Literature Review: Focal NED in Prostate Cancer

NED in prostate cancer generally refers to the presence of NE cells focally in otherwise typical conventional adenocarcinomas (Figure 4). The NE cells are indistinguishable from the non-NE cancer cells morphologically and are usually identified by immunohistochemical study for NE markers or less commonly, by electron microscopy. Chromogranin-A is the most commonly used marker and is considered to be sensitive and specific. All carcinomas of the prostate have at least some NED (Abrahamsson et al, 1987) when multiple generic NE markers and/or specific peptides/neuropeptides are used and tissue preparation is controlled. About 5-10% of prostatic carcinomas have rather extensive multifocal NED. The significance of NED as an independent prognostic factor in androgen responsive prostate cancer is controversial. Some studies showed independent prognostic significance (Dema et al, 1996; Weinstein et al, 1996; Theodorescu et al, 1997; Cohen et al, 1991; Bollito et al, 2001; Yu et al, 2001) while many others did not (Bohrer and Schmoll, 1993; Aprikian et al, 1994: Cohen et al, 1994; Allen et al, 1995; Noordzij et al, 1995; Bubendorf et al, 1996; McWilliam et al, 1997; Speights et al, 1997; Abrahamsson et al, 1998; Casella et al, 1998; Segawa et al, 2001; Bostwick et. al. 2002; Steineck et al, 2002). There is more consistent evidence based on immunohistochemical and serologic studies that NE differentiation is a prognostic factor in androgen independent prostate cancer (Krijnen et al, 1997; Jiborn et al, 1998; Ischia et al, 2000; Berruti et al, 2000). NED increases in high grade/high stage tumors (Abrahamsson et al, 1989; Bohrer and Schmoll, 1993) and, particularly, in androgen deprived (Ahlgren, 2000; Ismail et al, 2002) and androgen independent tumors (Jiborn et al, 1998; Ito et al, 2001; Hirano et al, 2004), although divergent findings have been reported (Kollermann and Helpap, 2001; Li et al, 2003). Consistent with these findings, serum chromogranin-A levels are increased in patients with advanced, androgen independent cancers (Deftos et al, 1996; Cussenot et al, 1996; Berruti et al, 2000; Ferrero-Pous et al, 2001; Isshiki et al, 2002). Measuring serum chromogranin A levels may be of value in prostate cancer patients with false negative PSA or %F-PSA (Ahel et al, 2001) and can be used to monitor treatment response (Zaky Ahel et al, 2001). In patients with advanced prostate cancer receiving hormonal therapy, increase in the serum levels of chromogranin-A may precede PSA elevation and signal treatment failure (Chuang et al, 2003) and correlates with bone metastasis (Tarle et al, 2002). Intermittent administration of complete androgen deprivation therapy significantly reduces the increase in serum chromogranin-A levels in comparison to continuous therapy (Sciarra et al, 2003). The serum levels of NSE may also have prognostic significance (Kamiya et al, 2003; Hvamstad et al, 2003). Other serum markers such as chromogranin B, secretoneurin, which is a proteolytic product of secretogranin II (chromogranin C), and gastrin-releasing peptide/ProGRP may serve as additional prognostic and/or diagnostic markers (Angelsen et al, 1997B; Ischia et al, 2000; Lilleby et al, 2001; Yashi et al, 2002, 2003; Nagakawa et al, 2002). Serum calcitonin appears to be a more specific marker for small cell carcinoma of the prostate (Sim et al, 1996).).

Androgen Deprivation and Neuroendocrine Differentiation

In addition to histologic studies, there is biochemical evidence that androgen deprivation may induce NE activity in prostate cancer. Neutral endopeptidase 24.11 (NEP) is a cell surface enzyme expressed by prostatic epithelial cells and functions to cleave and inactivate a variety of neuropeptides. Down-regulation of NEP after androgen deprivation may lead to increased secretion of neuropeptides such as neurotensin by the NE cells. Interestingly, only androgen-deprived tumor cells respond to the growth-promoting effect of neurotensin (Sehgal et al, 1994). The expression and catalytic activity of NEP are lost in androgen-independent but not androgen-dependent prostate cancer cell lines. In vivo, metastatic cancer cells from patients with androgen-independent prostate cancer commonly show decreased levels of NEP compared with those from patients with androgen-dependent prostate cancer. Growth of androgen-independent cancer cells is inhibited by overexpression of NEP or incubation with recombinant NEP (Papandreou et al, 1998).

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