Researchers shed light on cancer susceptibility using ’supermice’

At any given time, there are many cells in our body that are in the process of dividing, yet they almost never go out of control to give rise to cancers. Cell proliferation is normally kept in check by a group of gatekeeper genes called “tumor suppressors”. Of these, the Ink4a/ARF locus has been of considerable interest since this locus is inactivated in a majority of human cancers. This locus encodes two different proteins that act together to check uncontrolled tumor development.

A study to be published in the November 15 issue of Genes and Development illustrates the importance of these gene products in controlling cancer in mammals. The Tumor Suppressor group headed by Manuel Serrano at the Spanish National Cancer Center (CNIO) has used recombinant DNA technology to generate transgenic mice carrying an extra copy of the Ink4a/ARF tumor suppressor locus. The resulting “Super Ink4a/Arf” mice carry three copies of the Ink4a/Arf genes and were compared to their normal littermates that lacked the transgene and had only two copies.

These mice were put through a battery of tests and were found to be significantly resistant to a variety of tumorigenic stimuli. Cells derived from the super Ink4a/Arf mice were more resistant to acquiring the ability to divide indefinitely and alterations by oncogenes, two important features of a successful cancer. In addition, the animals developed cancers at a much lower rate upon treatment with different types of carcinogens. The presence of an extra copy of these genes and increased cancer resistance had no apparent effect on the lifespan or fertility of these “supermice”. These results are consistent with earlier work done by

Serrano’s group who had showed similar results with yet another “supermouse”, this one carrying an extra copy of another tumor suppressor gene, p53, which is also mutated or inactivated in a majority of human tumors. Serrano attributes this increased tumor resistance to the modest increase in the levels of gene products gained by having an extra copy of the genes stating “These quantitatively modest changes have nonetheless a significant impact on cancer incidence.”

What impact does this study have on human health and disease? The results of this study imply that differences in gene expression levels of tumor suppressors may contribute significantly to the risk of developing cancers and may influence the way therapeutics are being developed. Serrano says “I fantasize about a hypothetical drug that moderately increases the activity of p53, p16Ink4a or ARF. This may translate in a big benefit regarding cancer susceptibility.”