MET signalling in primary colon epithelial cells leads to increased transformation irrespective of aberrant Wnt signalling.
It has been shown that in hereditary and most sporadic colon tumours, components of the Wnt pathway are mutated. The Wnt target MET has been implicated in the development of colon cancer. Here, we show that overexpression of wild-type or a constitutively activated form of MET in colon epithelial cells leads to increased transformation irrespective of Wnt signalling. Fetal human colon epithelial cells without aberrant Wnt signalling were transfected with wild-type or mutated MET constructs. Expression of these constructs leads to increased phosphorylation of MET and its downstream targets PKB and MAPK. Upon stimulation with HGF, the expression of E-cadherin is downregulated in wild-type MET-transfected cells, whereas cells expressing mutated MET show low E-cadherin levels independent of stimulation with ligand. This implies a higher migratory propensity of these cells. Furthermore, fetal human colon epithelial cells expressing the mutated form of MET have colony-forming capacity in soft agar, while cells expressing wild-type MET show an intermediate phenotype. Subcutaneous injection of mutated MET-transfected cells in nude mice leads to the formation of tumours within 12 days in all mice injected. At this time point, mock-transfected cells do not form tumours, while wild-type MET-transfected cells form subcutaneous tumours in one out of five mice. We thus show that MET signalling can lead to increased transformation of colon epithelial cells independent of Wnt signalling and in this way could play an essential role in the onset and progression of colorectal cancer.
Boon
E M J
EM
Academic Medical Centre, Department of Pathology, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Kovarikova
M
M
Derksen
P W B
PW
van der Neut
R
R
D000818:Animals; D015820:Cadherins / Q000032:analysis; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000209:etiology*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins
D015820:Cadherins; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D051153:Wnt Proteins; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met