PPARalpha deficiency in inflammatory cells suppresses tumor growth.
Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)alpha is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARalpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARalpha expressing granulocytes are necessary for tumor growth. Neutralization of thrombospondin-1 restores tumor growth in PPARalpha-deficient mice. These findings suggest that the absence of PPARalpha activity renders inflammatory infiltrates tumor suppressive and, thus, may provide a target for inhibiting tumor growth by modulating stromal processes, such as angiogenesis.
Kaipainen
Arja
A
Vascular Biology Program, Department of Surgery, Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Kieran
Mark W
MW
Huang
Sui
S
Butterfield
Catherine
C
Bielenberg
Diane
D
Mostoslavsky
Gustavo
G
Mulligan
Richard
R
Folkman
Judah
J
Panigrahy
Dipak
D
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018827:Carcinoma, Lewis Lung / Q000235:genetics / Q000473:pathology; D002461:Cell Line, Transformed / Q000637:transplantation; D016510:Corneal Neovascularization / Q000235:genetics; D006098:Granulocytes / Q000502:physiology*; D007249:Inflammation; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000235:genetics / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology / Q000517:prevention & control; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D019700:Thrombospondin 1 / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
D009363:Neoplasm Proteins; D047493:PPAR alpha; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse