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.