期刊
CANCER RESEARCH
卷 76, 期 17, 页码 4970-4980出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-15-3541
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资金
- NCI NIH HHS [R01 CA185650, R01 CA173499, R01 CA205067, P30 CA012197] Funding Source: Medline
- NINDS NIH HHS [R01 NS087169] Funding Source: Medline
Brain metastasis is one of the chief causes of mortality in breast cancer patients, but the mechanisms that drive this process remain poorly understood. Here, we report that brain metastatic cells expressing high levels of c-Met promote the metastatic process via inflammatory cytokine upregulation and vascular reprogramming. Activated c-Met signaling promoted adhesion of tumor cells to brain endothelial cells and enhanced neovascularization by inducing the secretion of IL8 and CXCL1. Additionally, stimulation of IL1 beta secretion by activation of c-Met induced tumor-associated astrocytes to secrete the c-Met ligand HGF. Thus, a feed-forward mechanism of cytokine release initiated and sustained by c-Met fed a vicious cycle that generated a favorable microenvironment for metastatic cells. Reinforcing our results, we found that pterostilbene, a compound that penetrates the blood-brain barrier, could suppress brain metastasis by targeting c-Met signaling. These findings suggest a potential utility of this natural compound for chemoprevention. (C) 2016 AACR.
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