Endothelial Ca2+ Signaling and the Resistance to Anticancer Treatments: Partners in Crime

Intracellular Ca2+ signaling drives angiogenesis and vasculogenesis by stimulating proliferation, migration, and tube formation in both vascular endothelial cells and endothelial colony forming cells (ECFCs), which represent the only endothelial precursor truly belonging to the endothelial phenotype. In addition, local Ca2+ signals at the endoplasmic reticulum (ER)-mitochondria interface regulate endothelial cell fate by stimulating survival or apoptosis depending on the extent of the mitochondrial Ca2+ increase. The present article aims at describing how remodeling of the endothelial Ca2+ toolkit contributes to establish intrinsic or acquired resistance to standard anti-cancer therapies. The endothelial Ca2+ toolkit undergoes a major alteration in tumor endothelial cells and tumor-associated ECFCs. These include changes in TRPV4 expression and increase in the expression of P2X7 receptors, Piezo2, Stim1, Orai1, TRPC1, TRPC5, Connexin 40 and dysregulation of the ER Ca2+ handling machinery. Additionally, remodeling of the endothelial Ca2+ toolkit could involve nicotinic acetylcholine receptors, gasotransmitters-gated channels, two-pore channels and Na⁺/H⁺ exchanger. Targeting the endothelial Ca2+ toolkit could represent an alternative adjuvant therapy to circumvent patients' resistance to current anti-cancer treatments.