Inflammation and Pancreatic Cancer: Focus on Metabolism, Cytokines, and Immunity

Abstract

Systemic and local chronic inflammation might enhance the risk of pancreatic ductal adenocarcinoma (PDAC), and PDAC-associated inflammatory infiltrate in the tumor microenvironment concurs in enhancing tumor growth and metastasis. Inflammation is closely correlated with immunity, the same immune cell populations contributing to both inflammation and immune response. In the PDAC microenvironment, the inflammatory cell infiltrate is unbalanced towards an immunosuppressive phenotype, with a prevalence of myeloid derived suppressor cells (MDSC), M2 polarized macrophages, and T_reg, over M1 macrophages, dendritic cells, and effector CD4⁺ and CD8⁺ T lymphocytes. The dynamic and continuously evolving cross-talk between inflammatory and cancer cells might be direct and contact-dependent, but it is mainly mediated by soluble and exosomes-carried cytokines. Among these, tumor necrosis factor alpha (TNFα) plays a relevant role in enhancing cancer risk, cancer growth, and cancer-associated cachexia. In this review, we describe the inflammatory cell types, the cytokines, and the mechanisms underlying PDAC risk, growth, and progression, with particular attention on TNFα, also in the light of the potential risks or benefits associated with anti-TNFα treatments.

Keywords: S100A8; S100A9; TNFα; Treg lymphocytes; anti-TNFα; cytokines; inflammation; miRNA; myeloid derived suppressor cells; pancreatic cancer; tumor associated macrophages.

Figure 1

Tumor necrosis factor alpha (TNFα) role in tumor promotion and in tumor-associated inflammation. In adiposity-associated systemic inflammation (metaflammation), pro-inflammatory M1 macrophages infiltrate the adipose tissue prevailing over M2 macrophages. Low amounts of TNFα, produced by M1 macrophages, might cause DNA damage by inducing reactive oxygen (ROS) and nitrogen (RNS) species. When normal pancreatic ductal cells (NC), but mainly stem cells (SC) are targeted, the failure of DNA repair after damage results in the clonal expansion of tumor cells (TC) and tumor establishment. Within the tumor microenvironment, made of stroma, tumor-associated fibroblasts (F), and inflammatory cells, including M1 and M2 macrophages, TNFα is produced by both TC and M1 macrophages. TNFα exerts effects on TC, inducing proliferation; on F, inducing stroma production and desmoplasia; and on distant sites concurring in causing cancer-associated cachexia and insulin resistance.