Activating peroxisome proliferator-activated receptor gamma mutant promotes tumor growth in vivo by enhancing angiogenesis.
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.
Tian
Lifeng
L
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Zhou
Jie
J
Casimiro
Mathew C
MC
Liang
Bing
B
Ojeifo
John O
JO
Wang
Min
M
Hyslop
Terry
T
Wang
Chenguang
C
Pestell
Richard G
RG
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002472:Cell Transformation, Viral / Q000235:genetics; D042783:Endothelial Cells / Q000473:pathology / Q000502:physiology; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008055:Lipids / Q000096:biosynthesis; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D008055:Lipids; D047495:PPAR gamma