Correlation of overexpression of the low-affinity p75 neurotrophin receptor with augmented invasion and heparanase production in human malignant melanoma cells

The role of growth factor receptors in regulating the progression of human melanocytes toward tumorigenicity and ultimately a malignant phenotype is poorly understood. In particular, the autocrine and paracrine influences that modulate cellular invasion and extracellular matrix (ECM)-degradative enzymes in melanoma cells remain undefined at the molecular level. The low- affinity p75 neurotrophin receptor (p75(NTR)), a cysteine-rich transmembrane glycoprotein, is frequently expressed in advanced stages of human melanoma, but the biological consequences of this expression are unknown, p75(NTR) can enhance the invasive potential of brain-metastatic melanoma cells in vitro. We have extended here these results and related the level of p75(NTR) in human metastatic melanoma cells to their invasive potential to target organs other than brain. Fluorescence activated cell sorting (FACS) analysis showed that 3 melanoma cell lines (SK-MEL-146, SK-MEL-119, 70W) had differential p75(NTR) contents, whereas SK-MEL-147 cells had elevated amounts of p75(NTR). Two other melanoma cell lines (SK-MEL-94, SK-MEL-110) with point mutations in the p75(NTR) transmembrane domain had reduced (SK-MEL-94) or absent (SK-MEL- 110) p75(NTR). We also examined these cell lines for presence of TrkA receptor, the high-affinity receptor for nerve growth factor (NGF), the prototypic neurotrophin. No TrkA receptor expression was detected in any of the cell lines. The extent of p75(NTR) expression correlated with the capability of NGF to promote cellular invasion and with production of heparanase, an important ECM-degradative enzyme. Melanoma cells sorted for high p75(NTR) expression (p75(NTR-H) cells) had markedly greater (9- to 13- fold increase) invasive capabilities in response to NGF exposure than those sorted for low p75(NTR) expression (p75(NTR-L) cells). Additionally, NGF induced a 8- to 10-fold increase of heparanase activity in p75(NTR-H) cells. Thus, we propose that p75(NTR)-mediated trophic support profoundly affects melanoma cell invasion to neurotrophin-rich organs.