Apoptosis: Signaling pathways in pancreatic cancer pathogenesis

Conventional and investigational cancer therapies have had little to no effect on the course of pancreatic cancer disease progression. Because apoptosis plays a major role in the effects of conventional chemo- and radiotherapy, it has been widely assumed that apoptotic pathways must be disrupted more frequently in pancreatic cancer than they are in other solid malignancies. However, comprehensive genomic characterizations of primary pancreatic cancers do not support this conclusion. Rather, it appears that one of the recently identified molecular subtypes of pancreatic cancer (quasimesenchymal/basal-like/squamous) that shares similarities with basal-like breast and bladder cancers contains tumors that are most likely to be apoptosis sensitive and responsive to conventional chemotherapy. Otherwise it is not immediately obvious how the molecular and genomic properties of pancreatic cancers would be expected to impart apoptosis resistance, providing indirect but strong support for the conclusions that late diagnosis and the extent to which tumor-stromal interactions reinforce apoptosis resistance represent the truly unique challenges to effective clinical control of the disease. This book chapter will provide an update of what has been learned recently about the molecular control of apoptosis in pancreatic cancer and how the information might be exploited in the design of more effective therapeutic regimens.