Progression of prostate cancer from a subset of p63-positive basal epithelial cells in FG/Tag transgenic mice.
Transgenic mice that allow targeting of SV40 T antigen (Tag) to the prostate provide a unique model to identify cancer-initiating cells and follow their progression from a normal cell phenotype into prostate cancer cells. We have developed the FG/Tag transgenic mouse model of prostate cancer using the human fetal globin (FG) promoter linked to Tag. Immunohistochemistry results show that before the development of prostate intraepithelial neoplasia (PIN), a subset of p63(+) basal epithelial cells expresses Tag. As in the case of human prostate cancer, there is a loss of p63(+) basal cells with neoplastic progression, and a long period of time is required for PIN lesions to develop into palpable prostate tumors. Other immunohistochemistry results show cellular heterogeneity in FG/Tag PIN lesions and primary tumors with neuroendocrine differentiation. Cell lines derived from primary prostate tumors showed characteristics of a neuroendocrine-epithelial intermediate cell type. The FG promoter has high transcriptional activity in intermediate (DU 145, PC-3) and p63(+) basal epithelial (LHSR-AR) prostate cancer cells. Therefore, the unexpected development of prostate cancer in the FG/Tag mice may be due to the presence of DNA elements in the FG promoter that can target Tag to specific basal or intermediate cells. We conclude that FG/Tag mouse is a unique model of prostate cancer because the initiating cells are a subset of p63(+) basal (possibly stem cells), which may be the true cells of origin for carcinogenesis in aggressive human prostate cancer.
Reiner
Teresita
T
Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
de Las Pozas
Alicia
A
Parrondo
Ricardo
R
Perez-Stable
Carlos
C
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D004847:Epithelial Cells / Q000737:chemistry; D005914:Globins / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000032:analysis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D015534:Trans-Activators / Q000032:analysis
D000952:Antigens, Polyomavirus Transforming; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D005914:Globins