NE cells are normally present as a minor component in benign prostate and prostatic adenocarcinomas and their functions remain unclear. It has been observed that in cultured LNCaP cells, a cell line with luminal cell features, androgen withdrawal induces differentiation toward a NE phenotype (Burchardt et al. 1999
), suggesting that hormonal therapy in PC patients may drive luminal-type cancer cells into NE cancer cells. One interesting hypothesis is that the normally quiescent NE tumor cells may provide growth signals to the adjacent non-NE cancer cells through a paracrine mechanism, contributing to therapeutic failure and the progression to castration-resistant state (Vashchenko & Abrahamsson 2005
, Huang et al. 2007
, Yuan et al. 2007
, Sun et al. 2009
). Occasionally, the recurrent tumor contains pure populations of highly aggressive NE tumor cells and is classified as SCNC, although SCNC can also be seen in patients without a history of adenocarcinoma. With the advent of novel drugs such as Abiraterone and MDV3100 that show superior efficacy in the inhibition of AR signaling, we expect that the incidence of prostatic SCNC will only increase.
The cell of origin and the molecular basis for prostatic adenocarcinoma remain controversial. These issues are even less clear for prostatic SCNC. Our results are consistent with a model in which the NE cells in benign prostate and prostatic adenocarcinoma are normally quiescent due to the growth inhibitory function of an autocrine mechanism involving the IL8–CXCR2–p53 pathway. Mutation of p53
leads to inactivation of the above pathway leading to hyper-proliferation of NE cells with the resultant SCNC as shown in . In fact, in the absence of functional P53, activation of CXCR2 by IL8 appears to stimulate cell growth (), suggesting that CXCR2 may elicit both growth inhibitory and growth stimulatory pathways. Normally, the P53-mediated growth-inhibitory pathway may dominate. Once P53 is mutated, CXCR2 activation becomes growth promoting and oncogenic. This hypothesis is supported by previous reports showing that a CXCR2-neutralizing antibody can inhibit PC3 cell proliferation (Reiland et al. 1999
) and deletion of CXCR2 inhibits TRAMP tumors (Shen et al. 2006
Figure 5 The function of IL8–CXCR2–p53 pathway in controlling the proliferation of NE cells in benign prostate, adenocarcinoma, and SCNC. The model on the left suggests that autocrine activation of CXCR2 by IL8 activates the p53 pathway, which (more ...)
Therefore, we have identified a potential cell-of-origin as well as a molecular target for prostatic SCNS. It is unclear whether the NE cells in both benign prostate and adenocarcinoma can be the cells of origin for SCNS. It is possible that pure SCNC arising de novo may result from p53 mutation in NE cells of benign prostate, although we cannot exclude the possibility that SCNC always arises from NE cells of adenocarcinoma, but in some cases, the rapidly proliferating tumor NE cells have completely overtaken the slow-growing adenocarcinoma, resulting in the histological appearance of a pure SCNC. For those SCNCs that coexist with prostatic adenocarcinoma and those that are recurrent tumors in patients with a history of adenocarcinoma treated with hormonal therapy, the most likely mechanism appears to be p53 mutation in the NE cells of adenocarcinoma. For these patients, a likely scenario is that within the adenocarcinoma, a p53 mutation occurs in NE cell(s) during the course of hormonal therapy leading to the development of SCNC. The rapidly proliferating NE cells of SCNC can coexist with adenocarcinoma initially but eventually become the only component as adenocarcinoma cells usually have a low proliferation rate and this component can be completely overtaken by SCNC. Because of its distinct cell of origin and molecular alteration, SCNC is an entirely different disease from adenocarcinoma. In contrast to adenocarcinoma, prostatic SCNC is a disease of NE differentiation, likely has its cell of origin in NE cells of benign prostate and/or adenocarcinoma, with p53 mutation as the underlying molecular mechanism, and does not respond to hormonal therapy, which has proven to be effective, at least initially, in nearly all patients with prostatic adenocarcinomas.
Our results are consistent with findings in cell line models. We have shown that PC3 cells, a PC cell line originally derived from a patient’s bone metastasis, have NE features in that they express NE markers CgA and NSE (Palapattu et al. 2009
). Like NE cells in human prostate and prostatic adenocarcinoma, PC3 cells express IL8 (Ma et al. 2009
) and IL8 receptor CXCR2 (Reiland et al. 1999
) and are positive for CD44 (Palapattu et al. 2009
). Unlike NE cells in benign prostate and adenocarcinoma, PC3 cells are highly proliferative and biologically aggressive, features shared by SCNCs. Consistent with this notion, it has been shown that PC3 cells contain a p53
mutation and restoration of p53 function inhibits tumor cell growth (Isaacs et al. 1991
). Therefore, we have proposed that PC3 cells may actually represent a cell line of SCNC (Tai et al. 2011
Our model is supported by animal models of PC. Transgenic mice expressing SV40 early genes including T antigen (TRAMP) develop aggressive carcinomas with abundant NE tumor cells similar to human prostatic SCNC (Greenberg et al. 1995
, Masumori et al. 2001
), as do p53−/−Rb−/−
double knockout mice (Zhou et al. 2006
). In both models, the AR-responsive probasin promoter was used to drive the expression of the transgene or the Cre recombinase. Although AR is not usually expressed in NE cells, it is possible that a low level of AR is present in NE cells at some point of mouse prostate development and is sufficient to activate the probasin promoter. We hypothesize that in these animals, inactivation of p53 in NE cells of the prostate leads to malignant transformation and rapid proliferation of NE cells, resulting in the development of a malignant tumor with abundant NE tumor cells mimicking human prostatic SCNC. Notably, in both models, there are also areas of glandular formation resembling adenocarcinoma, which probably results from inactivation of p53 and/or Rb in luminal epithelial cells. In most of the TRAMP tumor tissues we have examined, NE tumor cells predominate, likely reflecting the highly proliferative nature of the malignant NE tumor cells.
The findings described here are also consistent with a previous report by De Marzo’s group who reported positive nuclear staining for p53 and a p53
mutation in a case of SCNC intermixed with adenocarcinoma (Hansel et al. 2009
). The p53
mutation discovered in their study differs from that identified in our cases, suggesting that a variety of p53
mutations may be found if a large number of SCNCs are sequenced.
It is noteworthy that SV40 T antigen inactivates both p53 and Rb in TRAMP tumors and the Nikitin group has shown that both p53 and Rb need to be inactivated in order for invasive tumors to develop (Zhou et al. 2006
). It is possible that, inactivation of Rb as well as p53 in NE cells is required for the development of prostatic SCNC in men. However, unlike p53 for which mutations are usually associated with protein accumulation in the nucleus detectable by immunohistochemistry, assaying for the inactivation of Rb pathway is not straightforward. Therefore, additional studies need to be performed to determine whether the Rb pathway, which appears to be important for prostatic adenocarcinoma (Balk & Knudsen 2008
), is also involved in the pathogenesis of prostatic SCNC in men.