title: Activation of P2X7 and P2Y11 purinergic receptors inhibits migration and normalizes tumor-derived endothelial cells via cAMP signaling.
abstract: Purinergic signaling is involved in inflammation and cancer. Extracellular ATP accumulates in tumor interstitium, reaching hundreds micromolar concentrations, but its functional role on tumor vasculature and endothelium is unknown. Here we show that high ATP doses (>20 μM) strongly inhibit migration of endothelial cells from human breast carcinoma (BTEC), but not of normal human microvascular EC. Lower doses (1-10 μM result ineffective. The anti-migratory activity is associated with cytoskeleton remodeling and is significantly prevented by hypoxia. Pharmacological and molecular evidences suggest a major role for P2X7R and P2Y11R in ATP-mediated inhibition of TEC migration: selective activation of these purinergic receptors by BzATP mimics the anti-migratory effect of ATP, which is in turn impaired by their pharmacological or molecular silencing. Downstream pathway includes calcium-dependent Adenilyl Cyclase 10 (AC10) recruitment, cAMP release and EPAC-1 activation. Notably, high ATP enhances TEC-mediated attraction of human pericytes, leading to a decrease of endothelial permeability, a hallmark of vessel normalization. Finally, we provide the first evidence of in vivo P2X7R expression in blood vessels of murine and human breast carcinoma. In conclusion, we have identified a purinergic pathway selectively acting as an antiangiogenic and normalizing signal for human tumor-derived vascular endothelium.
authors: Department of Life Sciences &Systems Biology, University of Torino, Torino, Italy.
authors: D
authors: D
authors: Avanzato
authors: Department of Life Sciences &Systems Biology, University of Torino, Torino, Italy.
authors: T
authors: T
authors: Genova
authors: Department of Life Sciences &Systems Biology, University of Torino, Torino, Italy.|Nanostructured Interfaces and Surfaces Centre of Excellence (NIS), University of Torino, Torino, Italy.
authors: A
authors: A
authors: Fiorio Pla
authors: Department of Life Sciences &Systems Biology, University of Torino, Torino, Italy.
authors: M
authors: M
authors: Bernardini
authors: Department of Life Sciences &Systems Biology, University of Torino, Torino, Italy.
authors: S
authors: S
authors: Bianco
authors: Dept. of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors: B
authors: B
authors: Bussolati
authors: Department of Clinical and Biological Sciences, University of Torino, Torino, Italy.
authors: D
authors: D
authors: Mancardi
authors: Candiolo Cancer Research Center, Torino, Italy.
authors: E
authors: E
authors: Giraudo
authors: Candiolo Cancer Research Center, Torino, Italy.
authors: F
authors: F
authors: Maione
authors: Department of Medical Sciences, Torino, Italy.
authors: P
authors: P
authors: Cassoni
authors: Department of Medical Sciences, Torino, Italy.
authors: I
authors: I
authors: Castellano
authors: Department of Life Sciences &Systems Biology, University of Torino, Torino, Italy.|Nanostructured Interfaces and Surfaces Centre of Excellence (NIS), University of Torino, Torino, Italy.
authors: L
authors: L
authors: Munaron
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism*; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C109734:P2RY11 protein, human; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D000255:Adenosine Triphosphate; D000242:Cyclic AMP