Orai1 and Transient Receptor Potential Channels as Novel Molecular Targets to Impair Tumor Neovascularization in Renal Cell Carcinoma and other Malignancies

Francesco      Moccia; Silvia      Dragoni; Valentina      Poletto; Vittorio      Rosti; Franco      Tanzi; Carlo      Ganini; Camillo      Porta

doi:10.2174/18715206113139990315

Abstract

The term “angiogenic switch” describes one of the earlier events of tumorigenesis, that occurs when the balance between proand anti-angiogenic factors shifts towards a pro-angiogenic outcome. This leads to the transition from a microscopic indolent lesion to a macroscopic and vascularised primary tumor, that may eventually metastasize and spread to distant sites. The molecular mechanisms underlying such a critical step in the carcinogenetic process have been extensively investigated. Both local endothelial cells (ECs) and endothelial progenitor cells (EPCs), recruited from bone marrow, have been implicated in the angiogenic switch, which is ultimately triggered by a plethora of growth factors released by cancer cells, pivotal among which is vascular endothelial growth factor (VEGF); indeed, VEGF both activates ECs nearby the growing tumor, and leads to EPC mobilization into the circulation. In kidney, in particular, the frequent mutation of the Von Hippel Lindau tumor suppressor gene leads to an overproduction of pro-angiogenic factors which makes this neoplasm quite sensitive to antiangiogenic drugs. However, it is now evident that the use of VEGF(Rs) inhibitors in everyday clinical practice is not as effective as observed in murine models.

The investigation of alternative signaling pathways involved in the angiogenic switch is, therefore, imperative in order to induce tumor regression whereby preventing harmful drawback consequences. Ca²⁺ entry across the plasma membrane has long been known to stimulate mature ECs to undergo angiogenesis. Recent work from several groups worldwide has then outlined that members of the Transient Receptor Potential (TRP) super-family of cationic channels and Orai1 provide the pathway for such proangiogenic Ca²⁺ signal. In addition, Canonical TRP 1 (TRPC1) and Orai1 channels control proliferation and tubulogenesis in both normal EPCs and EPCs isolated from peripheral blood of tumor patients. As a consequence, TRP channels and Orai1 might serve as novel molecular targets to develop alternative and more effective strategies of angiogenesis inhibition.

Keywords: Angiogenesis, endothelial cells, endothelial progenitor cells, store-operated Ca²⁺ entry, TRP channels, tumor.

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