Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner
Mouse β-Defensin 14 (Defb14) Promotes Tumor Growth by Inducing Angiogenesis in a CCR6-Dependent Manner
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DOI：
10.4049/jimmunol.1102442
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发表时间：
2012-05-15
影响因子：
4.4
通讯作者：
Hehlgans, Thomas
中科院分区：
文献类型：
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作者：
Roehrl, Johann;Huber, Barbara;Hehlgans, Thomas
已知β-防御素具有抗微生物活性，属于先天免疫系统抵抗入侵病原体的分子屏障。此外，已经显示β-防御素超家族的一些成员具有促进局部先天性炎症和全身适应性免疫应答的能力，部分地由与CCR 6的相互作用介导。我们发现，小鼠β-防御素14（mBD 14，Defb 14），一个新发现的小鼠β-防御素超家族成员，在小鼠纤维肉瘤肿瘤组织中表达。过表达mBD 14的肿瘤细胞在同系C57 BL/6小鼠中表现出实体瘤生长增强，同时这些肿瘤的血管化增加。此外，mBD 14过表达肿瘤表现出促血管生成MIP-2（CXCL 2）的表达增加离体。相反，血管内皮生长因子的表达没有受到影响。肿瘤浸润性白细胞的细胞分析显示，在源自mBD 14过表达肿瘤细胞的实体瘤中，CCR 6（+）B220（+）淋巴细胞显著增加。在CCR 6缺陷小鼠中，mBD 14过表达的纤维肉瘤的肿瘤生长增强被消除，这被CCR 6（+）B220（+）淋巴细胞浸润减少所抵消，表明CCR 6表达对宿主细胞的要求。以前，活化的LT α β（+）淋巴细胞与表达光敏素β受体的纤维肉瘤肿瘤细胞的相互作用已被确定为一种新的CXCL 2依赖性促血管生成途径。在mBD 14过表达的纤维肉瘤肿瘤细胞中共表达可溶性光毒素β-受体：IG融合蛋白（一种CXCL 2依赖性血管生成的抑制剂）可消除增强的实体瘤生长。因此，我们得出结论，肿瘤浸润宿主细胞表达mBD 14导致CCR 6（+）B220（+）淋巴细胞的化学吸引，这反过来又启动了促血管生成途径，导致血管生成增强和肿瘤组织发育。免疫学杂志，2012，188：4931-4939。
beta-defensins are known for their antimicrobial activity and belong to the molecular barrier of the innate immune system against invading pathogens. In addition, it has been shown that some members of the beta-defensin superfamily have the capacity to promote local innate inflammatory and systemic adaptive immune responses, mediated in part by the interaction with CCR6. We found that mouse beta-defensin 14 (mBD14, Defb14), a newly identified member of the mouse beta-defensin superfamily, is expressed in mouse fibrosarcoma tumor tissue. Tumor cells overexpressing mBD14 demonstrated enhanced solid tumor growth in syngeneic C57BL/6 mice concomitant with increased vascularization of these tumors. Furthermore, mBD14-overexpressing tumors demonstrated increased expression of proangiogenic MIP-2 (CXCL2) ex vivo. In contrast, vascular endothelial growth factor expression was not affected. Cellular analysis of tumor-infiltrating leukocytes revealed a significant increase of CCR6(+) B220(+) lymphocytes in solid tumors derived from mBD14-overexpressing tumor cells. Enhanced tumor growth of mBD14-overexpressing fibrosarcomas was abolished in CCR6-deficient mice, which was paralleled by decreased infiltration of CCR6(+) B220(+) lymphocytes, indicating the requirement of CCR6 expression on host cells. Previously, the interaction of activated, LT alpha beta(+), lymphocytes with lymphotoxin beta-receptor- expressing fibrosarcoma tumor cells has been identified as a new CXCL2-dependent proangiogenic pathway. Co-expression of a soluble lymphotoxin beta-receptor:Ig fusion protein, an inhibitor of CXCL2-dependent angiogenesis, in mBD14-overexpressing fibrosarcoma tumor cells abolished enhanced solid tumor growth. Thus, we conclude that mBD14 expression by tumor-infiltrating host cells results in the chemoattraction of CCR6(+) B220(+) lymphocytes, which in turn initiates a proangiogenic pathway leading to enhanced angiogenesis and organized tumor tissue development. The Journal of Immunology, 2012, 188: 4931-4939.