Insight on P2X7 receptor role as oncogene

Activation of P2X7 receptor is impacting almost all recognized cancer hallmarks [Hanahan D, Weinberg RA. Cell. 2011;144(5):646–674] including sustained proliferation [Baricordi OR, Melchiorri L, Adinolfi E, Falzoni S, Chiozzi P, Buell G, Di Virgilio F. J Biol Chem. 1999; 274(47):33206–8; Adinolfi E, CallegariMG, Ferrari D, Bolognesi C, Minelli M,Wieckowski MR, Pinton P, Rizzuto R, Di Virgilio F. Mol Biol Cell. 2005; 16(7):3260–72], deregulation of cellular energetics [Adinolfi et al. 2005; Amoroso F, Falzoni S, Adinolfi E, Ferrari D, Di Virgilio F. Cell Death Dis. 2012; 3:e370], activation of tissue invasion [Jelassi B, Chantôme A, Alcaraz-Pérez F, Baroja-Mazo A, Cayuela ML, Pelegrin P, Surprenant A, Roger S. Oncogene. 2011; 30(18):2108–22] and neovascularization [Adinolfi E, Raffaghello L, Giuliani AL, Cavazzini L, Capece M, Chiozzi P, Bianchi G, Kroemer G, Pistoia V, Di Virgilio F. Cancer Res. 2012;72(12):2957–69]. Nevertheless, a clear cut demonstration that P2X7 receptor can affect carcinogenesis in vivo was missing. Aim of our studies was to verify the effect of P2X7 expression and blockade in animal models of cancer. Tumor tested included colon cancer, melanoma and neuroblastoma modeled either in syngeneic or in xenograft systems. In all this settings P2X7 was increasing tumoral engraftment and growth rate also affecting blood vessels formation [Adinolfi et al., 2012]. Signaling cascades involved in P2X7 mediated transformation included the HIF-1 alpha-VEGF and PI3Kinase-GSK3 axes. Of interest for the therapy of cancers that are still lacking a cure, such as advanced stages neuroblastoma and melanoma, was the power of different P2X7 inhibitors to in vivo reduce cancer growth. In summary, our data demonstrate an oncogenic role for P2X7 receptor and suggest it as easily approachable therapeutic target as its antagonists are in clinical trials for other diseases and will be soon available at patient’s bed.