Origin of androgen-insensitive poorly differentiated tumors in the transgenic adenocarcinoma of mouse prostate model.
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.
Huss
Wendy J
WJ
Department of Urologic Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. wendy.huss@roswellpark.org
Gray
Danny R
DR
Tavakoli
Keyvan
K
Marmillion
Meghan E
ME
Durham
Lori E
LE
Johnson
Mac A
MA
Greenberg
Norman M
NM
Smith
Gary J
GJ
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
D000728:Androgens; D000952:Antigens, Polyomavirus Transforming; C496503:Foxa2 protein, mouse; D011944:Receptors, Androgen; D016708:Synaptophysin; D051542:Hepatocyte Nuclear Factor 3-beta; D001973:Bromodeoxyuridine