Figure 9.

The core position of pancreatic stellate cells in the dysplastic stroma reaction in PaCa. (A) PSC abundantly contain lipid droplets and lay close to the acinar cells in the healthy pancreas. They become activated by injury or inflammation, with a contribution of inflammatory cytokines, growth factors and ROS. Recurrent injury promotes autokrine signaling with further provision of growth factors, inflammatory cytokines, and chemokines. They partly loose the lipid droplets and become dispersed throughout the pancreatic stroma, where they affect the ECM, PaCa cells, leukocytes, and nerves. (B) Main factors contributing to PSC activation are PDGF and IL33 that assist proliferation and migration, Wnt2-β-catenin and IHH-MMP14 also contribute to the migratory phenotype and IHH-/SHH-Cox2 to proliferation. ELANE-AP1, Wnt2-β-catenin, and Smad3-ERK-TGFß1-Cox2 support collagen secretion, the latter two also support αSMA expression. (C) PSC activation is accompanied by the generation of a very dense ECM rich in HA and collagen, the recruitment of CAF, TAM, MDSC, and Treg, but a paucity of T cells in the dense ECM. Finally, they are engaged in a most intense crosstalk with the PaCa cells. Full name of proteins are listed in Table S1. PSC become activated at an early stage of PaCa initiation. Signals promoting PSC activation contribute to PSC collagen and αSMA expression, proliferation, and migration. aPSC are supposed to account for the ECM formation, to crosstalk with the tumor cells, to recruit and reprogram of leukocytes and to interact with the intrapancreatic nerves, some of these activities are detailed in the following figures.