PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis.
Several drugs approved for a variety of indications have been shown to exhibit antiangiogenic effects. Our study focuses on the PPARgamma ligand rosiglitazone, a compound widely used in the treatment of type 2 diabetes. We demonstrate, for the first time to our knowledge, that PPARgamma is highly expressed in tumor endothelium and is activated by rosiglitazone in cultured endothelial cells. Furthermore, we show that rosiglitazone suppresses primary tumor growth and metastasis by both direct and indirect antiangiogenic effects. Rosiglitazone inhibits bovine capillary endothelial cell but not tumor cell proliferation at low doses in vitro and decreases VEGF production by tumor cells. In our in vivo studies, rosiglitazone suppresses angiogenesis in the chick chorioallantoic membrane, in the avascular cornea, and in a variety of primary tumors. These results suggest that PPARgamma ligands may be useful in treating angiogenic diseases such as cancer by inhibiting angiogenesis.
Panigrahy
Dipak
D
Surgical Research Laboratory, Children's Hospital, Department of Surgery, Harvard Medical School, Boston, Massachusetts, USA.
Singer
Samuel
S
Shen
Lucy Q
LQ
Butterfield
Catherine E
CE
Freedman
Deborah A
DA
Chen
Emy J
EJ
Moses
Marsha A
MA
Kilroy
Susan
S
Duensing
Stefan
S
Fletcher
Christopher
C
Fletcher
Jonathan A
JA
Hlatky
Lynn
L
Hahnfeldt
Philip
P
Folkman
Judah
J
Kaipainen
Arja
A
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002417:Cattle; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006801:Humans; D008024:Ligands; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000502:physiology*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; C089946:2,4-thiazolidinedione