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.

• Authors: Wendy J Huss, Danny R Gray, Keyvan Tavakoli, Meghan E Marmillion, Lori E Durham, Mac A Johnson, Norman M Greenberg, Gary J Smith
• Journal: Neoplasia (New York, N.Y.) (Neoplasia) Vol. 9 Issue 11 Pg. 938-50 (Nov 2007) ISSN: 1476-5586 [Electronic] United States
• PMID: 18030362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Androgens
• Antigens, Polyomavirus Transforming
• Foxa2 protein, mouse
• Receptors, Androgen
• Synaptophysin
• Hepatocyte Nuclear Factor 3-beta
• Bromodeoxyuridine

Topics

• Adenocarcinoma (pathology)
• Androgens (physiology)
• Animals
• Antigens, Polyomavirus Transforming (analysis, genetics)
• Apoptosis
• Bromodeoxyuridine (metabolism)
• Cell Proliferation
• Disease Models, Animal
• Hepatocyte Nuclear Factor 3-beta (analysis)
• Lymphatic Metastasis
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Orchiectomy
• Prostatic Neoplasms (blood supply, metabolism, pathology)
• Receptors, Androgen (analysis)
• Simian virus 40 (immunology)
• Synaptophysin (analysis)