Journal
ONCOTARGET
Volume 6, Issue 12, Pages 10016-10029Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3540
Keywords
Stat3; VEGFR2; Stat3 inhibitor; brain metastasis; brain endothelial cells
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Funding
- U.S. Department of Defense Breast Cancer Research Program Center of Excellence Award [W81XWH-06-2-0033]
- NCI [P50CA127001]
- NSC [102-2320-B-010-032]
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Brain metastasis is a major cause of morbidity and mortality in patients with breast cancer. Our previous studies indicated that Stat3 plays an important role in brain metastasis. Here, we present evidence that Stat3 functions at the level of the microenvironment of brain metastases. Stat3 controlled constitutive and inducible VEGFR2 expression in tumor-associated brain endothelial cells. Furthermore, inhibition of Stat3 by WP1066 decreased the incidence of brain metastases and increased survival in a preclinical model of breast cancer brain metastasis. WP1066 inhibited Stat3 activation in tumor-associated endothelial cells, reducing their infiltration and angiogenesis. WP1066 also inhibited breast cancer cell invasion. Our results indicate that WP1066 can inhibit tumor angiogenesis and brain metastasis mediated by Stat3 in endothelial and tumor cells.
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