Targeting Inflammation in Cancer Prevention and Therapy

Abstract

Inflammation is associated with the development and malignant progression of most cancers. As most of the cell types involved in cancer-associated inflammation are genetically stable and thus are not subjected to rapid emergence of drug resistance, the targeting of inflammation represents an attractive strategy both for cancer prevention and for cancer therapy. Tumor-extrinsic inflammation is caused by many factors, including bacterial and viral infections, autoimmune diseases, obesity, tobacco smoking, asbestos exposure, and excessive alcohol consumption, all of which increase cancer risk and stimulate malignant progression. In contrast, cancer-intrinsic or cancer-elicited inflammation can be triggered by cancer-initiating mutations and can contribute to malignant progression through the recruitment and activation of inflammatory cells. Both extrinsic and intrinsic inflammation can result in immunosuppression, thereby providing a preferred background for tumor development. In clinical trials, lifestyle modifications including healthy diet, exercise, alcohol, and smoking cessation have proven effective in ameliorating inflammation and reducing the risk of cancer-related deaths. In addition, consumption of certain anti-inflammatory drugs, including aspirin, can significantly reduce cancer risk, suggesting that common nonsteroidal anti-inflammatory drugs (NSAID) and more specific COX2 inhibitors can be used in cancer prevention. In addition to being examined for their preventative potential, both NSAIDs and more potent anti-inflammatory antibody-based drugs need to be tested for their ability to augment the efficacy of more conventional therapeutic approaches on the basis of tumor resection, radiation, and cytotoxic chemicals. Cancer Prev Res; 9(12); 895-905. ©2016 AACR.

Figure 1. Mechanisms linking obesity, inflammation and cancer

In obesity, enlarged adipocytes secrete pro-inflammatory adipokines such as leptin, TNF-α, CCl-2 and IL-6 and localy induce an M1 macrophage phenotype. In addition to macrophages mast- and T-cells infiltrate adipose tissue in obesity and aggravate an inflammatory state. The adipose tissue-derived inflammatory mediators also exert their effects systemically and may activate inflammatory pathways such as NF-kB and STAT3 pathway in pre malignant and malignant cells and promote a microenvironment favorable for tumorigenesis.

Figure 2. Inflammation in ALD

Alcohol consumption increases gut permeability and facilitates translocation of bacteria-derived LPS from the gut to the liver. LPS activates TLR4-TRIF/IRF-3 pathway in Kupffer cells, which results in increased proinflammatory cytokine production subsequently leading to hepatocyte damage. Alcohol consumption also activates complement C3 and C5, which bind to the receptors on Kupffer cells and increase their TNF-α production, which leads to activation of NF-kB and other inflammatory pathways in hepatocytes and hepatocyte injury. In response to pro-inflammatory stimuli hepatocytes secrete chemokines to attract more inflammatory cells.

Figure 3. Targeting STAT3 pro-inflammatory pathway

Schematic representation of the major targetable events during STAT3 activation, and the corresponding compounds with cancer-preventive properties.