Inflammation and Cancer: Microenvironment, Cytokines, MicroRNA and p53  Free radicals are ubiquitous in our body and are generated by normal physiological processes, including aerobic metabolism and inflammatory responses, to eliminate invading pathogenic microorganisms (1). Because free radicals can also inflict cellular damage, several defenses have evolved both to protect our cells from radicals-such as the p53 pathway and antioxidant scavengers and enzymes-and to repair DNA damage (2). Free radicals can cause an adaptive increase in certain of the protective base excision repair enzymes. Paradoxically, if the increase in these enzymes is imbalanced, e.g., the DNA glycosylase is increased more than the apurinic endonuclease, frameshift mutations occur as a novel etiology of microsatellite instability (3). Understanding the relationship between chronic inflammation and cancer provides insights into the molecular mechanisms involved. In particular, we highlight the interactions among nitric oxide, microRNAs and p53 as crucial pathways in inflammatory-mediated carcinogenesis. The balance of pro- and anti-inflammatory cytokines and microRNAs within cancers and in the tissue macroenvironment also predicts lung, colon, and liver cancer diagnosis and prognosis (4-8). Current studies are investigating the mechanistic interactions between these cytokines and microRNAs and the combination of independent biomarker and clinical endpoints to improve prediction of cancer prognosis and therapeutic outcome. References: 1. Hussain, S. P., Hofseth, L. J., and Harris, C. C. (2003). Radical causes of cancer. Nat. Rev. Cancer 4, 276-285. 2. Hofseth, L. J., Saito, S., Hussain, S. P., Espey, M. G., Miranda, K. M., Araki, Y., Jhappan, C., Higashimoto, Y., He, P., Linke, S. P., Quezado, M.M., Zurer, I., Rotter, V., Wink, D. A., Appella, E. and Harris, C. C. (2003) Nitric oxide-induced cellular stress and p53 activation in chronic inflammation. Proc. Natl. Acad. Sci. USA, 100, 143-148. 3. Hofseth, L. J., Khan, M. A., Ambrose, M., Nikolayeva, O., Xu-Welliver, M., Kartalou, M., Hussain, S. P., Roth, R. B., Zhou, X., Mechanic, L. E., Zurer, I., Rotter, V., Samson, L. D. and Harris, C. C. (2003) The adaptive imbalance in base excision repair enzymes generates microsatellite instability in chronic inflammation. J. Clin. Invest., 112, 1887-1894. 4. Seike, M., Yanaihara, N., Bowman, E. D., Zanetti, K. A., Budhu, A., Kumamoto, K., Mechanic, L. E., Matsumoto, S., Yokota, J., Shibata, T., Sugimura, H., Gemma, A., Kudoh, S., Wang, X. W. and Harris, C. C. (2007) Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. J. N. C. I., 99, 1257-1269. 5. Yanaihara, N., Caplen, N., Bowman, E., Kumamoto, K., Yi, M., Stephens, R. M., Okamoto, A., Yokota, J., Tanaka, T., Calin, G. A., Liu, C.-G., Croce, C. M. and Harris, C. C. (2006) microRNA expression signature predicts lung cancer diagnosis and prognosis. Cancer Cell 9, 189-198. 6. Budhu, A., Forgues, M., Ye, Q. H., Jia, H. L., He, P., Zanetti, K. A., Kammula, U. S., Chen, Y., Qin, L. X., Tang, Z. Y. and Wang, X. W. (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10, 99-111. 7. Budhu, A., Jia, H. L., Forgues, M., Liu, C. G., Goldstein, D., Lam, A., Zanetti, K. A., Ye, Q. H., Qin, L. X., Croce, C. M., Tang, Z. Y. and Wang, X. W. (2008) Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology 47, 897-907. 8. Schetter, A. J., Leung, S. Y., Sohn, J. J., Zanetti, K. A., Bowman, E. D., Yanaihara, N., Yuen, S. T., Chan, T. L., Kwong, D.L.W., Au, G. K. H., Liu, C. G., Calin, G. A., Croce, C. M. and Harris, C. C. (2008) MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299, 425-436.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr SY04-2.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

American Association for Cancer Research
2009