Polyunsaturated Fatty Acids from Astrocytes Activate PPAR? Signaling in Cancer Cells to Promote Brain Metastasis.

ABSTRACT: Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor ? (PPAR?) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPAR? in brain metastatic cancer cells. PPAR? activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPAR? activators to the invading cancer cells. In clinical samples, PPAR? signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPAR? antagonists significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic role for PPAR? signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPAR? blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPAR? signaling. This protumor effect of PPAR? in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPAR? has diverse functions at different stages of cancer development.This article is highlighted in the In This Issue feature, p. 1631.

SUBMITTER: Zou Y 

PROVIDER: S-EPMC6891206 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature