Figure 2. Hedgehog signalling in pancreatic ductal adenocarcinoma.

Although the pancreatic ductal adenocarcinoma (PDAC) epithelium overexpresses Hedgehog (Hh), ligand-dependent canonical signalling is activated in stromal cells, including cancer-associated fibroblasts, infiltrating bone marrow-derived cells and subsets of endothelial cells, through the patched (PTC)–smoothened (SMO) axis. In turn, these cells directly proliferate or produce factors that might enhance tumour cell growth (potentially through secreted growth factors or by changing extracellular matrix (ECM) composition) and angiogenesis in a paracrine fashion (the factors that have been identified are indicated). Furthermore, cancer-associated fibroblasts and other Hh-responsive cells might produce cytokines and other molecules that communicate with infiltrating immune cells. Conversely, autocrine activation through this canonical pathway does not seem to occur in the tumour epithelium. Gli activity is maintained in part by activation of GLI1 through alternative signalling pathways, such as mutant KRAS expression and transforming growth factor-β (TGFβ) signalling. ANGPT1, angiopoietin 1; IGF, insulin-like growth factor; MMP9, matrix metalloproteinase 9; VEGFA, vascular endothelial growth factor A.