Editors' ChoiceCarcinogenesis

IL-11 Trumps IL-6 in Gastrointestinal Cancer

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Science Signaling  03 Sep 2013:
Vol. 6, Issue 291, pp. ec208
DOI: 10.1126/scisignal.2004692

Members of the interleukin (IL)–6 family of secreted cytokines stimulate gp130 and STAT3 (signal transducer and activator of transcription 3) signaling in solid tumors from various tissue origins, and increased STAT3 activation is associated with poor patient prognosis. Reagents that target IL-6 or its receptor IL-6Rα are under investigation as therapeutics in human clinical trials. Putoczki et al. demonstrated that the IL-6 family member IL-11 may be a better therapeutic target in gastrointestinal cancer (also see Grivennikov). mRNA expression for IL-11, but not for IL-6, correlated with STAT3 activation in human colorectal cancer (CRC) samples. Mice lacking the IL-11 receptor (IL-11Rα) showed decreased STAT3 activation and fewer and smaller tumors in a pharmacological model of colitis-associated cancer (CAC). Knockout of IL-6 also reduced tumor burden, but to a lesser degree, and combining IL-11 with IL-6 knockout did not further reduce the number of tumors. Similarly, knockout of IL-11Rα, but not of IL-6, prevented colon tumor formation in genetic models of CRC, including those with activated β-catenin signaling (APCmin/+) or those that combined a chemical mutagen with activated STAT3 signaling (gp130F/F). IL-11 is required in myeloid-lineage cells for innate immune system function, and hematopoetic reconstitution experiments indicated that wild-type mice lethally irradiated with CAC and transplanted with IL-11Rα–deficient bone marrow developed tumors, whereas CAC-challenged and irradiated IL-11Rα knockout mice reconstituted with wild-type bone marrow did not. Heterozygous knockout of IL-11Rα or STAT3 reduced tumor burden in gp130F/F mice. Moreover, systemic treatment with miL-11 Mutein, a recombinant protein antagonist of IL-11, prevented the formation of tumors in gp130F/F or CAC-challenged mice and reduced the growth of xenografts of two different human gastrointestinal cancer cell lines in immune-compromised mice. Thus, IL-11 activates STAT3 signaling in gastrointestinal tumors, and pharmacological inhibition of IL-11 is a potentially viable therapeutic strategy in this disease.

T. L. Putoczki, S. Thiem, A. Loving, R. A. Busuttil, N. J. Wilson, P. K. Ziegler, P. M. Nguyen, A. Preaudet, R. Farid, K. M. Edwards, Y. Boglev, R. B. Luwor, A. Jarnicki, D. Horst, A. Boussioutas, J. K. Heath, O. M. Sieber, I. Pleines, B. T. Kile, A. Nash, F. R. Greten, B. S. McKenzie, M. Ernst, Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24, 257–271 (2013). [PubMed]

S. I. Grivennikov, IL-11: A prominent pro-tumorigenic member of the IL-6 family. Cancer Cell 24, 145–147 (2013). [PubMed]

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