Neuroendocrine differentiation in the 12T‐10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells

Abstract

BACKGROUND. Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. It has been demonstrated that the paracrine action of NE cells facilitates the progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy. METHODS. To investigate the pathways that are involved in NE differentiation of prostate cancer, we have looked at the expression of genes known to be involved in endocrine differentiation of b-cells in the pancreas. This study has been performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10). RESULTS. Immunohistochemical studies have shown that the neuroendocrine prostate tumors express the transcription factors Foxa2, mouse achaete-scute homolog-1 (mash-1), neurogenin3 (Ngn3) and Nkx2.2. These tumors show a loss of hairy/enhancer of split (Hes-1), a gene that inhibits NE differentiation. Human NE prostate cancers also express Foxa2 and human achaete-scute homolog-1 (HASH-1). These genes are expressed in NE prostate tumors in the similar sequential manner as they appear in a pancreatic b-cell endocrine differentiation. Foxa2 expression is detected in early prostatic intraepithelial neoplasia (PIN). Mash-1 expression is detected in a few clusters within low grade PIN lesions and Nkx2.2 expression is rarely detected in individual scattered cells within the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. Subsequent NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresses Ngn3 but does not express Nkx2.2 whereas liver metastases do not express Ngn3 but express Nkx2.2. CONCLUSIONS. These results suggest that Ngn3 and Nkx2.2 expression are markers for sitespecific metastasis and/or transcriptionally regulated genes that are required for organ-specific Abbreviations: NE, neuroendocrine; NED, neuroendocrine differentiation; PIN, prostatic intraepithelial neoplasia; AR, androgen receptor; RT-PCR, reverse transcription-polymerase chain reaction;LGPIN, low grade prostatic intraepithelial neoplasia, HGPIN, high grade prostatic intraepithelial neoplasia.

NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM

“…Mechanism of action of NeuroD1 is carried out by downstream targets, which include the signaling molecules, the tyrosine kinase TrkB and NCAM. Neuroendocrine differentiation of tumors has become a topic of interest as differentiation of these tumors from epithelial cells has been hypothesized to be involved in acquisition of invasive/ metastatic phenotypes (12,14,16). NeuroD1 expression has recently been speculated to contribute to the transformation of epithelial cells to neuronal-like cells (12); this transformation may be the onset or termination neuroendocrine differentiation of prostate and other neuroendocrine cancers.…”

“…NeuroD1 is overexpressed in several aggressive neural/ neuroendocrine cancers including SCLC, medulloblastoma, gastric and prostate cancers, and pituitary adenomas (10)(11)(12)(13)(14)(15)(16). To characterize the mechanisms of NeuroD1 action in lung tumor pathogenesis, we analyzed a panel of lung cell lines.…”

A Prominent Couple

“…INSM1 recruits cyclin D1 and histone deacetylase 3 (HDAC3) leading to altered histone H3/4 acetylation and reduced promoter activity of target genes [70]. Further, concordant mechanisms in the endocrine differentiation of β-cells and NED in PCa have been suggested [71][72][73]. INSM1 was shown to co-occupy regulatory sequences that maintain the gene expression program in endocrine β-cells together with the bHLH protein NEUROD1 and FoxA2.…”

“…Absent AR expression and disproportional low PSA levels are hallmarks of NEPC [70,71]. NE foci exist within virtually all human prostate adenocarcinomas, reported incidence rates range from 25-90% [67,72,73]. It was suggested that the different morphologic manifestations of NEPC, i.e.…”

“…In 2014, the highest incidence rates for PCa in the US were in the age group of [65][66][67][68][69][70][71][72][73][74] years, while between 1975-1995 the incidence rates were in the group of 75 years or older indicating that the diagnosis is currently made at younger age [7]. The incidence rates for PCa are highly variable between different geographical areas, with highest incidence in industrialized countries [6].…”