The chemokine receptor CXCR2 is a key mediator of neutrophil migration

The chemokine receptor CXCR2 is a key mediator of neutrophil migration that also plays a role in tumor development. Ly6G+ cell depletion purged CXCR2-dependent tumor-associated leukocytes suppressed established skin tumor growth and colitis-associated tumorigenesis and reduced 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 restorative and prophylactic potential in the treating cancer. Intro Swelling and tumorigenesis are linked. Chronic swelling can travel tumorigenesis and tumors are inherently proinflammatory with infiltrating leukocytes regarded as crucial for tumor maintenance and development (1 EBR2 2 In colorectal tumor for instance ulcerative colitis raises risk higher than 20-collapse (3); NSAIDs decrease it by around 50% (4); and inflammatory infiltrate information predict patient result (5). Substances that travel tumor-driven or tumor-inducing swelling possess substantial PCI-24781 potential as restorative focuses on. Among these are inflammatory chemokine receptors heptahelical G protein-coupled receptors that mediate the biological effects of secreted inflammatory chemokines. They are key regulators of inflammation in a spectrum of physiological and pathological contexts. Established cancers often constitutively produce a subset of proinflammatory chemokines which through multiple chemokine receptors are thought to shape leukocyte infiltrate regulate other stromal cells and in some instances directly control tumor cells (6). However the overlapping chemokine binding profiles of inflammatory chemokine PCI-24781 receptors means that it may not be possible to identify individual chemokine receptors with sufficiently profound effects on de novo tumor development to represent realistic targets for cancer therapy or prophylaxis. Chemokines that activate the chemokine receptor CXCR2 are expressed by a wide variety of established human cancer types. The chemokines CXCL1 CXCL2 CXCL3 CXCL5 CXCL6 CXCL7 and CXCL8 all activate human CXCR2; CXCL6 and CXCL8 also signal through human CXCR1 (7). Although mouse CXCR2 binds a similar spectrum of chemokines mice lack and genes are highly homologous and coregulated. Mouse also binds mouse CXCR1 (8) although the function of this receptor in vivo is unclear. Neutrophils readily identified by expression of Ly6G (a component of the Gr1 epitope) are the predominant CXCR2+ cells among blood leukocytes and CXCR2 is a key regulator of their recruitment and effector responses (7 9 Depending on the context both pro- and antitumor activities have been attributed to neutrophils (10). CXCR2 is also expressed by neutrophil precursors in the bone marrow that can be released during systemic inflammation and by many Gr1+CD11b+ cells in tumor-bearing mice a population that likely includes neutrophils their precursors and polymorphonuclear myeloid-derived suppressor cells (MDSCs) (11 12 CXCR2 can also be found on endothelial cells (13) where it can mediate angiogenesis (14) and augment neutrophil recruitment (15). It is also seen on some tumor cells and can be induced by activated oncogenes (e.g. ras) (16). Its function on transformed cells is context dependent. For example CXCR2 is required for the optimal growth of ras-transformed keratinocytes in vivo (17) and has been shown to stimulate tumor cell growth survival and motility in several model systems (18-20). In contrast induction of CXCR2 and its ligands by oncogenic K-ras reinforces senescence in vitro (21) predicting a role in tumor suppression in vivo. PCI-24781 In some cancers such as prostate cancer CXCR2 is expressed by early premalignant cells but downregulated during tumor progression (21-23). Collectively these observations – many of which have come from studying cell lines in culture or transplanted into mice – suggest that CXCR2 operating on multiple cell types could have positive and negative influences on cancer initiation development and invasion. Since CXCR2 inhibitors are under development for the treatment of a variety of inflammatory disorders (24 25 it is critical that the overall role of CXCR2 during tumorigenesis. PCI-24781