Literature Review: Models of Neuroendocrine Differentiation

Animal Models

Animal models of prostate cancer recapitulate human diseases and provide more evidence suggesting the importance of NED in prostate cancer. In xenograft models of human prostate cancer, NED increases markedly after castration (Burchardt et al, 1999; Jongsma et al, 1999, 2000, 2002; de Pinieux et al, 2001) and precedes the emergence of increased cancer cell proliferation and progression to hormone-independent cancer (Huss et al, 2004). Extensive NED is also seen in an allograft model of androgen-independent prostate cancer (Masumori et al, 2004). In a transgenic mouse model of prostate cancer (TRAMP), the degree of NED correlates with the degree of tumor differentiation with the poorly differentiated tumors showing significantly more NED. Castration of TRAMP mice leads to aggressive and highly metastatic cancers in the majority of the cases, reflecting androgen-independent growth. NED was detected in the majority of the primary and metastatic tumors in such animals (Kaplan-Lefko et al, 2003). Animal models of NE/small cell prostate carcinoma have also been established and should prove useful in studying the molecular basis of NE phenotype (Garabedian et al, 1998; Hu et al, 2002; True et al, 2002).

Prostate Cancer Cell Lines

In vitro, LNCaP cells, an androgen-dependent cell line, can be induced to show NED by androgen deprivation or agents that increase intracellular levels of cAMP. The NE phenotype is rapidly lost upon withdrawal of inducing agents (Cox et al, 1999). These findings support the transdifferentiation model and suggest that the tumor NE cells may be derived from non-NE tumor cells. The caveat of this model is that NED of LNCaP cells is an “all or none” phenomenon and all cells acquire NE phenotype under appropriate culture conditions while NED in human cancers is focal, making interpretation of the in-vitro findings difficult. Alternatively, some investigators believe that NE cells may be derived from the same stem cell or pluripotent cell that give rise to luminal secretory cells (Bonkhoff and Remberger, 1996; Rumpold et al, 2002). In comparison to secretory epithelial cells, the NE cells, whether benign or malignant, generally do not express androgen receptor and PSA. They are considered terminally differentiated and post-mitotic (Bonkhoff et al, 1991, 1995, 1997). However, a recent report suggests that the malignant NE cells may possess proliferative activity (Huss et al, 2004). The origin of NE cells in prostate cancer is not entirely known. A population of transiently proliferating/amplifying intermediate cells has been identified which may be the common precursor for NE cells and other epithelial cells of the prostate (Xue et al, 1997; Schalken and van Leenders, 2003). Nonetheless, it is generally accepted that NE cells in prostate cancer are malignant since they are present in metastatic prostate cancers (Roudier et al, 2003, 2004).

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