Substance P secreted by breast cancer cells induces BBB endothelial cells to successively secret tumor necrosis factor alpha (TNFα) and angiopoietin-2 (Ang-2), which further activate their receptors to reorganize endothelial cytoskeleton and destabilize inter-endothelial adhesion complexes to alter distribution of tight junction proteins such as claudin-5 [76,77,78,79]. Here, TNF is linked to breast carcinoma.