title: Genetic and pharmacological inactivation of the purinergic P2RX7 receptor dampens inflammation but increases tumor incidence in a mouse model of colitis-associated cancer.
abstract: Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools, we found unexpectedly that while P2RX7 mediated inflammatory responses, it also acted at an early time to suppress CAC development. P2RX7 blockade enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. The proliferative effects of P2RX7 blockade were associated with an increased production of TGFβ1 that was sufficient to stimulate the proliferation of intestinal epithelial cells. Finally, P2RX7 blockade also altered immune cell infiltration and promoted Treg accumulation within lesions of the digestive system. Taken together, our findings reveal an unexpected role for P2RX7 in preventing CAC, suggesting cautions in the use of P2RX7 inhibitors to treat IBD given the possibility of increasing risks CAC as a result.
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Laboratory of Clinical and Experimental Pathology and Biobank, Pasteur Hospital, Nice, France. Centre Antoine Lacassagne, Nice, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Hofman
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Centre Antoine Lacassagne, Nice, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Cherfils-Vicini
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Centre Antoine Lacassagne, Nice, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Bazin
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Laboratory of Clinical and Experimental Pathology and Biobank, Pasteur Hospital, Nice, France. Centre Antoine Lacassagne, Nice, France.
authors.forename: Marius
authors.initials: M
authors.lastname: Ilie
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Centre Antoine Lacassagne, Nice, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Juhel
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Laboratory of Gastroenterology, Archet II Hospital, Nice, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Hébuterne
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Centre Antoine Lacassagne, Nice, France. Department of Medical Genetics, Archet 2 Hospital, CHU of Nice, Nice, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Gilson
authors.affiliation: University of Nice-Sophia Antipolis, Nice, France. iBV, UMR7277 CNRS-UMR1091 INSERM, Nice, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Schmid-Alliana
authors.affiliation: INSERM U905, Rouen, France. Institute for Research and Innovation in Biomedicine (IRIB), Normandy University, Rouen, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.affiliation: INSERM U905, Rouen, France. Institute for Research and Innovation in Biomedicine (IRIB), Normandy University, Rouen, France.
authors.forename: Sahil
authors.initials: S
authors.lastname: Adriouch
authors.affiliation: Institute for Research on Cancer and Aging, Nice, France; IRCAN U1081 UMR CNRS 7284, Nice Cedex, France. University of Nice-Sophia Antipolis, Nice, France. Centre Antoine Lacassagne, Nice, France. vouret@unice.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vouret-Craviari
mesh_terms: D000818:Animals; D003092:Colitis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D015994:Incidence; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis
chemical_list: C546469:P2rx7 protein, mouse; D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1