Progression of familial adenomatous polyposis (FAP) colonic cells after transfer of the src or polyoma middle T oncogenes: 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 potential 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 the function and phenotypic transformations induced by these oncogenes in familial adenomatous polyposis (FAP) colonic epithelial cells. Functional expression of these oncoproteins induced the adenoma-to-carcinoma conversion, overexpression of the hepatocyte growth factor (HGF) receptor Met, but failed to confer invasiveness in vivo and in vitro, or to produce alterations in cell proliferation and differentiation. In contrast, PC-msrc cells became susceptible to the HGF-induced invasion of collagen gels and exhibited sustained activation of the pp60src tyrosine kinase and Tyr phosphorylation of the 120-kDa E-cadherin, which was further increased by HGF Transcripts of HGF were clearly identified 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) experimental activation of src and PyMT pathways directly induces tumorigenicity and Met upregulation in a colon adenoma cell line; (2) HGF-activated Met and src cooperate in inducing invasion; (3) in view of the molecular associations between catenins and cadherin or the tumour-suppressor gene product APC, the cell adhesion molecule E-cadherin may constitute a downstream effector of src and Met.
Empereur
S
S
INSERM U55, Hôpital Saint-Antoine, Paris, France.
Djelloul
S
S
Di Gioia
Y
Y
Bruyneel
E
E
Mareel
M
M
Van Hengel
J
J
Van Roy
F
F
Comoglio
P
P
Courtneidge
S
S
Paraskeva
C
C
Chastre
E
E
Gespach
C
C
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D015820:Cadherins / Q000378:metabolism; D051177:Catenins; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002645:Chickens; D003094:Collagen; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D005782:Gels; D016391:Genes, src; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009857:Oncogenes; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D014183:Transplantation, Heterologous; D051178:alpha Catenin; D000095002:Delta Catenin
D025601:Adenomatous Polyposis Coli Protein; D000952:Antigens, Polyomavirus Transforming; D015820:Cadherins; D051177:Catenins; D015815:Cell Adhesion Molecules; C495272:Ctnna1 protein, mouse; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D005782:Gels; D010750:Phosphoproteins; D051178:alpha Catenin; D019000:Phosphotyrosine; D017228:Hepatocyte Growth Factor; D003094:Collagen; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D000095002:Delta Catenin