title: Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis.
abstract: The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. However, CXCR2 influences tumors through multiple mechanisms and might promote or inhibit tumor development depending on context. Here, we used several mouse models of spontaneous and inflammation-driven neoplasia to define indispensable roles for CXCR2 in benign and malignant tumors. CXCR2-activating chemokines were part of the secretome of cultured primary benign intestinal adenomas (ApcMin/+) and highly expressed by all tumors in all models. CXCR2 deficiency profoundly suppressed inflammation-driven tumorigenesis in skin and intestine as well as spontaneous adenocarcinoma formation in a model of invasive intestinal adenocarcinoma (AhCreER;Apcfl/+;Ptenfl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in ApcMin/+ mice. Ly6G+ neutrophils were the dominant source of CXCR2 in blood, and CXCR2 deficiency attenuated neutrophil recruitment. Moreover, systemic Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis, and reduced ApcMin/+ adenoma formation. CXCR2 is thus a potent protumorigenic chemokine receptor that directs recruitment of tumor-promoting leukocytes into tissues during tumor-inducing and tumor-driven inflammation. Similar leukocyte populations were also found in human intestinal adenomas, which suggests that CXCR2 antagonists may have therapeutic and prophylactic potential in the treatment of cancer.
authors.affiliation: Beatson Institute of Cancer Research, Glasgow, United Kingdom.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jamieson
authors.forename: Mairi
authors.initials: M
authors.lastname: Clarke
authors.forename: Colin W
authors.initials: CW
authors.lastname: Steele
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.forename: Jens
authors.initials: J
authors.lastname: Neumann
authors.forename: Andreas
authors.initials: A
authors.lastname: Jung
authors.forename: David
authors.initials: D
authors.lastname: Huels
authors.forename: Michael F
authors.initials: MF
authors.lastname: Olson
authors.forename: Sudipto
authors.initials: S
authors.lastname: Das
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000236:Adenoma / Q000139:chemically induced / Q000378:metabolism; D000818:Animals; D017849:Animals, Inbred Strains; D001397:Azoxymethane; D002471:Cell Transformation, Neoplastic; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000378:metabolism; D003877:Dermatitis, Contact / Q000473:pathology; D016264:Dextran Sulfate; D015870:Gene Expression; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism; D010212:Papilloma / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011230:Precancerous Conditions / Q000139:chemically induced* / Q000473:pathology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D018709:Statistics, Nonparametric; D013755:Tetradecanoylphorbol Acetate; D047368:Tumor Burden
chemical_list: D019743:Chemokines, CXC; D023063:Receptors, Interleukin-8B; D015127:9,10-Dimethyl-1,2-benzanthracene; D016264:Dextran Sulfate; D009195:Peroxidase; D001397:Azoxymethane; D013755:Tetradecanoylphorbol Acetate