Increased dosage and amplification of the focal adhesion kinase gene in human cancer cells

Focal adhesion kinase (pp125(FAK)) is present at sites of cell/extracellula r matrix adhesion and has been implicated in the control of cell behaviour. In particular, as a key component of integrin-stimulated signal transducti on pathways, pp125(FAK) is involved in cellular processes such as spreading , motility, growth and survival. In addition, a number of reports have indi cated that pp125(FAK) may be up-regulated in human tumour cells of diverse origin, and consequently, a role has been proposed for pp125(FAK) in the de velopment of invasive cancers. However, to date the mechanisms that lead to elevated pp125(FAK) expression in tumour cells have not been determined. H ere ne used iii situ hybridization to confirm chromosome 8q as the genomic location of the human fak gene and report that elevation of pp125(FAK) prot ein in cell lines derived from invasive squamous cell carcinomas is accompa nied by gains in copy number of the fak gene in all cases examined, In addi tion,,ve observed increased fak copy number in frozen sections of squamous cell carcinomas. Furthermore, increased dosage of the fak gene was also obs erved in many cell lines derived from human tumours of lung, breast and col on, including two cell lines Calu3 and HT29, in which fak was amplified. In addition, in an in vitro model for human colon cancer progression there wa s a copy number gain of the fak gene during conversion from adenoma to carc inoma, which was associated with increased pp125(FAK) protein expression, T hus, ne show for the first time that many cell lines derived from invasive epithelial tumours hare increased dosage of the fak gene, which may contrib ute to the elevated protein expression commonly observed, Although other ge nes near the fak locus are coamplified or increased in copy number, includi ng the proto-oncogene c-myc, the biological properties of pp125(FAK) in con trolling the growth, survival and invasiveness of tumour cells, suggest tha t it may contribute to the selection pressure for maintaining increased dos age of the region of chromosome 8q that encodes these genes.