TGF-β Is a Critical Target Linked to Diet and the Risk of Cancer

Various dietary components may modify chronic inflammatory processes at the stage of cytokine production, amplification of nuclear factor-κB–mediated inflammatory gene expression, and the release of anti-inflammatory cytokine, transforming growth factor-β. This review provides a synopsis of the strengths and weaknesses of the evidence that specific bioactive food components influence inflammation-related targets linked to cancer. A target repeatedly surfacing as a site of action for several dietary components is transforming growth factor β. Whereas the use of dietary intervention strategies offers intriguing possibilities for maintaining normal cell function by modifying a process that is essential for cancer development and progression, more information is needed to characterize the minimum quantity of the bioactive food components required to bring about a change in inflammation-mediated cancer, the ideal time for intervention, and the importance of genetics in determining the response. Unquestionably, the societal benefits of using foods and their components to prevent chronic inflammation and associated complications, including cancer, are enormous. A varietyof bioactive food components have been shown to modulate inflammatory responses and to attenuate carcinogenesis (1–3). However, the effects of diet on the molecular mechanisms accounting for the changes in inflammation and carcinogenesis are not well understood. Whereas inflammation is a crucial protective response to tissue injury or infection, uncontrolled chronic inflammatory responses can result in serious complications, including cancer (4). The frequency of cancer and overall mortality has major societal implications in the United States in terms of quality of life and loss of productivity (5–7). This review points to potential use of bioactive food components for modifying molecular targets involved with chronic inflammation and, as a consequence, the attenuation of carcinogenesis. Inflammatory Processes and Cancer Inflammation is initiated by the synthesis and secretion of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, IL-12, and IFN-γ in macrophages in response to an inflammatory insult (8). The binding of proinflammatory cytokines to their receptors triggers the mitogen-activated protein kinase pathway, which ultimately results in the activation of two redox-sensitive transcription factors, nuclear factor-κB (NF-κB) and the c-Jun part of activating protein-1 (9). These transcription factors activate the expression of a wide variety of genes including cytokines (TNF-α and IL-1β), chemokines, adhesion molecules, and inducible effector enzymes such as inducible nitric oxide synthase (INOS) and cyclooxygenase-2 (COX-2), thereby generating a feed-forward loop that amplifies the inflammatory response (10). The changes in proinflammatory cytokines have multiple links with the production of anti-inflammatory cytokines including IL-4, IL-10, transforming growth factor-β (TGF-β), peroxisome proliferator activated receptor-γ (PPAR-γ), and the cellular redox defense system including manganese superoxide dismutase, glutathione, and catalase (11). These feedback mechanisms serve as controlling points where the amplification of the inflammatory processes can be disconnected and thereby reduce subsequent cancer risk. The unchecked activation of NF-κB/COX-2 and the inactivation of TGF-β signaling are recognized to be fundamental to the formation of tumors (12, 13). Mouse models with mutations in the genes coding for the inhibitors of κB kinase (IKKα and IKKβ) have provided compelling evidence about the critical role for NF-κB in coupling inflammation and cancer (14). Overall, the imbalance between anti-inflammatory and proinflammatory mediators may precipitate the neoplastic transformation in various cancer sites (Fig. 1). Modulating Effects of Bioactive Food Components on the Proinflammatory and Anti-inflammatory Molecules Evidence exists that a host of food components, including α-linolenic acid, n-3 and n-6 polyunsaturated fatty acids, Authors' Affiliations: Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland and Laboratory of Cancer Prevention, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, Maryland Received 7/15/2008; revised 9/24/2008; accepted 10/29/2008; published OnlineFirst 3/3/09. Note: G. Bobe is currently a fellow in the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, NIH, Bethesda, MD 20892. Requests for reprints: Young S. Kim, Nutritional Science Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Boulevard, Room 3156, Bethesda, MD 20892. Phone: 301-496-0126; Fax: 301-4803925; E-mail: yk47s@nih.gov. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-08-0141 200 Cancer Prev Res 2009;2(3) March 2009 www.aacrjournals.org Cancer Research. on June 23, 2017. © 2009 American Association for cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst March 3, 2009; DOI: 10.1158/1940-6207.CAPR-08-0141