Neuropilin-2: a novel biomarker for malignant melanoma?

Abstract

Neuropilin-2 (NRP2), 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 NRP2 function in vivo is effective in inhibiting tumor cell metastasis, we sought to determine the clinical relevance of NRP2 expression in cutaneous melanoma. Immunohistochemical analysis of NRP2 expression was evaluated in nevomelanocytic proliferations that included a tissue microarray (TMA) and histologic sections (HS) from samples of primary melanomas (n=42; 40 TMA, 2 HS), metastatic melanomas (n=30; 22TMA, 8 HS) and nevi (n=30; 5 TMA, 25HS), as well as a panel of normal human tissues and select non-melanocytic tumors. Staining for grading and intensity of NRP2 expression was estimated semi-quantitatively as follows for the former: <20%, 20-60% and >60% of tissue present and, for the latter from 0-3 with 3 being the highest and 0 the lowest intensity. In nevomelanocytic proliferations, >20% staining for NRP2 was noted in 36/42 cases (86%) of primary melanoma, in 27/30 cases (90%) of metastatic melanoma and in 9/30 cases (30%) of nevi with differences achieving statistical significance between melanoma (primary and metastatic) and nevi (p<0.0001). For staining intensity, an intensity of 2 or more was noted in 36/42 cases (86%) of primary melanoma, in 17/30 cases (57%) of metastatic melanoma and in 7/23 (30%) of nevi with differences achieving statistical significance between melanoma (primary and metastatic) and nevi (p<0.0001). In normal human tissue, consistently strong NRP2 staining was noted in kidney (glomerular endothelial cells, collecting tubules and collecting ducts), skin (epidermal keratinocytes) and testes (epithelium of the seminiferous tubules), while 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 co-culture methodology with melanoma and endothelial cells, we have demonstrated successful up-regulation of NRP2 and confirmed the critical role of NRP2 in melanoma-endothelial interactions. Since these co-culture methods were developed to model melanoma metastasis, the significantly increased and enhanced expression of NRP2 staining in primary and metastatic melanoma versus nevi in the current study suggests that it is also relevant in vivo.

Neuropilin-2 as a useful marker in the differentiation between Spitzoid malignant melanoma and Spitz nevus

“…Our data are similar to those of other investigators, who found NRP2 to be expressed in 86% of primary MM and 90% of metastatic MM. 16 We found that the majority of SMM (15/19, 79%) showed diffuse staining pattern with moderate to strong staining intensity and moderate or high SIS. In 4 of 19 SMM cases (21%) the staining was weak and the SIS was low.…”

“…NRP2 staining is normally seen in liver, kidney, fallopian tubes, pancreas, placental tissue, testis, prostate, striated muscle cells, and suprabasal epidermis. 16 We used suprabasal epidermis as an internal positive control for NRP2.…”

“…15 NRP2 has recently been shown to have a critical role in melanoma-endothelial interactions and lymphangiogenesis of MM. 16,17 Based on the expression of NRP2 in cutaneous MM we hypothesized that NRP2 could be a potential biomarker to distinguish SMM from SN.…”

Lymphangiogenesis and Anti-lymphangiogenesis in Cutaneous Melanoma

“…Based on this hypothesis, neuropilin-2 expression in malignant melanoma was studied and demonstrated in 86% of primary melanoma cases and in 90% of metastatic cases (50). Current data support the interaction between neuropilin and melanoma tumor cells and, taking into account the large number of positive cases, it may be considered as a biomarker of great interest in diagnosis.…”

Neuropilin-2: Novel Biomarker and Therapeutic Target for Aggressive Prostate Cancer

“…Such complexes could regulate and facilitate VEGF signalling and receptor trafficking. The presence of such complexes could be an explanation for most of the data 168 , ovarian 86,146,147 , pancreatic 91,148 , prostate 149,169 , renal cell carcinoma 180 , squamous 181 , melanoma 167 , ovarian 147,190,191 , pancreatic 84,188,[192][193][194] , breast 38,186,197,198 , colon 113,197 , lung 143,189,197 , melanoma 197,199 , ovarian 190 , pancreatic 193,194 …”