Significance of Vascular Endothelial Growth Factor (VEGF)-C and VEGF-D in the Progression of Cutaneous Melanoma.
BACKGROUND
Induction of tumor lymphangiogenesis by vascular endothelial growth factor (VEGF)-C and VEGF-D promotes metastasis in many human cancers.


OBJECTIVE
The aim of this study was to examine the role of VEGF-C and VEGF-D in lymphangiogenesis and lymph node metastasis in patients with cutaneous melanoma.


METHODS
Fifty-four melanoma specimens (18 with lymph node metastasis, 36 nonmetastatic) were investigated by immunostaining for VEGF-C, VEGF-D, and for lymphatic endothelial marker D2-40. VEGF-C and VEGF-D expression was assessed as a percentage and intensity of stained tumor cells, tumor-associated macrophages and fibroblasts. The quantification of lymphangiogenesis was conducted by computer-assisted morphometric analysis.


RESULTS
The expressions of both VEGF-C and VEGF-D in tumor cells were significantly higher in lymph node metastatic melanomas compared with nonmetastatic melanomas (P = .015 VEGF-C; P = .005 VEGF-D). There was no statistically significant difference between metastatic and nonmetastatic melanomas regarding the expression of VEGF-C and VEGF-D in macrophages and fibroblasts. Metastatic melanomas showed a significantly higher intratumoral and peritumoral lymphatic vessel density (LVD) compared with nonmetastatic melanomas (P = .000 intratumoral, P = .000 peritumoral). Melanomas with VEGF-C positive tumor cells showed a significantly higher intratumoral and peritumoral LVD compared with VEGF-C negative tumor cells group of melanomas (P = .006 intratumoral, P = .010 peritumoral). VEGF-C expression in macrophages, fibroblasts, as well as VEGF-D expression in tumor cells, macrophages, and fibroblasts, showed no correlation with the intratumoral and peritumoral LVD.


CONCLUSIONS
Our findings show the significance of VEGF-C in tumor cells in the induction of intratumoral and peritumoral lymphangiogenesis. This study suggests that both VEGF-C and VEGF-D in tumor cells promote lymph node metastasis, and that the immunohistochemical analysis of expression can be a useful tool for predicting clinical behavior of cutaneous melanoma.
Clinical Center of Banja Luka, Republic of Srpska, Bosnia and Herzegovina zoki12s@yahoo.com.
Zorica
Z
Špirić
Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Živka
Ž
Eri
Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
Mirela
M
Erić
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000502:physiology; D008207:Lymphatic Metastasis / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D042582:Vascular Endothelial Growth Factor C / Q000032:analysis / Q000096:biosynthesis*; D042643:Vascular Endothelial Growth Factor D / Q000032:analysis / Q000096:biosynthesis*; D055815:Young Adult
D014408:Biomarkers, Tumor; C467486:VEGFC protein, human; C579459:VEGFD protein, human; D042582:Vascular Endothelial Growth Factor C; D042643:Vascular Endothelial Growth Factor D
VEGF-C; VEGF-D; lymph node metastasis; lymphangiogenesis; melanoma