Neuropilin-2: A novel biomarker for malignant melanoma?
Neuropilin-2, a cell surface receptor involved in angiogenesis and axonal guidance, has recently been shown to be a critical mediator of tumor-associated lymphangiogenesis. Given that lymphangiogenesis is a major conduit of metastasis in melanomas and that blocking neuropilin-2 function in vivo is effective in inhibiting tumor cell metastasis, we sought to determine the clinical relevance of neuropilin-2 expression in cutaneous melanoma. Immunohistochemical analysis of neuropilin-2 expression was evaluated in nevomelanocytic proliferations that included a tissue microarray and histologic sections from samples of primary melanomas (n = 42; 40 for tissue microarray, 2 for histologic sections), metastatic melanomas (n = 30; 22 for tissue microarray, 8 for histologic sections), and nevi (n = 30; 5 for tissue microarray, 25 for histologic sections), as well as a panel of normal human tissues and select nonmelanocytic tumors. Staining for grading and intensity of neuropilin-2 expression was estimated semiquantitatively as follows for the former: less than 20%, 20% to 60%, and more than 60% of tissue present, and for the latter from 0 to 3, with 3 being the highest and 0 the lowest intensity. In nevomelanocytic proliferations, more than 20% staining for neuropilin-2 was noted in 36 (86%) of 42 cases of primary melanoma, in 27 (90%) of 30 cases of metastatic melanoma, and in 9 (30%) of 30 cases of nevi with differences achieving statistical significance between melanoma (primary and metastatic) and nevi (P < .0001). For staining intensity, an intensity of 2 or more was noted in 36 (86%) of 42 cases of primary melanoma, in 17 (57%) of 30 cases of metastatic melanoma and in 7 (30%) of 23 cases of nevi, with differences achieving statistical significance between melanoma (primary and metastatic) and nevi (P < .0001). In normal human tissue, consistently strong neuropilin-2 staining was noted in kidney (glomerular endothelial cells, collecting tubules, and collecting ducts), skin (epidermal keratinocytes), and testes (epithelium of the seminiferous tubules), whereas in tumoral tissue, consistently strong staining was noted only in renal cell carcinoma but not in any of the other tumors studied. More recently, using a heterotypic coculture methodology with melanoma and endothelial cells, we have demonstrated successful up-regulation of neuropilin-2 and confirmed the critical role of neuropilin-2 in melanoma-endothelial interactions. Because these coculture methods were developed to model melanoma metastasis, the significantly increased and enhanced expression of neuropilin-2 staining in primary and metastatic melanoma versus nevi in the current study suggests that it is also relevant in vivo.