Origin of Androgen-Insensitive Poorly Differentiated Tumors in the Transgenic Adenocarcinoma of Mouse Prostate Model

Abstract

Following castration, the transgenic adenocarcinoma of mouse prostate (TRAMP) model demonstrates rapid development of SV40-Tag-driven poorly differentiated tumors that express neuroendocrine cell markers. The cell population dynamics within the prostates of castrated TRAMP mice were characterized by analyzing the incorporation of 5-bromodeoxyuridine (BrdUrd) and the expression of SV40-Tag, synaptophysin, and androgen receptor (AR). Fourteen days postcastration, the remaining epithelial cells and adenocarcinoma cells were nonproliferative and lacked detectable SV40-Tag or synaptophysin expression. In contrast, morphologically distinct intraglandular foci were identified which expressed SV40-Tag, synaptophysin, and Ki67, but that lacked AR expression. These proliferative SV40-Tag and synaptophysin-expressing intraglandular foci were associated with the rare BrdUrd-retaining cells. These foci expanded rapidly in the postcastration prostate environment, in contrast to the AR- and SV40-Tag-expressing adenocarcinoma cells that lost SV40-Tag expression and underwent apoptosis after castration. Intraglandular foci of synaptophysin-expressing cells were also observed in the prostates of intact TRAMP mice at a comparable frequency; however, they did not progress to rapidly expanding tumors until much later in the life of the mice. This suggests that the foci of neuroendocrine-like cells that express SV40-Tag and synaptophysin, but lack AR, arise independent of androgen-deprivation and represent the source of the poorly differentiated tumors that are the lethal phenotype in the TRAMP model.

Lobe-Specific Carcinogenesis in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) Mouse Model

“…The other three tumors were not traceable to any lobe location due to their overwhelming large sizes. These data were consistent with two recent studies showing a preponderance of SYP positive NECa arising from VP in the TRAMP mice of both C57BL/6 and FVB backgrounds [9,10]. In contrast, the weight of macroscopic tumor-free VP lobes was only slightly increased in TRAMP mice compared to their wild type littermates at 24 WOA (Table 2 [15]), whereas the DLP lobes underwent significant expansion (more than doubled) in the TRAMP mice in one study where these lobes were compared side by side [14,15].…”

“…However, several recent studies have suggested that the poorly-differentiated neuroendocrine (NE)-like carcinomas (NECa) [9,10] belonged to a distinct lineage from the epithelial lesions, which included low and high grade PIN, WD to MD "adenocarcinomas" of the original classification by Dr. Greenburg [8]. Those epithelial lesions were recently termed "atypical hyperplasias of T-Ag" (AHT) to distinguish from the human prostate cancer pathogenesis because they did not invade adjacent tissues [9].…”

“…In the C57BL/6 background, the lifetime incidence of NECa was estimated to be about 20% whereas in the FVB background, 87% NECa incidence was recorded by as early as 16 weeks of age and reached 100% by 20 weeks of age [9]. Furthermore, these NECa mostly arose in the ventral prostate (VP) lobes instead of the DLP in both strains [9,10]. Tissue reconstitution experiments carried out by Chiaverotti et al indicated that NECa did not arise from the trans-differentiation of preexisting AHT [9].…”

Interleukin-1β Promotes Skeletal Colonization and Progression of Metastatic Prostate Cancer Cells with Neuroendocrine Features

“…The acquisition of a neuroendocrine phenotype is frequently induced by the ADT commonly used for patients with advanced prostate adenocarcinoma (9,34,35) and is also observed in transgenic animal models of prostate cancer upon castration (36). These observations would suggest that the convergence of ADTinduced neuroendocrine transdifferentiation and increased expression of IL-1b underpins the propensity of prostate cancer cells to colonize the skeleton and eventually progress to secondary bone lesions.…”

Iodine Uptake and Prostate Cancer in the TRAMP Mouse Model

“…undifferentiated cancer at 18 or 30 wks. Nevertheless, in the TRAMP model, it was found that prostate cancer could progress to an invasive neuroendocrine phenotype (42,43). It would be interesting to analyze the role of iodine in the acquisition of the neuroendocrine phenotype, since recent studies in neuroblastoma cells show that I 2 induces antiproliferative effects and sensitizes these cells to the differentiating effects of retinoic acid (9,44).…”