Vascular endothelial growth factor‐C expression correlates with lymph node localization of human melanoma metastases

Abstract

BACKGROUND Melanoma metastasizes by different mechanisms comprising direct invasion of the surrounding tissue and spreading via the lymphatic or vascular system. Despite their clinical relevance, the molecular mechanisms that guide the route of spreading and localization of the metastases in different tissues are not well known. Recent studies in different tumor types have shown that vascular endothelial growth factor‐C (VEGF‐C), which displays a high specificity for lymphatic endothelium, is involved in tumor‐induced lymphangiogenesis and lymphatic metastatic spread. The authors studied the expression of VEGF‐C in cultured human melanoma cells derived from cutaneous and lymph node metastases as well as in metastatic melanoma tissue specimens to assess a possible involvement of this growth factor in lymph node localization of melanoma metastases. METHODS VEGF‐C expression was evaluated in vitro on human melanoma cell lines established from cutaneous and lymph node metastasis specimens by reverse transcriptase‐polymerase chain reaction, Northern blot analysis, and immunofluorescence analysis. Immunohistochemical analysis of 42 tissue specimens of melanoma metastases and 10 tissue specimens of primary skin melanomas was also performed. RESULTS Preferential expression of VEGF‐C was detected in lymph node‐derived tumor cell lines at both the mRNA and protein levels. The association between VEGF‐C production and lymph node localization of metastases was confirmed by the in vivo analysis. In addition, analysis of 10 patients, from whom specimens of both the primary skin melanoma and melanoma metastases were available, indicated a correlation between VEGF‐C expression in the primary tumor and lymph node localization of metastases. CONCLUSIONS The findings of the current study demonstrate that VEGF‐C expression is correlated with localization of melanoma metastases in the lymph nodes and suggest that VEGF‐C expression in primary skin melanoma may be predictive of lymph node metastatic dissemination. Cancer 2003;98:789–97. © 2003 American Cancer Society. DOI 10.1002/cncr.11583

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…Indirectly, tumor-induced lymphangiogenesis is correlated with metastasis in a number of cancer models, including colorectal, breast, prostate, head and neck cancer, and melanoma [93][94][95][96][97][98][99], and expression of Semaphorin…”

Lymphatic vessel density is associated with CD8+ T cell infiltration and immunosuppressive factors in human melanoma

“…38-40 In human melanoma, increased intra- and peritumoral LVD as well as the lymphatic growth factor VEGF-C strongly correlate with metastatic dissemination. 17 , 33 , 41-43 Lymphatic vessels may support migration of tumor cells, but may also modulate immune cells, as recently demonstrated in primary tumors and draining LNs in mice, 24 , 25 , 44 raising the possibility that lymphatics mediate immune suppression and poor clinical outcome in cancer patients. 19 , 31 , 42 Because corresponding human data are missing, we performed a very wide IHC analysis.…”

Lymphangiogenesis and Its Relationship With Lymphatic Metastasis and Prognosis in Malignant Melanoma

“…A significant relationship between high VEGF-C and VEGF-D expression and poor prognosis has been reported in many different tumor types (Onogawa et al, 2004;Miyata et al, 2006;Shida et al, 2006;Mylona et al, 2007), although few studies have reported on VEGF-C expression and its prognostic significance in malignant melanoma (Goydos and Gorski, 2003;Schietroma et al, 2003), and to our knowledge, none have reported on the prognostic significance of VEGF-D in malignant melanoma. Mylona et al (2007) confirmed VEGF-C as an independent indicator of poor prognosis in breast carcinoma, and similar results have been shown for several cancer types (Herrmann et al, 2007;Mohammed et al, 2007).…”