Neurotrophin receptor p75^NTR suppresses growth and nerve growth factor‐mediated metastasis of human prostate cancer cells

Abstract

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.

CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression

“…15,[28][29][30][31] Among the targets that CASZ1 suppresses are the metastasis enhancers HGF and KITLG. 32,33 Preliminary studies have not identified a single critical target gene that mediates CASZ1 functions and current studies are aimed at delineating the targets and signaling pathways by which CASZ1 suppresses tumor growth and metastasis.…”

Distribution and significance of nerve growth factor receptor (NGFR/p75NTR) in normal, benign and malignant breast tissue

“…These findings give further indirect evidence to the reported tumour/metastasis suppressor properties of NGFR. [7][8][9][10][11][12][13] Furthermore, studies addressing the prognostic impact of NGFR expression in basal-like carcinomas are warranted.…”

“…4 Studies in prostate and urothelial cancer suggest that NGFR may act as a tumour suppressor, negatively regulating cell growth and proliferation. [7][8][9][10][11][12][13] Previous studies on NGFR expression in breast carcinomas showed no direct association between the expression of this receptor and either diseasefree or overall survival. 14 However, the ratio between NGF:NGFR was reported to be of prognostic significance.…”

Epigenetic Inactivation and Tumor-Suppressor Behavior of NGFR in Human Colorectal Cancer

“…In breast cancer and melanoma, p75NGFR acts as an oncogene, increasing cell proliferation, survival, and migration (6,(20)(21)(22). In contrast, in prostate cancer and neuroblastoma, p75NGFR acts as a tumor-suppressor gene, inducing apoptosis and inhibiting cell proliferation and invasion (23)(24)(25)(26)(27). Although p75NGFR is a conditional tumor suppressor in several types of cancers, the function of p75NGFR in colorectal cancer remains unclear.…”

“…The culture medium was changed every 24 hours. An equivalent concentration of DMSO was used in the control group.…”