Inflammatory macrophages in pancreatic acinar cell metaplasia and initiation of pancreatic cancer

Abstract

The roles of inflammatory macrophages in pancreatic tissue and the development of pancreatic cancer have not been well characterized. Recently it was shown that inflammatory macrophages, besides their function in clearing dead cells, also initiate pancreatic acinar cell metaplasia to duct-like progenitor cells. While in pancreatitis this is a reversible process, in context of an oncogenic stimulus this process is irreversible and can lead to the formation of precancerous lesions. Recent work now indicates that acquisition of an activating Kras mutation in acinar cells initiates signaling that leads to chemoattraction of M1-poliarized macrophages. This oncogene-caused chronic microinflammation can accelerate the pathogenesis of pancreatic cancers.

Figure 1. Inflammatory macrophages drive the ADM process during acute pancreatitis

During acute pancreatitis acinar cells can either undergo cell death or a transdifferentiation process named acinar-to-ductal metaplasia (ADM). ADM changes their phenotype to pancreatic progenitor-like cells, which could be important for pancreatic repopulation. Inflammatory macrophages can initiate ADM through release of cytokines and chemokines. They also regulate removal of dead cells and modulation of the microenviroment. The net effect of these different functions of inflammatory macrophages possibly leads to pancreatic regeneration.

Figure 2. M1-polarized macrophages contribute to the initiation of pre-neoplastic lesions

Acinar cells that acquire an activating Kras mutation (i.e. KrasG12D) can cause microinflammation by expressing chemoattractants for M1 macrophages. M1 macrophages then drive ADM and the formation of pre-neoplastic lesions by providing cytokines, chemokines and proteinases that modulate pancreatic microenvironment.