Editors' ChoiceCancer

AID-ing inflammatory carcinogenesis

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Science Translational Medicine  20 Apr 2016:
Vol. 8, Issue 335, pp. 335ec65
DOI: 10.1126/scitranslmed.aaf7823

Environmental factors such as UV light, ionizing radiation, chemical mutagens, and viral infection drive somatic mutation and tumor formation. Some tumors that arise by somatic mutation, however, do so in the apparent absence of an environmental mutagen, suggesting a role for endogenous players in tumor initiation. In support of this hypothesis, Nonaka et al. present evidence that an endogenous protein, activation-induced cytidine deaminase (AID), is up-regulated in inflamed tissue, resulting in the accumulation of somatic mutations and cancer.

AID, normally expressed in B cells, induces point mutations and gene recombination to diversify the antibody repertoire. Deregulated AID activity can cause B cell lymphoma, and transgenic mice broadly overexpressing AID develop T cell lymphoma, lung carcinoma, and melanoma. To test the hypothesis that AID is involved in UV-independent skin carcinogenesis, the authors expressed AID under a keratinocyte-specific promoter and observed spontaneous formation of skin and oral cancers in a dose-dependent manner. Interestingly, low levels of AID expression synergized with two-step chemical carcinogenesis of the skin, whereas AID knockout animals were protected. The authors demonstrated that AID acts as both a tumor initiator and mild promoter, contributing to Hras and Trp53 mutagenesis and increased malignant conversion, respectively. Importantly, inflammatory stimuli induced expression of AID in murine and human skin cells; human cutaneous tumors and inflammatory lesions express AID; and cutaneous tumors arising in sun-protected regions revealed mutational patterns consistent with AID activity.

Epidemiological data link chronic inflammation and carcinogenesis, and the data presented by Nonaka et al. provide direct evidence that AID functions as an endogenous mutagen driving transition between these two states. Furthermore, these data indicate that up-regulation of AID, at least in skin, may be an early indicator of carcinogenic potential in chronically inflamed tissue, as well as a potential therapeutic target to limit initiation and malignant conversion.

T. Nonaka et al., Involvement of activation-induced cytidine deaminase in skin cancer development. J. Clin. Invest. 126, 1367–1382 (2016). [Full Text]

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