Functional analysis of secreted caveolin-1 in mouse models of prostate cancer progression.
Previously, we reported that caveolin-1 (cav-1) is overexpressed in metastatic prostate cancer and that virulent prostate cancer cells secrete biologically active cav-1. We also showed that cav-1 expression leads to prosurvival activities through maintenance of activated Akt and that cav-1 is taken up by other cav-1-negative tumor cells and/or endothelial cells, leading to stimulation of angiogenic activities through PI-3-K-Akt-eNOS signaling. To analyze the functional consequences of cav-1 overexpression on the development and progression of prostate cancer in vivo, we generated PBcav-1 transgenic mice. Adult male PBcav-1 mice showed significantly increased prostatic wet weight and higher incidence of epithelial hyperplasia compared with nontransgenic littermates. Increased immunostaining for cav-1, proliferative cell nuclear antigen, P-Akt, and reduced nuclear p27(Kip1) staining occurred in PBcav-1 hyperplastic prostatic lesions. PBcav-1 mice showed increased resistance to castration-induced prostatic regression and elevated serum cav-1 levels compared with nontransgenic littermates. Intraprostatic injection of androgen-sensitive, cav-1-secreting RM-9 mouse prostate cancer cells resulted in tumors that were larger in PBcav-1 mice than in nontransgenic littermates (P = 0.04). Tail vein inoculation of RM-9 cells produced significantly more experimental lung metastases in PBcav-1 males than in nontransgenic male littermates (P = 0.001), and in cav-1(+/+) mice than in cav-1(-/-) mice (P = 0.041). Combination treatment with surgical castration and systemic cav-1 antibody dramatically reduced the number of experimental metastases. These experimental data suggest a causal association of secreted cav-1 and prostate cancer growth and progression.
Watanabe
Masami
M
Scott Department of Urology, Baylor College of Medicine, Texas, USA.
Yang
Guang
G
Cao
Guangwen
G
Tahir
Salahaldin A
SA
Naruishi
Koji
K
Tabata
Ken-Ichi
K
Fattah
Elmoataz Abdel
EA
Rajagopalan
Kartik
K
Timme
Terry L
TL
Park
Sanghee
S
Kurosaka
Shinji
S
Edamura
Kohei
K
Tanimoto
Ryuta
R
Demayo
Francesco J
FJ
Goltsov
Alexei A
AA
Thompson
Timothy C
TC
D000704:Analysis of Variance; D000727:Androgen-Binding Protein / Q000235:genetics; D000728:Androgens / Q000378:metabolism; D000818:Animals; D051242:Caveolin 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D018450:Disease Progression; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009919:Orchiectomy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011470:Prostatic Hyperplasia / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000097:blood / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000727:Androgen-Binding Protein; D000728:Androgens; D051242:Caveolin 1; D042461:Vascular Endothelial Growth Factor A; C027519:probasin; C467480:vascular endothelial growth factor A, mouse; D051057:Proto-Oncogene Proteins c-akt