Supplementary Figures S1-S7 from Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

Hofman, Paul; Cherfils-Vicini, Julien; Bazin, Marie; Ilie, Marius; Juhel, Thierry; Hébuterne, Xavier; Gilson, Eric; Schmid-Alliana, Annie; Boyer, Olivier; Adriouch, Sahil; Vouret-Craviari, Valérie

doi:10.1158/0008-5472.22407762.v1

00085472can141778-sup-133259_1_supp_2720152_n85cfl.pdf (801.79 kB)

Supplementary Figures S1-S7 from Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

journal contribution

posted on 2023-03-30, 23:29 authored by Paul Hofman, Julien Cherfils-Vicini, Marie Bazin, Marius Ilie, Thierry Juhel, Xavier Hébuterne, Eric Gilson, Annie Schmid-Alliana, Olivier Boyer, Sahil Adriouch, Valérie Vouret-Craviari

Supplementary Figures S1-S7. Figure S1: Characterization of heterozygous P2rx7 +/- mice Figure S2: The A740003 pharmacological inhibitor of P2RX7 dampens colitis Figure S3: P2rx7-dependent colonic epithelial cell proliferation Figure S4: Scoring of pre-cancerous dysplasic lesions Figure S5: Body weight curves of WT, P2rx7-/- and A438079-treated mice on a CAC regimen Figure S6: Histological examination of cancerous colonic lesions of WT and P2rx7-/- mice Figure S7: The cancerous microenvironment of P2rx7-/- mice is enriched in neutrophils

History

ARTICLE 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. Cancer Res; 75(5); 835–45. ©2015 AACR.