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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 Treg, 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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers worldwide, has a five-year survival rate of less than 6%, the lowest percentage for cancers in the period 2007–2013 [1]
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
We describe the inflammatory cell types, the cytokines, and the mechanisms underlying PDAC risk, growth, and progression, with particular attention on TNFα, in the light of the potential risks or benefits associated with anti-TNFα treatments
Summary
Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers worldwide, has a five-year survival rate of less than 6%, the lowest percentage for cancers in the period 2007–2013 [1]. The mechanism underlying the ability of the immune system to initially protect a host from tumor growth and subsequent cancer progression, so called cancer immunoediting [46], resides mainly within the tumor and the surrounding stroma, which include fibroblasts, pancreatic stellate cells, and infiltrating immune cells In this area, known as the tumor microenvironment, the local immune response primes local inflammation, generated and maintained mainly by cytokines, chemokines, and other reactive molecules, such as reactive oxygen species (ROS) and small peptides. In the PDAC setting, it has been shown that immune cells, and human pancreatic tumor cells, can produce and secrete TNFα at picogram levels This suggests that PDAC cells are regularly exposed to their endogenous autocrine stimuli that determine, through the activation of NF-κB and Sonic Hedgehog pathways and the recruitment of Treg at the cancer site, increased tumor cell invasiveness both in vitro and in vivo animal models [80,81,82]. Rheumatoid arthritis treated with adalimumab or etanercept [100]
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