title: The Significance of Ras Activity in Pancreatic Cancer Initiation.
abstract: The genetic landscape of pancreatic cancer shows nearly ubiquitous mutations of K-RAS. However, oncogenic K-Ras(mt) alone is not sufficient to lead to pancreatic ductal adenocarcinoma (PDAC) in either human or in genetically modified adult mouse models. Many stimulants, such as high fat diet, CCK, LPS, PGE2 and others, have physiological effects at low concentrations that are mediated in part through modest increases in K-Ras activity. However, at high concentrations, they induce inflammation that, in the presence of oncogenic K-Ras expression, substantially accelerates PDAC formation. The mechanism involves increased activity of oncogenic K-Ras(mt). Unlike what has been proposed in the standard paradigm for the role of Ras in oncogenesis, oncogenic K-Ras(mt) is now known to not be constitutively active. Rather, it can be activated by standard mechanisms similar to wild-type K-Ras, but its activity is sustained for a prolonged period. Furthermore, if the level of K-Ras activity exceeds a threshold at which it begins to generate its own activators, then a feed-forward loop is formed between K-Ras activity and inflammation and pathological processes including oncogenesis are initiated. Oncogenic K-Ras(mt) activation, a key event in PDAC initiation and development, is subject to complex regulatory mechanisms. Reagents which inhibit inflammation, such as the Cox2 inhibitor celecoxib, block the feed-forward loop and prevent induction of PDAC in models with endogenous oncogenic K-Ras(mt). Increased understanding of the role of activating and inhibitory mechanisms on oncogenic K-Ras(mt) activity is of paramount importance for the development of preventive and therapeutic strategies to fight against this lethal disease.
authors.affiliation: 1. Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston TX 77030, USA; 2. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston TX 77030, USA.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
authors.affiliation: 1. Department of GI Medical Oncology, University of Texas MD Anderson Cancer Center, Houston TX 77030, USA.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Lu
mesh_terms: D000818:Animals; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)
keywords: K-RAS