Figure 4. Crucial temporal thresholds of developmental signalling pathways and KRAS activity allow pancreatic epithelial neoplasia — pancreatic ductal adenocarcinoma initiation and progression.

KRAS activity above a crucial threshold can drive differentiated pancreatic cells (acinar cells, for example) into a de-differentiated, ductal state that persists in pancreatic epithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). For these de-differentiated ductal cells to become PanINs, β-catenin signalling must be maintained below a crucial low level. However, once the PanIN state is established, β-catenin signalling is reactivated in parallel with increasing expression of Hedgehog (Hh) ligand that activates target genes in stromal cells of the developing desmoplastic response. Gli activity in the developing tumour epithelium emerges independently of autocrine stimulation. Although Gli activity is probably active in PanINs, its role in the progression from PanIN to PDAC is unknown. Finally, Gli activity is probably important for PDAC maintenance. Figure is modified, with permission, from REF. 128 © (2000) American Association of Cancer Research.