Transdifferentiation of Prostate Cancer Cells to a Neuroendocrine Cell Phenotype in Vitro and in Vivo

Abstract

Exposure of LNCaP cells to a hormone deficient medium drastically increased cyclic AMP production and this may identify the biochemical pathway through which hormone depletion induces a neuroendocrine conversion of prostate cancer cells. Hormone depletion also reduced TGF-beta2 mRNA expression and this finding was consistent with our inability to demonstrate any effect of TGF-beta2 on neuroendocrine conversion in vitro. Finally, our demonstration of increased neuroendocrine cells found in LNCaP tumors growing in castrated immunodeficient mice suggests that the neuroendocrine cells associated with advanced human prostate tumors in vivo, arise from prostate cancer cells through the transdifferentiation process.

Phosphatidylinositol 3-Kinase-AKT-Mammalian Target of Rapamycin Pathway Is Essential for Neuroendocrine Differentiation of Prostate Cancer

“…This finding supports the trans-differentiation model and suggests that NE cells may be derived from the non-NE secretory-type cancer cells (13,14). However, the signaling pathway involved in the differentiation process is unclear.…”

“…Androgen withdrawal of the culture media leads to NED of LNCaP cells, a PC cell line (13), mimicking in vivo observation in PC patients treated hormonally. This finding supports the trans-differentiation model and suggests that NE cells may be derived from the non-NE secretory-type cancer cells (13,14).…”

“…LNCaP is a very useful model because androgen withdrawal induces NED, mimicking in vivo situations in PC patients receiving hormonal therapy (13). With this model, we and others have shown that protein-tyrosine phosphatases may play a role in NED (26 -28).…”

Overexpression of an α1H (Cav3.2) T-type Calcium Channel during Neuroendocrine Differentiation of Human Prostate Cancer Cells

“…This implies that neuroendocrine differentiation probably occurs through distinct intracellular pathways, as previously hypothesized (11), even if there are few evidences that depletion in androgens can increase intracellular cAMP (32) in prostate LNCaP cells. In addition, androgen removal increased the proportion of cells expressing the T-type calcium current and the overall calcium current density.…”

Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer

“…Burchardt et al reported that LNCaP cells inoculated into castrated mice induced a significant increase in NE cells compared with those in intact mice. 28 Although the mechanism of NE transdifferentiation induced by androgen deprivation of AR-dependent PCa cells has been investigated, the mechanism mediating NE differentiation is still not clear. 29 Our data demonstrated that fibroblasts stimulated proliferation and AR expression in PCa cells under androgen deprivation in vitro.…”