Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis
Inhibition of CXCR2 profoundly suppresses inflammation-driven and spontaneous tumorigenesis
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CXCR2 的抑制可显着抑制炎症驱动和自发性肿瘤发生
DOI：
10.1172/jci61067
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发表时间：
2012-09-01
影响因子：
15.9
通讯作者：
Sansom, Owen J.
中科院分区：
文献类型：
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作者：
Jamieson, Thomas;Clarke, Mairi;Sansom, Owen J.
趋化因子受体CXCR 2是中性粒细胞迁移的关键介质，也在肿瘤发展中起作用。然而，CXCR 2通过多种机制影响肿瘤，并可能根据情况促进或抑制肿瘤的发展。在这里，我们使用了几种自发性和炎症驱动的肿瘤形成的小鼠模型来定义CXCR 2在良性和恶性肿瘤中不可或缺的作用。CXCR 2激活趋化因子是培养的原发性良性肠腺瘤（Apc（Min/+））的分泌物组的一部分，并且在所有模型中的所有肿瘤中高度表达。CXCR 2缺陷在侵袭性肠腺癌模型（AhCreER;Apc（fl/+）;Pten（fl/fl）小鼠）中显著抑制皮肤和肠中炎症驱动的肿瘤发生以及自发性腺癌形成。肽蛋白介导的CXCR 2抑制减少了Apc（Min/+）小鼠的肿瘤发生。Ly 6 G（+）中性粒细胞是血液中CXCR 2的主要来源，CXCR 2缺乏会减弱中性粒细胞的募集。此外，全身Ly 6 G+细胞耗竭清除了CXCR 2依赖性肿瘤相关白细胞，抑制了已建立的皮肤肿瘤生长和结肠炎相关肿瘤发生，并减少了Apc（Min/+）腺瘤形成。因此，CXCR 2是一种有效的促肿瘤趋化因子受体，其在肿瘤诱导和肿瘤驱动的炎症期间指导促肿瘤白细胞向组织中的募集。在人肠腺瘤中也发现了类似的白细胞群，这表明CXCR 2拮抗剂在癌症治疗中可能具有治疗和预防潜力。
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.