Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis
Mice deficient in tumor necrosis factor-α are resistant to skin carcinogenesis
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DOI：
10.1038/10552
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发表时间：
1999-07-01
期刊：
影响因子：
82.9
通讯作者：
Balkwill, F
中科院分区：
文献类型：
--
作者：
Moore, RJ;Owens, DM;Balkwill, F
考虑到慢性炎症和上皮癌之间的联系（1，2），我们研究了缺乏促炎细胞因子TNF-α的小鼠对皮肤癌发生的易感性（3，4）（参考文献10）。5、6）。TNF-α（-/-）小鼠对良性和恶性皮肤肿瘤的发展具有抗性，无论是通过DMBA起始和TPA促进诱导还是通过DMBA重复给药诱导。TNF-α（-/-）小鼠在启动/促进期间发展的肿瘤数量是野生型小鼠的5-10%，在重复致癌物治疗后是野生型小鼠的25%。TNF-α在肿瘤发生发展过程中可影响肿瘤和基质细胞。TPA促进的早期阶段的特征在于角质形成细胞过度增殖和炎症。这些在TNF-α（-/-）小鼠中减少。在TPA处理的野生型皮肤中，TNF-α在表皮而不是真皮中被广泛诱导，表明真皮炎症受角质形成细胞TNF-α产生控制。TNF-α诱导的趋化因子的缺失也赋予了对皮肤肿瘤发展的一些抗性。TNF-α对癌症发生的后期阶段几乎没有影响，因为野生型和TNF-α（-/-）小鼠中的肿瘤具有相似的恶性进展率。这些数据提供的证据表明，促炎细胞因子是从头致癌所必需的，TNF-α对肿瘤促进的早期阶段是重要的。中和TNF-α产生的策略可能有助于癌症的治疗和预防。
Given the associations between chronic inflammation and epithelial cancer(1,2) , we studied susceptibility to skin carcinogenesis(3,4) in mice deficient for the pro-inflammatory cytokine TNF-alpha (refs. 5,6). TNF-alpha(-/-) mice were resistant to development of benign and malignant skin tumors, whether induced by initiation with DMBA and promotion with TPA or by repeated dosing with DMBA. TNF-alpha(-/-) mice developed 5-10% the number of tumors developed by wild-type mice during initiation/promotion and 25% of those in wild-type mice after repeated carcinogen treatment. TNF-alpha could influence tumor and stromal cells during tumor development. The early stages of TPA promotion are characterized by keratinocyte hyperproliferation and inflammation. These were diminished in TNF-alpha(-/-) mice. TNF-alpha was extensively induced in the epidermis, but not the dermis, in TPA-treated wild-type skin, indicating that dermal inflammation is controlled by keratinocyte TNF-a production. Deletion of a TNF-alpha inducible chemokine also conferred some resistance to skin tumor development. TNF-alpha has little influence on later stages of carcinogenesis, as tumors in wild-type and TNF-alpha(-/-) mice had similar rates of malignant progression. These data provide evidence that a pro-inflammatory cytokine is required for de novo carcinogenesis and that TNF-alpha is important to the early stages of tumor promotion. Strategies that neutralize TNF-alpha production may be useful in cancer treatment and prevention.