Editors' ChoiceCancer and Inflammation

Cancer Transformers

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Science Translational Medicine  04 Nov 2009:
Vol. 1, Issue 5, pp. 5ec18
DOI: 10.1126/scitranslmed.3000547

Multiple factors that affect cell division, growth, and survival have long been known to contribute to the etiology of cancer. Inactivation of tumor suppressor genes and the acquisition of oncogenic mutations help cancer cells overcome the normal mechanisms that control cellular proliferation. The progression from normal to malignant cells is also associated with environmental conditions like inflammation, but the molecular events underlying this process have not been described. Now, in this week’s issue of Cell, Struhl and colleagues identify a regulatory circuit governing inflammation-induced cellular transformation using an experimental model that exploits the short-term administration of tamoxifen on mammary epithelial cells (MCF10A). They characterize the phenotypic transformation of these cells as defined by multiple foci formation, colony formation, increased invasiveness, and tumor formation upon injection into nude mice.

In this seminal work, the authors show that transient activation of the Src kinase oncoprotein causes an epigenetic switch in which MCF10A cells that harbor and express an estrogen receptor-Src fusion protein are converted into self-renewing mammospheres that can be propagated for many generations. In the absence of the tamoxifen-induced initiating signal, the stable inheritance of the transformed cell state was shown to be mediated by a positive feedback loop involving activation of the NF-κB transcription factor. This activation directly up-regulated the microRNA processing factor Lin28, whose increased levels inhibited Let-7 microRNA, which in turn targeted the IL6 cytokine and inhibited its signaling pathway. This defined inflammatory feedback loop operates in cancer cells from diverse developmental lineages; eight out of 15 different kinds of cancer cell lines exhibited Lin28B overexpression, Let-7 downregulation, and high levels of IL6. Studies in mice also revealed that perturbation of any component of the regulatory circuit strongly suppressed tumor growth and restored gene expression patterns typical of nontransformed cells. Although gene expression and microRNA profiling studies are yet to come, taken together, the data produced by Struhl and colleagues show how cancer progression can involve an epigenetic switch in response to an inflammatory (or other environmental) signal rather than the more expected mutational change in a tumor suppressor or oncogene.

D. Illipolous et al., An epigenetic switch involving NF-κB, Lin28, Let-7 microRNA, and IL6 links inflammation to cell transformation. Cell 29 October 2009 (doi:10.1016/j.cell.2009.10.014). [Abstract]

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