Abstract 3443: Lymphangiogenic parameters in metastatic malignant melanoma: association with clinicopathological parameters and prognosis
Authors: Roger Mouawad, Sarah Watson, Jean-Philippe Spano, Rosa Conforti, Stephane Vignot, Thibaut De La Motte Rouge, David Khayat
Journal: Cancer Research (2010)

Abstract Background and aims: Regional lymph node metastasis is one of the important indicators of malignant melanoma. Lymphatic or vascular systems are considered to provide a way whereby tumor cells can migrate to the lymph nodes either by direct invasion of surrounding tissue or spreading. Despite their clinical relevance, the mechanisms that guide the way of spreading are not well known. Recent studies have shown that Flt-4, a VEGF receptor, is activated by its ligand, VEGF-C. The resultant signaling pathway promotes angiogenesis and/or lymphangiogenesis, but the prognostic significance of these axes in malignant melanoma remains controversial. The aim of this study is to clarify therole of these factors and to evaluate the relationships between the VEGF-C/Flt-4 axis and lymphangiogenesis, lymph node metastasis, and prognosis in patients with metastatic malignant melanoma patients (MMM). The expressions of VEGF-C and VEGFR −3 were detected on 15 metastatic melanoma tumor by immunohistochemistry. Circulating form of VEGFC and Flt-4 were measured using ELISA assays in the sera of 90 patients with MMM in comparison to 50 healthy controls. Disease free Survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Results: High expressions of VEGF-C and VEGFR-3 proteins were concomitantly detected in the cytoplasm of melanoma tumors. VEGF-C was associated with VEGFR-3 expression and was significantly correlated with lymph node metastasis. Pretreatment median levels of sVEGF-C and sFlt-4 were significantly higher in MMM patients as compared to healthy ones (p=0.005, p&amp;lt;0.00001). None of the studied markers correlated with gender, age or LDH levels. An inverse correlation between Flt-4 expression &amp; its soluble form was noted (r=-0.33 p=0.040). A positive correlation between sVEGF-C &amp; sFlat-4 was observed (r’=0.430, p=0.0014). Furthermore, high expression &amp; levels of sVEGF-C, sFlat-4 correlated to high tumor burden (p=0.02, p=0.045). Only sVEGFC/sFlat-4 ratio showed a relationship with lymph node metastasis. Pretreatment sFlat-4 level was significantly different (p=0.0125) between R (n=40) &amp; NR patients (n=50) but not sVEGF-C level. After treatment, no change in the median sFlat-4 level was observed. By contrast, sVEGF-C increased specifically in NR patients with high tumor burden. Only elevated level of sFlat-4 concentration exert a significantly unfavorable impact on disease free survival (X2= 3.855, p=0.045). Conclusions: This study suggests that both VEGF-C and VEGFR-3 expression as well as their soluble forms are involved in peritumoral lymphangiogenesis and lymphatic metastasis. Furthermore, the VEGF-C/Flt-4 axis enhances cancer cell invasiveness, contributes to the promotion of cancer cell metastasis and may be clinically useful indicators for prognostic evaluation in patients with metastatic malignant melanoma. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3443.