MET expression in melanoma correlates with a lymphangiogenic phenotype

Hum Mol Genet. 2012 Aug 1;21(15):3387-96. doi: 10.1093/hmg/dds171. Epub 2012 May 7.

Abstract

Melanomas contain high frequencies of tumorigenic cells and their tumorigenic capacity resides in several distinct subpopulations within melanoma. Since their metastatic potential is linked to their ability to recruit lymphatic vessels, we aimed at identifying lymphangiogenic subpopulations by comparative in vitro analysis of single cell clones derived from a melanoma of a single patient. Selected lymphangiogenic clones were then grafted into severe combined immunodeficient mice, where they induced lymphangiogenesis and metastasized into sentinel nodes, whereas non-lymphangiogenic clones from the same patient did not metastasize. Transcriptome analysis revealed high expression of vascular endothelial growth factor C (VEGF-C) and platelet derived growth factor C (PDGF-C) as well as of the met proto-oncogene (MET) and its targets to be associated with this lymphangiogenic phenotype. Screening of a set of independently isolated melanoma cell lines from other patients confirmed this association between expression of high levels of MET and of VEGF-C and PDGF-C. Hence, we provide a model to screen for the lymphangiogenic potential of tumor cells. We show that the lymphangiogenic potential is heterogeneously distributed among melanoma cells within one given tumor and is associated with activation of MET signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism
  • Female
  • Humans
  • Lymph Nodes / pathology
  • Lymphangiogenesis / genetics*
  • Lymphatic Metastasis
  • Lymphokines / metabolism
  • Male
  • Melanoma / genetics
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mice, SCID
  • Middle Aged
  • Phenotype*
  • Platelet-Derived Growth Factor / metabolism
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism
  • Skin Neoplasms / genetics
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Transcriptome
  • Vascular Endothelial Growth Factor C / metabolism

Substances

  • Biomarkers, Tumor
  • Lymphokines
  • MAS1 protein, human
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Mas
  • Vascular Endothelial Growth Factor C
  • platelet-derived growth factor C
  • MET protein, human
  • Proto-Oncogene Proteins c-met