Expression of Snail in Epidermal Keratinocytes Promotes Cutaneous Inflammation and Hyperplasia Conducive to Tumor Formation

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 Research (Impact Factor: 9.33). 12/2010; 70(24):10080-9. DOI: 10.1158/0008-5472.CAN-10-0324
Source: PubMed


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.

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    • "Further support to the concept of a reciprocal interaction between tumour cells and TAMs was provided by a recent paper where SNAIL-expressing keratinocytes became locally invasive after macrophage recruitment elicited by M-CSF. (Du et al., 2010) In line with the above experimental evidence, high numbers of infiltrating TAMs have been significantly associated with advanced tumours and poor patient prognosis, in the majority of human tumours.(Bingle et al., 2002; Mantovani et al., 2008; Pollard, 2004; Qian and Pollard, 2010) There are, however, notable exceptions to this pro-tumour phenotype, probably dictated by their functional polarization. "
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