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 (Apc Min/+ ) 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;Apc fl/+ ;Pten fl/fl mice). Pepducin-mediated CXCR2 inhibition reduced tumorigenesis in Apc Min/+ 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 Apc Min/+ 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.

Neutrophils in cancer: neutral no more

“…Inflammation plays an essential role in initiating tumorigenesis by damaging specific tissues 100 (Figure 3). In these models, neutrophils are attracted to tumor-prone tissues via the CXCR2 ligands, CXCL1, CXCL2 and CXCL5 [101][102][103][104] . Application of these carcinogens to CXCR2-deficient mice, which show impaired neutrophil trafficking, prevents papilloma or adenoma formation 102,104 .…”

“…In these models, neutrophils are attracted to tumor-prone tissues via the CXCR2 ligands, CXCL1, CXCL2 and CXCL5 [101][102][103][104] . Application of these carcinogens to CXCR2-deficient mice, which show impaired neutrophil trafficking, prevents papilloma or adenoma formation 102,104 . Similarly, CXCR2 ligands are increased in several genetically engineered mouse models, including the intestinal adenoma Apc Min/+ model, the invasive intestinal adenocarcinoma Ah-CreER;Apc F/+ ;Pten F/F model and the spontaneous oral papilloma K14-CreER;Kras G12D/+ model.…”

“…Similarly, CXCR2 ligands are increased in several genetically engineered mouse models, including the intestinal adenoma Apc Min/+ model, the invasive intestinal adenocarcinoma Ah-CreER;Apc F/+ ;Pten F/F model and the spontaneous oral papilloma K14-CreER;Kras G12D/+ model. In these models, CXCR2 deficiency or inhibition retards tumor formation 102 . However, it should be noted that CXCR2 expression is not exclusive to neutrophils.…”

“…However, it should be noted that CXCR2 expression is not exclusive to neutrophils. Depletion of the entire neutrophil population using anti-Ly6G antibodies phenocopies CXCR2 deficiency and hinders tumorigenesis in both chemically induced 101,102 and spontaneous tumor models 102 . In a zebrafish model of Hras G12V -driven melanoma, wounding-induced inflammation increases the formation of tumors in a neutrophil-dependent manner 105 .…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…Similarly, neutrophil-derived Cathepsin G may increase the chemotactic activity of CXCL8, CXCL5 and CCL15 through Nterminal truncation [218]. Ly6G + neutrophils are the dominant source of CXCR2 in the blood, and CXCR2 deficiency attenuates neutrophil recruitment to the tumor bed [219]. Depletion of Ly6G + cells purged CXCR2-dependent tumor-associated leukocytes, suppressed established skin tumor growth and colitis-associated tumorigenesis [219].…”