Inflammation and cancer: molecular mechanisms and clinical consequences

Abstract

Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of anticancer treatments in cancer. It affects all stages of cancer, from the initiation of carcinogenesis to metastasis. Chronic inflammation induces immunosup-pression, providing an environment conducive to carcinogenesis, whereas acute inflammation induces an antitumor immune response, leading to tumor suppression. Solid tumors have an inflammatory tumor microenvironment (TME) containing cancer cells, immune cells, stromal cells, and soluble molecules, which plays a key role in tumor progression and therapy response. Both cancer cells and stromal cells in the TME are highly plastic and constantly change their phenotypic and functional properties. Cancer-associated inflammation, the majority of which consists of innate immune cells, plays an important role in cancer cell plasticity, cancer progression and the development of anticancer drug resistance. Today, with the combined used of advanced technologies, such as single-cell RNA sequencing and spatial molecular imaging analysis, the pathways linking chronic inflammation to cancer have been largely elucidated. In this review article, we highlighted the molecular and cellular mechanisms involved in cancer-associated inflammation and its effects on cancer progression and treatment response. We also comprehensively review the mechanisms linking chronic inflammation to cancer in the setting of GI cancers.

Keywords: adaptive immunity; cancer-associated fibroblasts; cancer-associated inflammation; gastro-intestinal cancer; innate immunity; tumor microenvironment.

Figure 1

Interaction between inflammatory cells and inflammatory molecules in the tumor microenvironment. The major inflammatory cells include T helper cell (Th1), regulatory T cells (Tregs), Cytotoxic CD8⁺ T cells, macrophages, myeloid-derived suppressor cells (MDSCs), naturel killer (NK) cells and dendritic cells (DCs). Abbreviations: CXCR, CXC-Chemokine receptor; CXCL, Chemokine (C-X-C motif) ligand, TGF-β, transforming growth factor-β; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon.

Figure 2

Genetic aberrations and molecules generating the inflammatory tumor microenvironment. (a) Oncogenes and aberrant signaling signals are key players in the development of inflammatory TME, leading to the production of inflammatory cytokines and chemokines. BRAF^V600D activates Wnt/β-catenin signaling, which in turn decreases production of CCL4, a chemokine important for the recruitment of CD103⁺ DCs. Additionally, BRAF^V600D evokes the production of IL-10 and IL-1α molecules, leading to tolerogenic DCs and CAFs in the TME. The KRAS^G12D mutation induces GM-CSF expression, which leads to accumulation of immunosuppressive CD11b⁺ myeloid cells in the TME. Inactivation of p53 activates signaling pathways that lead to polarization of the immunoactivating M1 phenotype to the immunosuppressive M2 phenotype. Many tumors secrete high levels of the monocyte/macrophage-promoting cytokine CSF-1. (b) A high mutational burden is associated with potent expression of tumor neoantigens and extensive infiltration of CD8⁺ T cells into the TME.

Figure 3

Cancer-associated inflammation that affects tumor growth and progression. Stress, cell death, obesity and bacterial infection and its components trigger the activation of innate immune cells and increase the expression of inflammatory mediators, which induce the recruitment of adaptive immune cells to damaged tissue. Myeloid cells, such as DCs, take up antigens and present them T cells, activating to CD8⁺ T cells. On the other hand, cell death may exert immunosuppressive and tolerogenic effects, thus inhibiting CD8+ T cell activation. Similarly, monocytes and macrophages can impede the anti-tumor activity of CD8+ T cells by producing IL-10, ARG1, IDO, and TGF. In the early stages of cancer, inflammation leads to the production of cytokines, such as IL-1, TNF, and IL-6, that promote tumor growth, as well as VEGF that supports neo-angiogenesis.