Given the early upregulation of VEGF in tumor cells in response to hypoxia in vitro (Figure 2C) and the increased expression of Ang-2 in brain microvessels in the hypoxic pre-metastatic niche (Figure 2A, B, D) demonstrated here, we hypothesized that early therapeutic inhibition of Ang-2 and VEGF-associated microenvironmental changes in hypoxic pre-metastatic niche may substantially affect metastatic growth in the brain (Figure 4A). Here, VEGFA is linked to neoplasm.