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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

Wu, Xinqia,b; Zhou, Juna,b; Rogers, Andrew M.a; Jänne, Pasi A.a,c; Benedettini, Elisae; Loda, Massimoa,d; Hodi, F. Stephena,b

Melanoma Research:
doi: 10.1097/CMR.0b013e3283507ffd
ORIGINAL ARTICLES: Basic research
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.

Author Information

aDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School

bMelanoma Disease Center, Dana-Farber/Brigham and Women’s Cancer Center

cLowe Center for Thoracic Oncology, Dana-Farber Cancer Institute

dDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

eDepartment of Medicine, Surgery and Dentistry, Division of Pathology, University of Milan, Milan, Italy

Correspondence to F. Stephen Hodi, MD, Department of Medical Oncology and Melanoma Disease Center, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA Tel: +1 617 632 5053; fax: +1 617 582 7992; e-mail: stephen_hodi@dfci.harvard.edu

Received June 14, 2011

Accepted December 16, 2011

© 2012 Lippincott Williams & Wilkins, Inc.