title: Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis.
abstract: Alterations in epidermal growth factor (EGF) expression are known to be of prognostic relevance in human melanoma, but EGF-mediated effects on melanoma have not been extensively studied. As lymph node metastasis usually represents the first major step in melanoma progression, we were trying to identify a potential role of primary tumor-derived EGF in the mediation of melanoma lymph node metastases. Stable EGF knockdown (EGFkd) in EGF-high (M24met) and EGF-low (A375) expressing melanoma cells was generated. Only in EGF-high melanoma cells, EGFkd led to a significant reduction of lymph node metastasis and primary tumor lymphangiogenesis in vivo, as well as impairment of tumor cell migration in vitro. Moreover, EGF-induced sprouting of lymphatic but not of blood endothelial cells was abolished using supernatants of M24met EGFkd cells. In addition, M24met EGFkd tumors showed reduced vascular endothelial growth factor-C (VEGF-C) expression levels. Similarly, in human primary melanomas, a direct correlation between EGF/VEGF-C and EGF/Prox-1 expression levels was found. Finally, melanoma patients with lymph node micrometastases undergoing sentinel node biopsy were found to have significantly elevated EGF serum levels as compared with sentinel lymph node-negative patients. Our data indicate that tumor-derived EGF is important in mediating melanoma lymph node metastasis.
authors.affiliation: Department of Dermatology, Medical University of Vienna, Vienna, Austria. andreas.bracher@meduniwien.ac.at
authors.forename: Andreas
authors.initials: A
authors.lastname: Bracher
authors.forename: Ana Soler
authors.initials: AS
authors.lastname: Cardona
authors.forename: Stefanie
authors.initials: S
authors.lastname: Tauber
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Fink
authors.forename: Andreas
authors.initials: A
authors.lastname: Steiner
authors.forename: Hubert
authors.initials: H
authors.lastname: Pehamberger
authors.forename: Heide
authors.initials: H
authors.lastname: Niederleithner
authors.forename: Peter
authors.initials: P
authors.lastname: Petzelbauer
authors.forename: Marion
authors.initials: M
authors.lastname: Gröger
authors.forename: Robert
authors.initials: R
authors.lastname: Loewe
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000097:blood; D002465:Cell Movement / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000097:blood; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology*; D008207:Lymphatic Metastasis; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D061206:Neoplasm Micrometastasis / Q000473:pathology; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000097:blood; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis* / Q000097:blood; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D000098551:Prospero-Related Homeobox 1 Protein; D004815:Epidermal Growth Factor