MET expression in melanoma correlates with a lymphangiogenic phenotype

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.

Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

“…This link between VEGF-C, lymphangiogenesis, and metastasis in melanoma is firmly established in several experimental models and in humans (Skobe et al, 2001;Goydos and Gorski, 2003;Schietroma et al, 2003;Dadras et al, 2005;Hoshida et al, 2006;Niederleithner et al, 2012;Swoboda et al, 2012;Bracher et al, 2013). It also suggests that VEGF-C is the master regulator of lymphangiogenesis in melanoma.…”

Expression of hepatocyte growth factor and c-Met in non-small-cell lung cancer and association with lymphangiogenesis

“…An increase in the number of lymphatic vessels in the tumor stroma is correlated with lymph node metastasis (3)(4)(5). Several growth factors, including vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF), insulin-like growth factor (IGF) I/II and hepatocyte growth factor (HGF) exhibit lymphangiogenic activity (6)(7)(8)(9)(10)(11)(12)(13). Among these growth factors, HGF and its receptor c-Met are frequently observed to be at high levels in the majority of types of solid tumor, and the overexpression of HGF and/or c-Met have also been correlated with the degree of tumor invasiveness (14)(15)(16)(17).…”

Positive sentinel lymph node metastasis from a metastasis in Melanoma

“…3 In addition, a large proportion of single melanoma cells isolated from primary tumors or distant metastases have been demonstrated to have the capacity to form tumors in immune deficient mice. 6 Early evidence of metastases metastasizing has been hypothesized in colorectal cancer from a case series of seven patients undergoing hepatic resection of liver metastases. At the time of surgery, disease was also found in the lymphatics draining the liver in the absence of other extrahepatic tumor.…”