Of mice and men

August 14, 2002

Mice are the most commonly used experimental system to model human genetics and disease. Although mice and humans share a strikingly similar genetic makeup, as a new paper in the August 15th issue of Genes & Development demonstrates, important caveats exist when applying what has been learned about gene function in mice to humans.

Dr. Christopher Counter and colleagues at Duke University Medical Center and the University of North Carolina Chapel Hill have discovered a significant difference in the pathway of Ras-mediated tumorigenesis in mice and humans.

The Ras gene plays an important role in human tumorigenesis. Ras is a proto-oncogene: It encodes a protein (Ras) which normally regulates cell growth, but certain oncogenic mutations in the Ras gene can result in the production of a mutated, constitutively active Ras protein. This mutated form of Ras can contribute to the transformation of normal cells into malignant cells by conferring upon them the ability for deregulated growth, proliferation and cancer cell invasion.

Ras is constitutively active in 30% of human tumors, including almost all pancreatic cancers, one half of colon and thyroid cancers, and one third of lung cancers. Thus, researchers from academia and industry, alike, have poured countless hours and dollars into the research and development of ways to interrupt the Ras pathway of tumor formation - using approaches largely based on studies done in mice. However, it has become increasingly clear in the last few years that mouse models of Ras-mediated tumorigenesis, although highly informative and powerful, do not fully recapitulate the spectrum of tumors seen in human patients with activating Ras mutations.

Dr. Counter explains that, "Mounting evidence implied that the process of cancer can be different between humans and the animal commonly used to study cancer in the lab, the mouse. We therefore asked, all things being equal, do mouse and human cells rely on identical pathways for tumor growth, and the answer was no."

The Ras signal can be propogated inside a cell through three main classes of effectors: Rafs, PI3-kinases, and RalGEFs. Each class of effector works in a slightly different fashion to transmit the cell growth signal throughout the cell. Previous research showed that in mice, Rafs are the primary effectors of Ras-mediated tranformation, with PI3-kinases playing a supporting role. Scientists were thus led to believe that Ras-mediated tranformation of human cells would follow a similar route.

Dr. Counter and colleagues show that this is not the case.

To study Ras tranformation of human cells, Dr. Counter and colleagues expressed oncogenic Ras, along with two other genes that are necessary for human tumor growth in culture, in primary human fibroblasts (cells of the connective tissue), embryonic kidney cells, and astrocytes (a type of cell found in the nervous system). The scientists found that in human cells, unlike in rodents, RalGEFs are the primary effectors of Ras-mediated tumorigenesis.

This surprising new result represents an unexpected new twist in the "model" route of Ras-induced tumor formation, and clearly demonstrates the importance of using multiple experimental systems to investigate complex biological processes like cancer formation. This work now posits RalGEFs and their interacting factors as novel targets for the rational design of anticancer therapies. The discovery also shows, as Dr. Counter states, that although "the gene Ras was identified to be involved in human cancer almost 20 years ago, we find it still has a few secrets left."

Cold Spring Harbor Laboratory

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