Epidermal Growth Factor Facilitates Melanoma Lymph Node Metastasis by Influencing Tumor Lymphangiogenesis

• Published in: Journal of investigative dermatology Vol. 133; no. 1; pp. 230 - 238
• Main Authors: Bracher, Andreas, Cardona, Ana Soler, Tauber, Stefanie, Fink, Astrid M., Steiner, Andreas, Pehamberger, Hubert, Niederleithner, Heide, Petzelbauer, Peter, Gröger, Marion, Loewe, Robert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013; Elsevier Limited
• Subjects: Animals; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - blood; Cell Movement - genetics; Endothelial Cells - metabolism; Endothelial Cells - pathology; Epidermal Growth Factor - biosynthesis; Epidermal Growth Factor - blood; Epidermal Growth Factor - genetics; Female; Gene Knockdown Techniques; Homeodomain Proteins - biosynthesis; Homeodomain Proteins - blood; Humans; Lymphangiogenesis - genetics; Lymphangiogenesis - physiology; Lymphatic Metastasis; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, SCID; Neoplasm Micrometastasis - pathology; Sentinel Lymph Node Biopsy; Skin Neoplasms - metabolism; Skin Neoplasms - pathology; Tumor Cells, Cultured; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - blood; Vascular Endothelial Growth Factor C - biosynthesis; Vascular Endothelial Growth Factor C - blood
• ISSN: 0022-202X; 1523-1747
• DOI: 10.1038/jid.2012.272

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.