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

J Invest Dermatol. 2013 Jan;133(1):230-8. doi: 10.1038/jid.2012.272. Epub 2012 Sep 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Biomarkers, Tumor
  • Homeodomain Proteins
  • Tumor Suppressor Proteins
  • VEGFC protein, human
  • Vascular Endothelial Growth Factor C
  • prospero-related homeobox 1 protein
  • Epidermal Growth Factor