Prostate cancer progression, metastasis, and gene expression in transgenic mice.
We previously reported that a transgenic mouse line containing the fetal globin promoter linked to the SV40 T antigen (T Ag) viral oncogene (Ggamma/T-15) resulted in prostate tumors. In this study, we further explored tumor origin, frequency, invasiveness, androgen sensitivity, and gene expression pattern. T Ag was detected in adult but not fetal and neonatal prostates, suggesting a role for androgens in tumor progression. However, castration shortly after prostate morphogenesis did not prevent tumor development, suggesting an androgen-independent phenotype. Tumors originated within ventral or dorsal prostate lobes and involved intraepithelial neoplasia, rapid growth in the pelvic region, and metastasis to lymph nodes and distant sites. In addition, the primary cancers could be propagated in nude mice or nontransgenic mice. Seventy-five percent of hemizygous and 100% of homozygous transgenic males developed prostate tumors, suggesting a T Ag dosage effect. Biochemical characterization of advanced tumors revealed markers of both neuroendocrine and epithelial phenotypes; markers of terminal differentiation are lost early in tumorigenesis. Tumor suppressor genes (p53 and Rb), normally bound to T Ag, were up-regulated; bcl-2 proto-oncogene, which prevents apoptosis, was slightly up-regulated. Myc, a stimulus to cell cycle progression, was unchanged. We propose the Ggamma/T-15 transgenic line as a model of highly aggressive androgen-independent metastatic prostate carcinoma with features similar to end-stage prostate cancer in humans.
Perez-Stable
C
C
Veterans Affairs Medical Center, and Department of Medicine, University of Miami School of Medicine, Florida 33101, USA.
Altman
N H
NH
Mehta
P P
PP
Deftos
L J
LJ
Roos
B A
BA
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000728:Androgens / Q000502:physiology; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma; D019254:Genes, bcl-2; D016259:Genes, myc; D016158:Genes, p53; D007633:Keratins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009919:Orchiectomy; D011230:Precancerous Conditions / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors
D000728:Androgens; D000952:Antigens, Polyomavirus Transforming; D053379:Chromogranin A; D002864:Chromogranins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D007633:Keratins