title: Activation of Src by c-Met overexpression mediates metastatic properties of colorectal carcinoma cells.
abstract: Overexpression and/or activation of c-Met, the protein tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF), and the protein tyrosine kinase, Src, have been implicated in the progression and metastasis of human colorectal carcinoma (CRC). Previously, through ribozyme-mediated c-Met downregulation, we demonstrated a causal role for c-Met in CRC tumorigenesis and the production of liver metastases from the highly metastatic CRC cell line, KM20. Analysis of signaling intermediates downstream of c-Met demonstrated a specific reduction of Src activity with minimal effect on Erk1/2 and Akt following c-Met downregulation. As Src has been shown to upregulate Vascular Endothelial Growth Factor (VEGF), we sought to determine if the reduced tumor size and incidence could be due to reduced vessel formation in the c-Met downregulated clones. Here we show that tumors produced from c-Met downregulated cells have significantly reduced vessel density in tumors, correlating with a reduction in VEGF production. Additionally, the Src selective inhibitor, PP2, significantly reduced basal VEGF production in KM20 parental cells, and this effect could be rescued by HGF treatment. PP2 reduced basal proliferation, migration, and anchorage-independent growth. Furthermore, PP2 treatment demonstrated a dose-dependent decrease in HGF induced migration. In contrast, PP2 treatment only had a minor effect on HGF induced anchorage-independent growth. Collectively, these data demonstrate a significant role for c-Met-mediated Src activation in processes involved in CRC tumorigenesis and liver metastasis.
authors.affiliation: Department of Cancer Biology, University of Texas M. D. Anderson Cancer Center, The Program in Cancer Biology, University of Texas-Houston Health Science Center, Graduate School of Biomedical Sciences, Houston, TX 77030, USA.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Herynk
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Nila U
authors.initials: NU
authors.lastname: Parikh
authors.forename: Gary E
authors.initials: GE
authors.lastname: Gallick
mesh_terms: D001345:Autoradiography; D015152:Blotting, Northern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D015536:Down-Regulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics* / Q000502:physiology*; D016391:Genes, src / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013778:Tetrazolium Salts; D013844:Thiazoles; D014410:Tumor Stem Cell Assay; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D018809:Proliferating Cell Nuclear Antigen; D013778:Tetrazolium Salts; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C022616:thiazolyl blue