Mouse tissues that undergo neoplastic progression after K-Ras activation are distinguished by nuclear translocation of phospho-ERK1/2 and robust tumor suppressor responses

摘要

Mutation of K-Ras is a frequent oncogenic event in human cancers, particularly cancers of lungs, pancreas, and colon. It remains unclear why some tissues are more susceptible to Ras-induced transformation than others. Here, we globally activated a mutant oncogenic K-Ras allele (K-Ras^G12D) in mice and examined the tissue-specific effects of this activation on cancer pathobiology, Ras signaling, tumor suppressor, DNA damage, and inflammatory responses. Within 5–6 weeks of oncogenic Ras activation, mice develop oral and gastric papillomas, lung adenomas and hematopoietic hyperproliferation and turn moribund. The oral, gastric and lung pre-malignant lesions display activated Erk1/2 and NF-κB signaling as well as activated tumor suppressor and DNA damage responses. Other organs such as pancreas, liver and small intestine do not exhibit neoplastic progression within six weeks following K-ras^G12D activation and do not show a potent tumor suppressor response. Even though robust Erk1/2 signaling is activated in all the tissues examined, the pErk1/2 distribution remains largely cytoplasmic in K-Ras^G12D refractory tissues (pancreas, liver and intestines) as opposed to a predominantly nuclear localization in K-Ras^G12D induced neoplasms of lung, oral, and gastric mucosa. The downstream targets of Ras signaling, pElk-1 and c-Myc, are elevated in K-Ras^G12D induced neoplastic lesions but not in K-Ras^G12D refractory tissues. We propose that oncogenic K-Ras refractory tissues delay oncogenic progression by spatially limiting the efficacy of Ras/Raf/Erk1/2 signaling, whereas K-Ras responsive tissues exhibit activated Ras/Raf/Erk1/2 signaling, rapidly form pre-malignant tumors, and activate potent anti-tumor responses that effectively prevent further malignant progression.