Neurotrophin receptor p75(NTR) suppresses growth and nerve growth factor-mediated metastasis of human prostate cancer cells.

The loss of tumor- and/or metastasis-suppressor gene function contributes to the transformation of human prostate epithelial cells to a malignant pathology. Such a putative tumor-suppressor and metastasis-suppressor gene(s) has been mapped to the region of 17q21, which coincidentally is in the vicinity of the human gene locus for the neurotrophin receptor p75(NTR). The p75(NTR) is expressed in normal human prostate epithelial cells and exhibits an inverse association of p75(NTR) expression with the malignant progression of the prostate, consistent with a pathologic role of the p75(NTR) as a putative tumor and metastasis suppressor. Utilizing stable transfectants of the TSU-pr1 and PC-3 human prostate tumor cell lines that exhibit a rank order (dose-dependent) increase in p75(NTR) protein expression, we investigated the effects of the p75(NTR) in combination with its predominant ligand, nerve growth factor (NGF), on tumor cell growth. A rank order (dose-dependent) increase in p75(NTR) expression was found to suppress the growth of prostate tumors in severe combined immunodeficient (SCID) mice. Treatment of these tumors with NGF stimulated both proliferation as indicated by PCNA expression and apoptosis as indicated by TUNEL assay, the net result of which was no change in the overall growth of the tumors. However, NGF was found to increase the formation of satellite tumors, both contiguous and noncontiguous with respect to the primary tumor mass, indicating dose-dependent induction of metastasis. Significantly, the formation of satellite tumors was suppressed by the expression of p75(NTR). This suggests that p75(NTR) is a tumor suppressor of growth and a metastasis suppressor of NGF-stimulated migration of human prostate tumor cells.