Journal
CELL REPORTS
Volume 10, Issue 7, Pages 1066-1081Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2015.01.035
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Funding
- NIH [CA155370, CA125550, CA151925, CA163191, RO1 NS064583]
- Cancer Prevention and Research Institute of Texas
- Metastasis Research Center at MD Anderson Cancer Center
- NIH/NCI CCSG New Faculty Award [P30CA016672]
- UT MDACC Khalifa Bin Zayed Al Nahya Foundation
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Strategies to target angiogenesis include inhibition of the vessel-stabilizing properties of vascular pericytes. Pericyte depletion in early-stage non-hypoxic tumors suppressed nascent angiogenesis, tumor growth, and lung metastasis. In contrast, pericyte depletion in advanced-stage hypoxic tumors with pre-established vasculature resulted in enhanced intra-tumoral hypoxia, decreased tumor growth, and increased lung metastasis. Furthermore, depletion of pericytes in post-natal retinal blood vessels resulted in abnormal and leaky vasculature. Tumor transcriptome profiling and biological validation revealed that angiopoietin signaling is a key regulatory pathway associated with pericyte targeting. Indeed, pericyte targeting in established mouse tumors increased angiopoietin-2 (ANG2/Angpt2) expression. Depletion of pericytes, coupled with targeting of ANG2 signaling, restored vascular stability in multiple model systems and decreased tumor growth and metastasis. Importantly, ANGPT2 expression correlated with poor outcome in patients with breast cancer. These results emphasize the potential utility of therapeutic regimens that target pericytes and ANG2 signaling in metastatic breast cancer.
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