FIGURE 4.

Disruption of the peritumoral blood-brain barrier in brain metastasis. Expression of VEGF and SH/VEGF by metastatic cells leads to alteration in TJ proteins such as occludin, claudin-1, and claudin-5 resulting in increased paracellular water influx. In addition to metastatic cells, tumor-infiltrating lymphocytes contribute to the production of VEGF as well as some cytokines including IL-2. Degradation of TJ proteins and the basal membrane is also potentiated by increased expression of matrix metalloproteinases such as MMP-2 and MMP-9. Activation of metalloproteinases is induced by overexpression of ET-1, which leads to up-regulation of ROS and eNOS. Increased expression of AQP4, a part of the glymphatic system on astrocytic endfeet around metastatic lesions, contributes to the development of vasogenic edema by the accumulation of CSF into the brain interstitium.