title: 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.affiliation: Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. wendy.huss@roswellpark.org
authors.forename: Wendy J
authors.initials: WJ
authors.lastname: Huss
authors.forename: Danny R
authors.initials: DR
authors.lastname: Gray
authors.forename: Keyvan
authors.initials: K
authors.lastname: Tavakoli
authors.forename: Meghan E
authors.initials: ME
authors.lastname: Marmillion
authors.forename: Lori E
authors.initials: LE
authors.lastname: Durham
authors.forename: Mac A
authors.initials: MA
authors.lastname: Johnson
authors.forename: Norman M
authors.initials: NM
authors.lastname: Greenberg
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Smith
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000728:Androgens / Q000502:physiology*; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000032:analysis / Q000235:genetics; D017209:Apoptosis; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051542:Hepatocyte Nuclear Factor 3-beta / Q000032:analysis; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D011944:Receptors, Androgen / Q000032:analysis; D013539:Simian virus 40 / Q000276:immunology; D016708:Synaptophysin / Q000032:analysis
chemical_list: D000728:Androgens; D000952:Antigens, Polyomavirus Transforming; C496503:Foxa2 protein, mouse; D011944:Receptors, Androgen; D016708:Synaptophysin; D051542:Hepatocyte Nuclear Factor 3-beta; D001973:Bromodeoxyuridine