Editors' ChoiceCancer

Our AIM is 2 prevent cancer

Sci. Signal.  25 Aug 2015:
Vol. 8, Issue 391, pp. ec234
DOI: 10.1126/scisignal.aad2821

Binding of cytosolic double-stranded DNA to the sensor AIM2 triggers activation of the inflammasome, a key component in host defenses against microbes. Mutations in AIM2 have been found in colorectal tumors, and two groups show that AIM2 also prevents colon cancer independently of its role in inflammasome activation. Wilson et al. subjected Aim2–/– mice to chemically induced colitis and found that these mice had more severe colitis symptoms, developed more precancerous polyps, and had a higher tumor load than had wild-type mice. However, the mRNA and protein abundance of cytokines that are produced downstream of inflammasome activation were similar between both genotypes. Akt is a kinase that promotes cellular proliferation and survival in response to growth factors, and the activation of this kinase was greater in the colons of Aim2–/– mice than in those of wild-type mice. Proliferation was enhanced in the colons of Aim2–/– mice subjected to chemically induced colitis compared with those of wild-type mice, and treatment with an Akt inhibitor reduced polyp numbers, polyp size, and tumor burden in Aim2–/– mice with colitis. Overexpressed AIM2 associated with and limited the activation of endogenous DNA-PK, a kinase that can phosphorylate and activate Akt. In the second paper, Man et al. (see also Rommereim and Subramanian) also found that Aim2–/– mice were more susceptible than were wild-type mice to developing colitis-associated colorectal cancer, although various markers of inflammasome activation were similar between the two genotypes. Chemically induced colitis resulted in greater proliferation of enterocytes in Aim2–/– mice, which was associated with increased Akt activation. Colonic epithelial stem cells are thought to be the cells of origin for several intestinal cancers, and those from Aim2–/– mice proliferated to a greater extent than did those from wild-type mice and they formed more three-dimensional organoids. Gut microbiota in Aim2–/– mice differed from that in wild-type mice, and two of the changes in the gut microbiota of Aim2–/– mice have been linked to the development of colon cancer. Co-housing of Aim2–/– and wild-type mice resulted in reduced tumorigenesis in Aim2–/– mice and increased tumorigenesis in wild-type mice. Thus, AIM2 prevents colorectal tumorigenesis through mechanisms that do not involve inflammasome activation. The contribution of AIM2 in radiosensitive, bone marrow–derived cells to colorectal tumorigenesis remains to be determined. Although Wilson et al. found that tumorigenesis was not altered in Aim2–/– mice that received bone marrow from wild-type mice, Man et al. found that tumorigenesis was increased in wild-type mice that received bone marrow from Aim2–/– mice.

J. E. Wilson, A. S. Petrucelli, L. Chen, A. A. Koblansky, A. D. Truax, Y. Oyama, A. B. Rogers, W. J. Brickey, Y. Wang, M. Schneider, M. Mühlbauer, W.-C. Chou, B. R. Barker, C. Jobin, N. L. Allbritton, D. A. Ramsden, B. K. Davis, J. P. Y. Ting, Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat. Med. 21, 906–913 (2015). [PubMed]

S. M. Man, Q. Zhu, L. Zhu, Z. Liu, R. Karki, A. Malik, D. Sharma, L. Li, R. K. S. Malireddi, P. Gurung, G. Neale, S. R. Olsen, R. A. Carter, D. J. McGoldrick, G. Wu, D. Finkelstein, P. Vogel, R. J. Gilbertson, T.-D. Kanneganti, Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 162, 45–58 (2015). [PubMed]

L. M. Rommereim, N. Subramanian, AIMing 2 curtail cancer. Cell 162, 18–20 (2015). [PubMed]