Chronic inflammation and cytokines in the tumor microenvironment

Abstract

Acute inflammation is a response to an alteration induced by a pathogen or a physical or chemical insult, which functions to eliminate the source of the damage and restore homeostasis to the affected tissue. However, chronic inflammation triggers cellular events that can promote malignant transformation of cells and carcinogenesis. Several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, have been shown to participate in both the initiation and progression of cancer. In this review, we explore the role of these cytokines in important events of carcinogenesis, such as their capacity to generate reactive oxygen and nitrogen species, their potential mutagenic effect, and their involvement in mechanisms for epithelial mesenchymal transition, angiogenesis, and metastasis. Finally, we will provide an in-depth analysis of the participation of these cytokines in two types of cancer attributable to chronic inflammatory disease: colitis-associated colorectal cancer and cholangiocarcinoma.

Figure 1

Schematic illustration of the role of cytokines in carcinogenesis. (a) During tissue injury or infection, an immune response activates the expression of proinflammatory mediators, such as TNF-α, IL-6, and IL-8 from macrophages and neutrophils. These cytokines can disrupt the epithelial barrier, induce RONS, and promote the infiltration of other inflammatory cells. (b) In chronic inflammation, proinflammatory cytokines such as TNF-α can induce DNA damage through RONS, which leads to tumor initiation. TGF-β can promote malignant transformation through EMT activation. Cytokines derived from CD4⁺lymphocytes, such as IFN-γ, IL-10, and IL-17, can participate in epithelial barrier disruption, M2 phenotypic transitions of macrophages, and angiogenesis, respectively. (c) Tumor growth and invasion are also favored by proinflammatory cytokines that stimulate cell proliferation, reduce apoptosis, and enhance EMT and angiogenesis; the latter is facilitated by VEGF and IL-8. Anti-inflammatory cytokines, such as IL-10 and TGF-β, contribute to tumor immune evasion. (d) Tumor-associated macrophages (TAM), tumor-infiltrating lymphocytes (TIL), and cancer-associated fibroblasts (CAF) secrete several factors that contribute to tumor growth and metastasis, while maintaining the immunosuppressive milieu.