Neuronal Trans‐Differentiation in Prostate Cancer Cells

Abstract

Neuroendocrine (NE) differentiation in prostate cancer (PCa) is an aggressive phenotype associated with therapy resistance. The complete phenotype of these cells is poorly understood. Clinical classification is based predominantly on the expression of standard NE markers. We analyzed the phenotype of NE carcinoma of the prostate utilizing in vitro methods, in silico, and immunohistochemical analyses of human disease. Results LNCaP cells, subjected to a variety of stressors (0.1% (v/v) fetal bovine serum, cyclic AMP) induced a reproducible phenotype consistent with neuronal trans-differentiation. Cells developed long cytoplasmic processes resembling neurons. As expected, serum deprived cells had decreased expression in androgen receptor and prostate specific antigen. A significant increase in neuronal markers also was observed. Gene array analysis demonstrated that LNCaP cells subjected to low serum or cAMP showed statistically significant manifestation of a human brain gene expression signature. In an in silico experiment using human data, we identified that only hormone resistant metastatic prostate cancer showed enrichment of the “brain profile”. Gene ontology analysis demonstrated categories involved in neuronal differentiation. Three neuronal markers were validated in a large human tissue cohort. This study proposes that the later stages of PCa evolution involves neuronal trans-differentiation, which would enable PCa cells to acquire independence from the neural axis, critical in primary tumors.

AKR1C3 mediates pan‐AR antagonist resistance in castration‐resistant prostate cancer

“…Under standard growth conditions, the resistant cells underwent a marked change in morphology, characterized by increased elongated neuronal‐like appearance (Figure 3A). Similar phenotypic changes have been observed using preclinical models cultured in androgen deprivation conditions 17 . The LNCaP JNJR cells formed clusters regardless of cell confluence while the LNCaP DMSO cells tended to separate until forming a confluent monolayer.…”

Gene Expression Signature Predictive of Neuroendocrine Transformation in Prostate Adenocarcinoma

“…SLC35D3, which showed a dramatic up-regulation also in NEPC PDXs from the independent dataset GSE59984 (data not shown), is specifically expressed in the substantia nigra, striatum, and olfactory bulb in mouse brain and it functions as an ER chaperone for dopamine receptor D1 trafficking to the plasma membrane [47]. Finally, it has been demonstrated that NEFM was diffusely expressed in prostate cancer cells undergoing neuronal trans-differentiation [48] and NOL4 was described as a biomarker for aggressiveness prostate cancer [49]. In our study, we derived a NEPC signature starting from primary prostate adenocarcinomas, as assessed by an experienced pathologist.…”

EMT, stemness and tumor plasticity in aggressive variant neuroendocrine prostate cancers

“…Several different AR + /PSA + prostate cancer cell lines can be reprogrammed to intermediary “metastable” states with cancer stem cell (CSC) properties (exemplified by NE differentiation markers, an invasive phenotype, and robust tumor-initiating potential) upon anti-androgen treatment [35, 36]. These states, however, are transient and can be reversed to AR + states by stopping the treatment.…”