Section of Cell and Developmental Biology, Division of Biological Sciences, University of California San Diego, Natural Science Building Room 6113, 9500 Gilman Drive, MC 0380, La Jolla, CA 92093, USA.
Cancer Res. 2010 Dec 15;70(24):10080-9. doi: 10.1158/0008-5472.CAN-10-0324.
Although metastasis is the most lethal consequence of tumor progression, comparatively little is known regarding the molecular machinery governing this process. In many carcinomas, there is a robust correlation between the expression of the transcription factor Snail and a poor prognosis, but the contribution of this protein to the metastatic process remains unresolved. Interestingly, the prolonged expression of Snail in epidermal keratinocytes is sufficient to recapitulate early features of metastasis. However, it does so without inducing a complete epithelial-mesenchymal transition (EMT), a developmental phenomenon mediated by Snail that is extensively invoked as the mechanism fueling tumorigenesis. Instead, we found that the local invasiveness of keratinocytes is the consequence of the recruitment and activity of macrophages. Moreover, keratinocyte proliferation is the product of an IL-17/IL-6/Stat3 signaling module initiated by activated resident γδT cells in the transgenic skin. Together, these phenotypes prime the transgenic skin for the formation and metastasis of tumors in response to chemically induced carcinogenesis. Thus, the contribution of Snail to the progression of carcinomas is largely through the creation of a hyperproliferative and inflammatory niche that facilitates tumor development and dissemination.
虽然转移是肿瘤进展最致命的后果，但对于控制这一过程的分子机制，人们知之甚少。在许多癌症中，转录因子 Snail 的表达与预后不良之间存在很强的相关性，但该蛋白对转移过程的贡献仍未得到解决。有趣的是，Snail 在表皮角质形成细胞中的长期表达足以重现转移的早期特征。然而，它并没有诱导完全的上皮-间充质转化（EMT），这是 Snail 介导的一种发育现象，被广泛认为是促进肿瘤发生的机制。相反，我们发现角质形成细胞的局部侵袭是巨噬细胞募集和激活的结果。此外，角质形成细胞的增殖是由激活的转基因皮肤中的固有γδT 细胞启动的 IL-17/IL-6/Stat3 信号模块产生的。这些表型共同使转基因皮肤对化学诱导的致癌作用形成和转移肿瘤做好准备。因此，Snail 对癌的进展的贡献主要是通过创造一个过度增殖和炎症的小生境，促进肿瘤的发展和扩散。
