Chemopreventive Strategies for Inflammation-Related Carcinogenesis: Current Status and Future Direction

Abstract

A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.

Keywords: chemoprevention; chronic inflammation; inflammation-related carcinogenesis.

Figure 1

Organs/tissues involved in inflammation-related cancers. The organs/tissues with inflammation induced by definitely carcinogenic agents (red circles) or by presumed carcinogenic agents (yellow circles) are sensitive to cancer development. Skin (psoriasis) and joint (rheumatoid arthritis), indicated by black circles, are resistant to inflammation-related carcinogenesis.

Figure 2

Causes of inflammation-related carcinogenesis. The proportion of definitely carcinogenic causes (a) or presumed carcinogenic causes (b) attributed to inflammation was derived from Table 1.

Figure 3

Schematic mechanism of inflammation-induced cancer development. Tissue damage causes inflammatory cell infiltration (i). Leukocytes produce ROS (ii) and NO (iii) resulting in oxidative/nitrative stress (DNA damage, lipid peroxidation, protein modification and, thus, mutation). Reduction of antioxidant enzymes (iv) and antioxidants (v), which scavenge ROS, leads to enhancement of oxidative stress. A positive feedback loop between NF-κB (vi) and pro-inflammatory cytokines (vii) is necessary for inflammation to become chronic. Anti-inflammatory cytokines (viii) are downregulated in inflammation-related carcinogenesis. Chemokines (ix) recruit leukocytes into inflammatory sites. In addition to ROS, NO and pro-inflammatory cytokines, COX-2 (x) promotes cell proliferation and angiogenesis and suppresses apoptosis and immunosurveillance. Inflammation also causes DNA methylation, which results in aberrant gene expression. Ten possible chemopreventive targets are shown in the red boxes. Factors that are decreased are shown in the green boxes. Pointed arrows indicate promotion/activation while T-shaped arrows indicate suppression.

Figure 4

Natural compounds and food products have multiple chemopreventive mechanisms of action against inflammation-related carcinogenesis. The numbers of mechanisms of action of natural compounds, food products, low-molecular weight compounds, COX inhibitors and others against inflammation-related cancer development were calculated based on Table 3.