Genetically Engineered Mice Harboring RAS Mutations as Models of Human Cancer: in Medias RAS

Abstract

The molecular and histopathological consequences of expressing a mutated ras gene have been the focus of intense studies for the past 30 years. Initially, introducing H-ras mutations as transgenes under the control of a heterologous promoter was shown to cause neoplastic changes where expressed, proving in-vivo the relevance of ras mutations to cancer. Lesions usually developed after a long latent period, and the additional mutation of tumor suppressor genes (such as p53) resulted in a more aggressive phenotype. In an attempt to better mimic genetic lesions found in human cancer, more recent studies have used the Cre-Lox recombination system to tissue-specific directed mutations in the endogenous K-ras allele. When expressed in the lungs, mice develop lesions that include hyperplasias, adenomas, invasive carcinomas, and occasionally metastatic lesions. When expressed in the pancreas, early pancreatic intraepithelial neoplastic lesions (PanIN) are induced, with progression of histological atypia that appears indistinguishable from human disease. Moreover, when crossed to a conditional Ink4a/ARF background (as is frequently found in human pancreatic adenocarcinoma), animals succumb to both local and distant disease within 12 weeks. Similarly, when the endogenous K-rasis mutated in hematopoietic cells, all mice die from a myeloproliferative disorder. By faithfully recapitulating both the genetic and pathophysiology of the cognate human malignancy, these models provide a means to dissect the relevant molecular pathways leading to cancer susceptibility, formation and progression; and to design and test prevention, early detection, and treatment strategies for human cancers that are driven by ras mutations