Editors' ChoiceCancer

Homegrown factors in colon cancer

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Sci. Signal.  17 May 2016:
Vol. 9, Issue 428, pp. ec114
DOI: 10.1126/scisignal.aag1382

Chronic intestinal inflammation is a risk factor for colorectal cancer (CRC). Inflammation can alter the composition of the gut microbiome and damages the mucosal lining of the intestine, enabling the interaction of gut microbes with the epithelia. Two studies describe how the mingling of microbes with intestinal cells may promote CRC development. Peuker et al. found that microbiota stimulated the proliferation of CRC-associated stem cells through the activation of calcineurin. Calcineurin is a phosphatase that activates transcription factors in the NFAT family. Some patients with poor prognosis carry a mutation in the catalytic subunit of calcineurin that causes constitutive activation. The expression of the gene encoding calcineurin was increased in patient CRC samples compared with normal intestinal epithelial cells, and the nuclear abundance of NFATc3 correlated with poor prognosis. Manipulating the expression and activity of calcineurin or NFATc3 in mouse models of CRC revealed that calcineurin-dependent activation of NFATc3, which included the induction of intestinal stem cell–associated genes, promoted tumor initiation and growth. Microbes trigger an innate immune response through the activation of Toll-like receptors (TLRs). CRC cells are positive for TLR2 and TLR4. The microbial population of mouse CRC-associated mucosa was enriched for those that trigger TLR4. TLR4 agonists stimulated the transcriptional activity of NFATc3 and proliferation in cultured CRC cells expressing functional but not inactive calcineurin. Treating CRC model mice with antibiotics or systemically deleting the gene encoding MYD88, which mediates the signal from TLR2 and TLR4 to interleukin-1 receptor–associated kinase (IRAK), prevented NFAT activation and tumor growth, which could be restored by expression of constitutively active NFATc3.

Kesselring et al. (see also Jenkins) found that IRAK-M, a negative regulator of TLR–MYD88–IRAK signaling, contributes to inflammation-associated CRC by promoting barrier dysfunction during early stages of the disease and stabilizing proliferative pathways during the latter stages. Whereas the abundance of IRAK-M was associated with suppressed inflammation in a carcinogen-induced mouse model of colitis, it was associated with increased tumor growth in these and transgenic Tp53ΔIEC mice and poor prognosis in CRC patients. Cultured CRC cells or the colons of mice exposed to agonists of either TLR2 or TLR4 or molecules that activate the WNT pathway exhibited increased abundance of IRAK-M. Analyzing microbial species, epithelial barrier function, and intracellular signaling pathway activity between carcinogen-treated wild-type and IRAK-M–deficient mice revealed that IRAK-M suppressed the inflammatory, antimicrobial response in intestinal epithelial cells while promoting the abundance of the transcription factor STAT3 and suppressing apoptosis. The two studies reveal that the detection of microbiota as a result of the breakdown of the intestinal mucosal barrier can trigger TLR-dependent transcriptional and proliferative responses in intestinal epithelial cells and these responses lead to tumorigenesis.

R. Kesselring, J. Glaesner, A. Hiergeist, E. Naschberger, H. Neumann, S. M. Brunner, A. K. Wege, C. Seebauer, G. Köhl, S. Merkl, R. S. Croner, C. Hackl, M. Stürzl, M. F. Neurath, A. Gessner, H.-J. Schlitt, E. K. Geissler, S. Fichtner-Feigl, IRAK-M expression in tumor cells supports colorectal cancer progression through reduction of antimicrobial defense and stabilization of STAT3. Cancer Cell 29, 684–696 (2016). [PubMed]

B. J. Jenkins, Multifaceted role of IRAK-M in the promotion of colon carcinogenesis via barrier dysfunction and STAT3 oncoprotein stabilization in tumors. Cancer Cell 29, 615–617 (2016). [PubMed]

K. Peuker, S. Muff, J. Wang, S. Künzel, E. Bosse, Y. Zeissig, G. Luzzi, M. Basic, A. Strigli, A. Ulbricht, A. Kaser, A. Arlt, T. Chavakis, G. R. van den Brink, C. Schafmayer, J.-H. Egberts, T. Becker, M. E. Bianchi, A. Bleich, C. Röcken, J. Hampe, S. Schreiber, J. F. Baines, R. S. Blumberg, S. Zeissig, Epithelial calcineurin controls microbiota-dependent intestinal tumor development. Nat. Med. 22, 506–515 (2016). [PubMed]