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Angiogenesis, Metastasis, and the Cellular Microenvironment

Arachidonic Acid–Induced Ca²⁺ Entry Is Involved in Early Steps of Tumor Angiogenesis

¹ Department of Animal and Human Biology; ² Nanostructured Interfaces and Surfaces Centre of Excellence; ³ Center for Complex Systems in Molecular Biology and Medicine-SysBioM; and ⁴ Department of Internal Medicine and Research Center of Experimental Medicine, University of Turin, Turin, Italy

Requests for reprints: Alessandra Fiorio Pla, Department of Animal and Human Biology, University of Torino, Via Accademia Albertina 13, 10123 Turin, Italy. Phone: 39-011-6704667; Fax: 39-011-6704508. E-mail: alessandra.fiorio{at}unito.it

Growth factor–induced intracellular calcium signals in endothelial cells regulate cytosolic and nuclear events involved in the angiogenic process. Among the intracellular messengers released after proangiogenic stimulation, arachidonic acid (AA) plays a key role and its effects are strictly related to calcium homeostasis and cell proliferation. Here, we studied AA-induced intracellular calcium signals in endothelial cells derived from human breast carcinomas (B-TEC). AA promotes B-TEC proliferation and organization of vessel-like structures in vitro. The effect is directly mediated by the fatty acid without a significant contribution of its metabolites. AA induces Ca²⁺_i signals in the entire capillary-like structure during the early phases of tubulogenesis in vitro. No such responses are detectable in B-TECs organized in more structured tubules. In B-TECs growing in monolayer, AA induces two different signals: a Ca²⁺_i increase due to Ca²⁺ entry and an inhibition of store-dependent Ca²⁺ entry induced by thapsigargin or ATP. An inhibitor of Ca²⁺ entry and angiogenesis, carboxyamidotriazole, significantly and specifically decreases AA-induced B-TEC tubulogenesis, as well as AA-induced Ca²⁺ signals in B-TECs. We conclude that (a) AA-activated Ca²⁺ entry is associated with the progression through the early phases of angiogenesis, mainly involving proliferation and tubulogenesis, and it is down-regulated during the reorganization of tumor-derived endothelial cells in capillary-like structures; and (b) inhibition of AA-induced Ca²⁺ entry may contribute to the antiangiogenic action of carboxyamidotriazole. (Mol Cancer Res 2008;6(4):535–45)