Ras genes, Ras oncogenes and cancer

Mariano Barbacid
Centro Nacional de Investigaciones Oncológicas (CNIO), (Spanish National Cancer Research Centre), Madrid, Spain

Ras oncogenes were first isolated from human tumours twenty five years ago. The development of sophisticated gene targeting technologies is now making it possible to study their pathological role in selected models that closely mimic the natural history of human tumours. For instance, widespread expression of an engineered endogenous K-Ras oncogene in postnatal mice only elicits tumours in lung, whereas other tissues such as intestine and pancreas (in which K-Ras oncogenes are often found in human tumours) are resistant. Yet, K-Ras oncogenes elicit adenocarcinomas in both of these tissues if mice lose the APC tumour suppressor (intestinal tumours) or if they suffer mild episodes of pancreatitis (pancreatic ductal adenocarcinomas). These observations illustrate how K-Ras oncogenes induce tumours in a tissue dependent context and highlight the differential responses of distinct cellular types to K-Ras induced transformation.

Similar experiments carried out with the highly related H-Ras oncogene revealed that, unlike K-Ras, this oncogene is well tolerated during embryonic development and does not induce tumours, at least with significant frequencies. Instead, mice homozygous for an endogenous H-Ras oncogene show facial dysmorphia and hypertrophic cardiomyopathies highly reminiscent of those observed in patients with Costello syndrome, a rare disease known to be caused by germ line expression of H-Ras oncogenes. These observations illustrate the close similarities between the pathogenic responses of mice and men to Ras oncogenes.

We are also interested in studying the role of the different Ras signalling pathways in normal cell proliferation. To this end, we have generated cells lacking the three members of the Ras family. These cells are null for H- and N-Ras and homozygous for a conditional (floxed) K-Ras allele. Cre-mediated removal of the floxed K-Ras alleles causes rapid cessation of cell proliferation accompanied by morphologic changes highly reminiscent of those displayed by senescent cells. However, cells lacking all three Ras proteins are not senescent and can be induced to proliferate if they express activated forms of various downstream elements of the Raf/Mek/Erk pathway, but not those of the RalGDS or the PI3Kinase pathways. These experiments will provide genetic evidence for the individual contributions of each of the Ras downstream signalling elements and possibly reveal unsuspected epistatic relationships with other molecules implicated in the control of cell proliferation.