Vascular PPAR?/? Promotes Tumor Angiogenesis and Progression.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which function as transcription factors. Among them, PPAR?/? is highly expressed in endothelial cells. Pharmacological activation with PPAR?/? agonists had been shown to increase their angiogenic properties. PPAR?/? has been suggested to be involved in the regulation of the angiogenic switch in tumor progression. However, until now, it is not clear to what extent the expression of PPAR?/? in tumor endothelium influences tumor progression and metastasis formation. We addressed this question using transgenic mice with an inducible conditional vascular-specific overexpression of PPAR?/?. Following specific over-expression of PPAR?/? in endothelial cells, we induced syngenic tumors. We observed an enhanced tumor growth, a higher vessel density, and enhanced metastasis formation in the tumors of animals with vessel-specific overexpression of PPAR?/?. In order to identify molecular downstream targets of PPAR?/? in the tumor endothelium, we sorted endothelial cells from the tumors and performed RNA sequencing. We identified platelet-derived growth factor receptor beta (Pdgfrb), platelet-derived growth factor subunit B (Pdgfb), and the tyrosinkinase KIT (c-Kit) as new PPAR?/? -dependent molecules. We show here that PPAR?/? activation, regardless of its action on different cancer cell types, leads to a higher tumor vascularization which favors tumor growth and metastasis formation.

SUBMITTER: Wagner KD 

PROVIDER: S-EPMC6952835 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature