Abstract
Obesity is a known risk factor for the development of pancreatic cancer, one of the deadliest types of malignancies. In recent years it has become clear that the pancreatic microenvironment is critically involved and a contributing factor in accelerating pancreatic neoplasia. In this context obesity-associated chronic inflammation plays an important role. Among several immune cells, macrophages have been shown to contribute to obesity-induced tissue inflammation. This review article summarizes the current knowledge about the role of pancreatic macrophages in early pancreatic cancer development. It describes the heterogenous origin and mixture of pancreatic macrophages, their role in pancreatic endocrine and exocrine pathology, and the impact of obesity on islet and stromal macrophages. A model is postulated, by which during obesity monocytes are recruited into the pancreas, where they are polarized into pro-inflammatory macrophages that drive early pancreatic neoplasia. This occurs in the presence of local inflammatory, metabolic, and endocrine signals. A stronger appreciation and more detailed knowledge about the role of macrophages in early pancreatic cancer development will lead to innovative preventive or interceptive strategies.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with an overall5-year survival rate of approximately 9% [1]
It is well accepted today that the majority of PDACs arise from precursor lesions, e.g., pancreatic intraepithelial neoplasia (PanIN), which progress from early PanIN-1 to advanced PanIN-3 and eventually invasive PDAC
Similar to the effect of obesity on the adipose tissue, we postulate that during obesity circulating monocytes will be recruited to the pancreas where they differentiate into M1 polarized inflammatory macrophages, thereby resulting in the observed increased number of total pancreatic macrophages
Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with an overall. A valid conceptual approach to improve the outcome of pancreatic cancer patients is to intercept early disease progression before the cancer becomes invasive and metastatic. This concept requires the identification of patients who are at high risk of developing the disease and/or detection of early disease as well as a detailed understanding of mechanisms that drive early tumor development. It is well accepted today that the majority of PDACs arise from precursor lesions, e.g., pancreatic intraepithelial neoplasia (PanIN), which progress from early PanIN-1 to advanced PanIN-3 and eventually invasive PDAC. In the presence of an oncogenic Kras mutation in acinar cells, ADMs may persist and progress to early PanIN lesions [11]. This review will summarize the current literature and our own data on the effects and mechanisms of obesity on pancreatic macrophages and their potential impact in early PDAC development
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