Modeling a Lethal Prostate Cancer Variant with Small-Cell Carcinoma Features

Abstract

Purpose Small-cell prostate carcinoma (SCPC) morphology predicts for a distinct clinical behavior, resistance to androgen ablation, and frequent but short responses to chemotherapy. We sought to develop model systems that reflect human SCPC and can improve our understanding of its biology. Experimental Design We developed a set of CRPC xenografts and examined their fidelity to their human tumors of origin. We compared the expression and genomic profiles of SCPC and large cell neuroendocrine carcinoma (LCNEC) xenografts to those of typical prostate adenocarcinoma xenografts. Results were validated immunohistochemically in a panel of 60 human tumors. Results The reported SCPC and LCNEC xenografts retain high fidelity to their human tumors of origin and are characterized by a marked upregulation of UBE2C and other mitotic genes in the absence of AR, retinoblastoma (RB1) and cyclin D1 (CCND1) expression. We confirmed these findings in a panel of CRPC patients' samples. In addition, array comparative genomic hybridization of the xenografts showed that the SCPC/LCNEC tumors display more copy number variations than the adenocarcinoma counterparts. Amplification of the UBE2C locus and microdeletions of RB1 were present in a subset, but none displayed AR nor CCND1 deletions. The AR, RB1, and CCND1 promoters showed no CpG methylation in the SCPC xenografts. Conclusion Modeling human prostate carcinoma with xenografts allows in-depth and detailed studies of its underlying biology. The detailed clinical annotation of the donor tumors enables associations of anticipated relevance to be made. Futures studies in the xenografts will address the functional significance of the findings.

Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas

“…To this end, in a previous study, we developed patient prostate tumor-derived xenografts (PDX) of AR-negative SCPC (AR ¡ SCPC) and compared the AR ¡ SCPC gene expression profiles to those of AR-positive adenocarcinomas (AR C ADENO) derived from men with CRPC. 7,8 In line with the findings of others, 9,10 we found that AR ¡ SCPC is characterized by a loss of prostate luminal epithelial markers and a gain of neural progenitor/stem cell markers. Because DNA methylation profiles reflect cellular differentiation, 11 we hypothesized that the DNA methylation profiles of AR ¡ and AR C are distinct and that specific DNA methylation markers might be used to detect AR ¡ disease, which is of therapeutic relevance.…”

The N-myc Oncogene: Maximizing its Targets, Regulation, and Therapeutic Potential

“…Similarly, short hairpin RNA (shRNA)-mediated silencing of N-myc in neuroblastoma cells has identified a 157 target-gene panel including those involved cell cycle, DNA repair, and neuronal differentiation genes; this panel has been associated with poor prognosis in patients with neuroblastoma. More recently, a similar set of N-myc-targeted genes has been observed in neuroendocrine prostate cancer, with upregulation of cell cycle and neuroendocrine type genes (35,56). In prostate cancer, Nmyc binds neuroendocrine and androgen-regulated gene promoters, suggesting direct involvement in neuroendocrine transformation.…”

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…Indeed, multiple potential 'drivers' of NEPC have been identified, almost all of which precede, accompany, or are controlled by a loss of AR expression or activity. For example, although the AR is a major regulator of PCa cell proliferation, in NEPC models without AR expression, mitotic deregulation that leads to hyperproliferation occurs upon the loss of RB1 and cyclin D1, which suggests that the loss of this key tumor suppressor pathway may actually precede the AR loss that is observed in NEPC (Tzelepi et al 2012). Indeed, up to 90% of NEPC tumors lack RB1 (Tan et al 2014), which highlights the importance of cell cycle regulators in this disease.…”