Macrophages in pancreatic cancer: starting things off on the wrong track

Abstract

Chronic inflammation drives initiation and progression of many malignancies, including pancreatic cancer. In this issue, Liou et al. (2013. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201301001) report that inflammatory macrophages are major players in the earliest stages of pancreatic cancer. They show that paracrine signals from the macrophages activate the nuclear factor κB transcriptional program in normal pancreatic acinar cells, resulting in acinar-ductal metaplasia, a dedifferentiated state that is poised for oncogenic transformation.

Figure 1.

Macrophages in pancreatic cancer initiation and progression. (A) Molecular mechanisms proposed for macrophage-derived PDA initiation. Liou et al. (2013) show that macrophages secrete RANTES and TNF during pancreatitis, thereby activating the NF-κB pathway in acinar cells. The latter induces the expression of MMP-9 to promote ADM (green arrows). Other mediators that may contribute to macrophage-induced ADM include IL-1α, the IL-6–STAT3 axis, and other NF-κB target genes, including SOX9 (red arrows; Miyatsuka et al., 2006; Fukuda et al., 2011; Lesina et al., 2011; Maniati et al., 2011; Kopp et al., 2012; Ling et al., 2012; Prévot et al., 2012; Sun et al., 2013). (B) Cellular evolution in PDA initiation and progression. In addition to the role of NF-κB in driving ADM and then PDA initiation (green arrows), it is possible that this pathway contributes to additional types of cellular reprogramming during PDA progression and metastasis (red arrows). Ub, ubiquitin; P, phosphorylation.