PROGRESSION OF FAMILIAL ADENOMATOUS POLYPOSIS (FAP) COLONIC CELLS AFTER TRANSFER OF THE SRC OR POLYOMA MIDDLE T-ONCOGENE - COOPERATION BETWEEN SRC AND HGF MET IN INVASION/

Little is known about the the signalling pathways driving the adenoma- to-carcinoma sequence in human colonic epithelial cells. Accumulation and activation of the src tyrosine kinase in colon cancer suggest a po tential role of this oncogene in this early progression, Therefore, we introduced either activated src (m-src), polyoma-MT alone or combined with normal c-src in the adenoma PC/AA/C1 cell line (PC) to define th e function and phenotypic transformations induced by these oncogenes i n familial adenomatous polyposis (FAP) colonic epithelial cells. Funct ional expression of these oncoproteins induced the adenoma-to-carcinom a conversion, overexpression of the hepatocyte growth factor (HGF) rec eptor Met, but failed to confer invasiveness in vivo and in vitro, or to produce alterations in cell proliferation and differentiation. in c ontrast, PC-msrc cells became susceptible to the HGF-induced invasion of collagen gels and exhibited sustained activation of the pp60(src) t yrosine kinase and Tyr phosphorylation of the 120-kDa E-cadherin, whic h was further increased by HGF Transcripts of HGF were clearly identif ied by reverse transcription - polymerase chain reaction (RT-PCR) and Southern blot in the parental and transformed PC cells, suggesting an autocrine mechanism. Taken together, the data indicate that: (1) exper imental activation of src and PyMT pathways directly induces tumorigen icity and Met upregulation in a colon adenoma cell line; (2) HGF-activ ated Met and src cooperate in inducing invasion; (3) in view of the mo lecular associations between catenins and cadherin or the tumour-suppr essor gene product APC, the cell adhesion molecule E-cadherin may cons titute a downstream effector of src and Met.