Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain

作者：Avraham Hava Karsenty^*; Jiang Shuxian; Fu Yigong; Nakshatri Harikrishna; Ovadia Haim; Avraham Shalom

来源：Journal of Pathology, 2014, 232(3): 369-381.

DOI：10.1002/path.4304

• breast cancer metastasis in brain
• tight junctions
• brain microvascular endothelial cells
• blood-brain barrier
• angiopoietin-2

Although the incidence of breast cancer metastasis (BCM) in brain has increased significantly in triple-negative breast cancer (TNBC), the mechanisms remain elusive. Using in vivo mouse models for BCM in brain, we observed that TNBC cells crossed the blood-brain barrier (BBB), lodged in the brain microvasculature and remained adjacent to brain microvascular endothelial cells (BMECs). Breaching of the BBBin vivo by TNBCs resulted in increased BBB permeability and changes in ZO-1 and claudin-5 tight junction (TJ) protein structures. Angiopoietin-2 expression was elevated in BMECs and was correlated with BBB disruption. Secreted Ang-2 impaired TJ structures and increased BBB permeability. Treatment of mice with the neutralizing Ang-2 peptibody trebananib prevented changes in the BBB integrity and BMEC destabilization, resulting in inhibition of TNBC colonization in brain. Thus, Ang-2 is involved in initial steps of brain metastasis cascade, and inhibitors for Ang-2 may serve as potential therapeutics for brain metastasis.

• 出版日期2014-2