Literature Review: Neuroendocrine Function in Prostate Carcinoma

The function of NED in prostate cancer has been extensively studied. Results from a recent study using xenograft mice and in-vitro assays suggest that NE cells may directly activate androgen-receptor, thus promoting growth of LNCaP tumor cells in the absence of androgen (Jin et al, 2004). Bombesin acts as a mitogen in prostate cancer and may do so through activation of the transcription factor Elk-1 and the immediate early gene c-fos (Xiao et al, 2002). In in-vitro assays, neuropeptides stimulate androgen-independent growth (Jongsma et al, 2000B) and the invasiveness of prostate cancer cell lines (Hoosein et al, 1993). Both protein tyrosine kinase and protein kinase C pathways may be required for the activity of neuropeptides (Aprikian et al, 1997; Allard et al, 2000; Salazar and Rozengurt, 1999; Sumitomo et al, 2000; Xiao et al, 2003). The activity of the type IV collagenases matrix metalloprotease (MMP) is up-regulated by neuropeptides (Sehgal and Thompson, 1998). MMPs are associated with a variety of biological activities, such as tumor invasion, metastasis, and angiogenesis. MT1-MMP protein and mRNA are expressed in androgen-independent PC-3, DU-145 and TSU-pr1 cells but not in the androgen-dependent LNCaP cells. GRP induces the expression of MT1-MMP protein in DU-145 cells and also increases Matrigel invasion by these cells (Nagakawa et al, 2000). High-grade tumors are more likely to express MMP-9 and bombesin than low-grade tumors (Ishimaru et al, 2002). Bombesin increases the expression of the proteolytic enzyme urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) and also stimulates secretion and activation of MMP-9 (Festuccia et al, 1998). Calcitonin affects growth and migration of certain prostate cancer cell lines and may play a role in the regulation of prostate cell growth and metastases, especially to the bone (Ritchie et al, 1997). Certain receptors for serotonin may be overexpressed in prostate cancer cells, particularly in high grade tumors, further supporting the hypothesis that NE products may promote androgen-independence of prostate cancer through a paracrine mechanism (Dizeyi et al, 2004).

NED may affect the apoptosis-resistance of prostate cancer.

The tissue levels of NSE correlate with Bcl-2, a major anti-apoptotic factor, and the Bcl-2-containing cancer cells are generally in close proximity to the NE cells (Segal et al, 1994), suggesting that NE cells may confer apoptosis-resistance to the neighboring cancer cells. Bombesin and calcitonin prevent apoptosis of prostate cancer cells in-vitro (Salido et al, 2000, 2004; Vilches et al, 2004). NE cells do not appear to undergo apoptosis (Bonkhoff et al, 1997; Fixemer et al, 2002) even though they are negative for Bcl-2 (Xue et al, 1997). They do express survivin, another anti-apoptotic factor (Xing et al, 2001), providing a molecular basis for the hypothesis that NE cells may endure stressful conditions and escape from apoptosis during cancer therapy.

NED may promote neovascularization of prostate cancer.

NE cells are the major producers of VEGF (Harper et al, 1996; Chevalier et al, 2002). VIP, which is produced by autonomic nerves and NE cancer cells of human prostate, stimulates NED and VEGF production in LNCaP cells (Collado et al, 2004). In benign prostatic tissue, there is negative to low level expression of VEGF. All prostate cancers stained positively for VEGF and staining intensity correlated with Gleason grade. Complete androgen block for three months before surgery decreased the level of VEGF and vascularization, except in the cell areas with NE features (Mazzucchelli et al, 2000). In radical prostatectomy specimens, there is a correlation between NE differentiation and neovascularization and both correlate with tumor grade and tumor stage. The number of NE cells was found to be the only predictor of neovascularization (Grobholz et al, 2000). Another study reported similar results and, in addition, found expression of VEGF to be significantly correlated with increased microvessel density, high tumor stage, poor differentiation and shortened disease-free survival (Borre et al, 2000). Bombesin stimulates expression of pro-angiogenic factors VEGF and IL-8 in PC-3 cells, possibly through NF-kappa B-dependent pathway (Levine et al, 2003). However, a recent study failed to show stimulation of proliferation, migration, or tube formation of human umbilical endothelial cells in-vitro by neurotensin and bombesin (Busby et al, 2004).

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