Oncogenic engagement of the Met receptor is sufficient to evoke angiogenic, tumorigenic, and metastatic activities in rat intestinal epithelial cells.
The deregulation of Met/hepatocyte growth factor (HGF) receptor tyrosine kinase signaling constitutes a common event in colorectal cancers. However, the physiopathological functions of such a deregulation remain poorly understood. In the present study, we investigated the role of the deregulation of Met receptor in the neoplastic transformation of intestinal epithelial cells. To do so, the normal, well-established and characterized rat intestinal epithelial IEC-6 cells were transduced with a retrovirus carrying the oncogenic constitutive active form of Met receptor, Tpr-Met. Herein, we show that compared with control IEC-6 cells, Tpr-Met-IEC-6 cells exhibit enhanced proliferation, loss of growth-contact inhibition, cell morphological alterations, actin cytoskeletal reorganization, loss of E-cadherin expression and anchorage-independent growth. Moreover, Tpr-Met-IEC-6 cells are conferred the capacity to produce the proangiogenic factor VEGF and to reduce the potent antiangiogenic factor thrombospondin-1. Of significance, Tpr-Met-IEC-6 cells are endowed with the ability to elicit angiogenic responses and to form tumors and metastases in vivo. Hence, our study demonstrates for the first time that the sole oncogenic engagement of Met receptor in normal intestinal epithelial cells is sufficient to induce a wide array of cancerous biological processes that are fundamental to the initiation and malignant progression of colorectal cancers.
Département d'Anatomie et de Biologie Cellulaire, Université de Sherbrooke, Québec, Canada.
Jimmy
J
Bernier
Walid
W
Chababi
Véronique
V
Pomerleau
Caroline
C
Saucier
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D049109:Cell Proliferation; D003599:Cytoskeleton; D004847:Epithelial Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D007413:Intestinal Mucosa; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism; D050490:Oncogene Protein tpr-met; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D019700:Thrombospondin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D015820:Cadherins; D050490:Oncogene Protein tpr-met; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met