The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors
The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors
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DOI：
10.1172/jci30068
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发表时间：
2007-07-01
影响因子：
15.9
通讯作者：
Graham, Gerard J.
中科院分区：
文献类型：
--
作者：
Nibbs, Robert J. B.;Gilchrist, Derek S.;Graham, Gerard J.
CC趋化因子的一个子集，通过CC趋化因子受体(CCRs)1至5发挥作用，在形成炎症反应中起重要作用。最近，我们和其他人证明了非典型趋化因子受体D6主动隔离和破坏许多促炎症CC趋化因子。这对于体内炎症的有效消解至关重要。炎症可以是致癌的，而致炎的CC趋化因子与癌症生物学的各个方面有关，但几乎没有证据支持这些分子在新生肿瘤的形成中起关键作用。在这里，我们表明D6缺陷小鼠对化学致癌方案的反应增加了对皮肤肿瘤发展的敏感性，并且值得注意的是，D6缺失足以使耐药小鼠对侵袭性鳞状细胞癌敏感。相反，在角质形成细胞中表达转基因D6可以抑制皮肤炎症，并可以在易感背景下提供相当大的保护作用，防止肿瘤形成。肿瘤敏感性一直与T细胞和肥大细胞的募集水平相关，T细胞和肥大细胞是已知的支持小鼠皮肤肿瘤发展的细胞类型。这些数据证明了促炎性CC趋化因子在新生肿瘤发生中的重要性，并揭示了D6对趋化因子的隔离是一种新的有效的肿瘤抑制方法。
A subset of CC chemokines, acting through CC chemokine receptors (CCRs) 1 to 5, is instrumental in shaping inflammatory responses. Recently, we and others have demonstrated that the atypical chemokine receptor D6 actively sequesters and destroys many of these proinflammatory CC chemokines. This is critical for effective resolution of inflammation in vivo. Inflammation can be protumorigenic, and proinflammatory CC chemokines have been linked with various aspects of cancer biology, yet there is scant evidence supporting a critical role for these molecules in de novo tumor formation. Here, we show that D6-deficient mice have increased susceptibility to cutaneous tumor development in response to chemical carcinogenesis protocols and, remarkably, that D6 deletion is sufficient to make resistant mouse strains susceptible to invasive squamous cell carcinoma. Conversely, transgenic D6 expression in keratinocytes dampens cutaneous inflammation and can confer considerable protection from tumor formation in susceptible backgrounds. Tumor susceptibility consistently correlated with the level of recruitment of T cells and mast cells, cell types known to support the development of skin tumors in mice. These data demonstrate the importance of proinflammatory CC chemokines in de novo tumorigenesis and reveal chemokine sequestration by D6 to be a novel and effective method of tumor suppression.