Functional analysis of secreted caveolin-1 in mouse models of prostate cancer progression.

Abstract

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.

• Authors: Masami Watanabe, Guang Yang, Guangwen Cao, Salahaldin A Tahir, Koji Naruishi, Ken-Ichi Tabata, Elmoataz Abdel Fattah, Kartik Rajagopalan, Terry L Timme, Sanghee Park, Shinji Kurosaka, Kohei Edamura, Ryuta Tanimoto, Francesco J Demayo, Alexei A Goltsov, Timothy C Thompson
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 7 Issue 9 Pg. 1446-55 (Sep 2009) ISSN: 1557-3125 [Electronic] United States
• PMID: 19737975 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Androgen-Binding Protein
• Androgens
• Caveolin 1
• Vascular Endothelial Growth Factor A
• probasin
• vascular endothelial growth factor A, mouse
• Proto-Oncogene Proteins c-akt

Topics

• Analysis of Variance
• Androgen-Binding Protein (genetics)
• Androgens (metabolism)
• Animals
• Caveolin 1 (blood, genetics, metabolism)
• Cell Line, Tumor
• Disease Models, Animal
• Disease Progression
• Lung Neoplasms (metabolism)
• Male
• Mice
• Mice, Transgenic
• Neoplasm Metastasis
• Neoplasm Transplantation
• Orchiectomy
• Promoter Regions, Genetic (genetics)
• Prostatic Hyperplasia (metabolism)
• Prostatic Neoplasms (blood, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Vascular Endothelial Growth Factor A (metabolism)