title: c-Met, epidermal growth factor receptor, and insulin-like growth factor-1 receptor are important for growth in uveal melanoma and independently contribute to migration and metastatic potential.
abstract: Uveal melanoma (UM) has a high propensity to develop hepatic metastases. We sought to define the mechanisms required for preferential liver homing and to understand further the biologic behavior of this disease. The Met tyrosine kinase receptor and its ligand hepatocyte growth factor are expressed in hepatocytes. We therefore considered Met/hepatocyte growth factor signaling as a candidate migration/growth factor for UM cells. We further explored the relationship between c-Met and other growth factor receptors prevalent in the liver and their roles in UM metastatic potential. UM cell lines were evaluated for c-Met, epidermal growth factor receptor (EGFR), and insulin-like growth factor-1R (IGF-1R) expression by immunoblotting, and gene amplification by comparative genomic hybridization and fluorescence in-situ hybridization. High c-Met, phosphorylated c-Met, and EGFR expression were noted in two of nine cell lines, independent of IGF-1R levels. Knockdown of c-Met decreased proliferation of high c-Met-expressing UM cells but did not induce apoptosis. Selective inhibitors of EGFR and IGF-1R decreased proliferation and induced apoptosis in UM cells regardless of the expression levels of c-Met, EGFR, and IGF-1R. Although c-Met, EGFR, and IGF-1R play proliferative roles, EGFR and IGF-1R are also critical for UM cell survival. High c-Met/EGFR-expressing cell lines possessed the greatest migration potential. c-Met knockdown and selective inhibitors of c-Met, EGFR, and IGF-1R revealed independent contribution of these receptors to migration. UM can be categorized by levels of c-Met and EGFR expression which are associated with migratory/invasiveness responses to soluble factors present at high levels in the liver. This provides biologic relevance for UM clinical behavior with potential therapeutic implications.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xinqi
authors.initials: X
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Rogers
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Elisa
authors.initials: E
authors.lastname: Benedettini
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002465:Cell Movement; D055028:Comparative Genomic Hybridization; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008113:Liver Neoplasms / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D014604:Uveal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000098943:Uveal Melanoma
chemical_list: D007334:Insulin-Like Growth Factor I; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met