Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesis

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 24; pp. 9236 - 9244
• Main Authors: Tian, Lifeng, Zhou, Jie, Casimiro, Mathew C, Liang, Bing, Ojeifo, John O, Wang, Min, Hyslop, Terry, Wang, Chenguang, Pestell, Richard G
• Format: Journal Article
• Language: English
• Published: United States 15.12.2009
• Subjects: Angiopoietin-like 4 Protein; Angiopoietins - metabolism; Animals; Breast Neoplasms - blood supply; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Movement - physiology; Cell Transformation, Viral - genetics; Endothelial Cells - pathology; Endothelial Cells - physiology; Female; Gene Expression Profiling; Humans; Lipids - biosynthesis; Mice; Mice, Transgenic; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; PPAR gamma - genetics; PPAR gamma - metabolism
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-2067

Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in a variety of cancer cells. The addition of ligand activates the receptor by inducing a conformational change in the receptor, which can be recapitulated by mutation. To investigate the role of activated PPARgamma signaling in breast cancer, we compared the function of a constitutively active PPARgamma (PgammaCA) mutant with the wild-type PPARgamma in ErbB2-induced mammary tumorigenesis in vivo. Tumor cells transduced with either PPARgamma or PgammaCA were implanted into immunocompetent FVB mice. Enhanced tumor growth was observed in PgammaCA-transduced cells, which was associated with increased angiogenesis and endothelial stem cells as evidenced by increased number of cells stained with von Willebrand factor, c-Kit, CD133, and CD31. Genome-wide expression profiling identified a group of genes within the angiogenesis pathway, including Angptl4, as targets of activated PPARgamma; PgammaCA also induced Angptl4 protein secretion in ErbB2-transformed mammary epithelial cells. Angptl4 promoted vascular endothelial cell migration; conversely, immunodepletion of Angptl4 reduced PgammaCA-mediated cellular migration. Collectively, these studies suggest that activated PPARgamma induces Angptl4 to promote tumor growth through enhanced angiogenesis in vivo.