has also been implicated in contributing to tumor invasiveness and metastasis in breast cancer, non-small cell lung cancer, prostate cancer and osteosarcomas [41][42][43].…”

“…Moreover, stimulation of cells with the growth factor heregulin (HRG), has been shown to affect the expression and serine phosphorylation status of the focal adhesion protein paxillin, resulting in both the induction of morphological changes in cell shape as well as the stimulation of cell scattering in the breast cancer epithelial cell line, MCF-7 [41][42][43]. Paxillin has also been implicated in contributing to tumor invasiveness and metastasis in breast cancer, non-small cell lung cancer, prostate cancer and osteosarcomas [41][42][43]. Lastly, over-expression of FAK has been documented in invasive and metastatic breast, colon, thyroid and prostate cancers [44,45].…”

Adhesive Mechanisms Regulating Invasion and Metastasis in Oral Cancer

“…In contrast, the (6 subunit is expressed in all carcinomas, (Kornberg, 1998;Almeida et al, 2000). FAK has been shown to be overexpressed in multiple invasive and metastatic tumor cancers (Komberg, 1998;Agochiya et al, 1999).…”

High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype

“…In our lab, human FAK was subsequently identified in high-grade sarcomas 12 and breast tumors. [13][14][15] FAK is overexpressed in a variety of human tumors in comparison with adjacent normal tissue, including breast, [13][14][15][16] colon, 13,14,17,18 thyroid, 19 ovarian, 20 cervix, 16 head and neck, 21 and esophagus. 22 Early work suggested that FAK might function in the later stages of tumor progression, such as invasion and metastasis, promoting adhesion in invading cells.…”