Neuroendocrine prostate tumors mimic endocrine differentiation of pancreatic beta cells in 12t-10 mice: foxa2 and mash-1 the key players in neuroendocrine differentiation of prostate tumors.

Abstract

Neuroendocrine (NE) prostate cancer develops as an aggressive disease that does not respond to androgen ablation therapy. The paracrine action of NE cells can facilitate progression of androgen dependent adenocarcinoma to an androgen independent state, suggesting a significant role for NE cells during failure of androgen ablation therapy. To investigate the pathways involved in NE differentiation of prostate cancer, we looked at the expression of genes involved in endocrine differentiation of -cells in the pancreas. This study was performed using the NE prostate cancer mouse model (12T-10) and the derivative allograft model (NE-10). Immunohistochemical studies show that neuroendocrine prostate tumors express 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 a sequence similar to pancreatic -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 the PIN lesion. Ngn3 and Nkx2.2 frequently appear in the invasive NE cancer. NE metastasis to lung and liver show a distinct gene expression pattern. The lung metastasis expresse Ngn3 but not Nkx2.2 whereas liver metastases express Nkx2.2 but not Ngn3 These results suggest that Ngn3 and Nkx2.2 expression are markers for site-specific metastasis and/or transcriptionally regulated genes required for organ-specific metastasis. This study indicates that a pathway similar to pancreatic -cell differentiation is involved in NE differentiation of prostate cancer. In the second part of this study the significance of Foxa2 expression in the formation of NE tumors was determined by conditionally knocking it out in the NE tumors of the TRAMP mice. The Foxa2 knocked out TRAMP mice could still develop NE prostate tumors that now started expressing mash-1. These results suggest that NE tumors can develop in the absence of Foxa2 and there are at the very least three classes of NE tumors, one that expresses Foxa2, one expresses mash-1 and one that expresses both.