Mutant KRAS in the initiation of pancreatic cancer.
Pancreatic ductal adenocarcinoma is the most common pancreatic neoplasm. There are approximately 33,000 new cases of pancreatic ductal adenocarcinoma annually in the United States with approximately the same number of deaths. Surgery represents the only opportunity for cure, but this is restricted to early stage pancreatic cancer. Pancreatic ductal adenocarcinoma evolves from a progressive cascade of cellular, morphological and architectural changes from normal ductal epithelium through preneoplastic lesions termed pancreatic intraepithelial neoplasia (PanIN). These PanIN lesions are in turn associated with somatic alterations in canonical oncogenes and tumor suppressor genes. Most notably, early PanIN lesions and almost all pancreatic ductal adenocarcinomas involve mutations in the K-ras oncogene. Thus, it is believed that activating K-ras mutations are critical for initiation of pancreatic ductal carcinogenesis. This has been proven through elegant genetically engineered mouse models in which a Cre-activated K-Ras(G12D) allele is knocked into the endogenous K-Ras locus and crossed with mice expressing Cre recombinase in pancreatic tissue. As a result, mechanistic insights are now possible into how K-Ras contributes to pancreatic ductal carcinogenesis, what cooperating events are required, and armed with this knowledge, new therapeutic approaches can be pursued and tested.
Deramaudt
Therese
T
Department of Medicine (GI) and Genetics, Abramson Cancer Center, 600 CRB, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA 19104, USA.
Rustgi
Anil K
AK
D000818:Animals; D044584:Carcinoma, Ductal / Q000235:genetics*; D004195:Disease Models, Animal; D011905:Genes, ras; D006801:Humans; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics*