Hedgehog signaling and pancreatic tumor development

Abstract

Numerous signaling pathways are misregulated in pancreatic ductal adenocarcinoma (PDAC), a highly malignant type of cancer. One of these is the Hedgehog (HH) pathway, which is normally involved in patterning processes in the developing embryo. Expression of the main ligand Sonic Hedgehog is an early event in carcinogenesis and correlates with the mutation of the KRAS oncogene, the cardinal molecular feature of pancreatic cancer. Recent data establish a functional role for HH signaling primarily in the tumor microenvironment, where it is involved in myofibroblast differentiation and the induction of stroma-derived growth promoting molecules. Given the protumorigenic functions of the abundant stromal desmoplasia typically associated with pancreatic cancer, targeting the HH pathway might prove beneficial in the treatment of the disease. First data using small molecule antagonists of HH signaling in mouse models of pancreatic cancer are promising and reveal a substantial, yet transient, effect on the myofibroblastic stroma. In this review, we try to give an outline on the current knowledge about HH signaling in pancreatic cancer including a perspective of using pharmacological inhibitors of this pathway in the clinic.