Mutant Mice Develop More Serious Forms of Cancer

A group of researchers from Harvard have found evidence that telomere attrition in aging telomerase-deficient mice, heterozygous for the p53 tumour suppressor gene, promotes the development of epithelial cancers.

Aged humans sustain a high rate of epithelial cancers such as carcinomas of the breast and colon, whereas mice carrying common tumour suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. This difference has been attributed to the variance between species with respect to their telomere length and regulation. Unlike the situation in humans, mice have promiscuous telomerase activity and long telomeres which has been suggested as the reason why they don't develop epithelial carcinomas.

In this study, telomerase-deficient, p53-heterozygous mice were inbred for 5 to 7 generations with the resulting mice having shortened telomeres. As they aged, half of these mice developed lymphomas and sarcomas, but unexpectedly, the remaining mice developed epithelial carcinomas. These data indicate that the telomeres from these mice may have become critically short in epithelial tissues, with the malfunctioning telomeres catalyzing genomic rearrangements that initiated and sustained the development of cancer.

Cancers develop in several distinct steps, with cells of increasing aggressiveness and capability emerging over time. Cells that lack telomerase may undergo widespread genomic disarray leading them to become cancer cells. This disarray can reach a point in which the cell is no longer viable and it dies. Alternatively, the activation of telomerase can allow the addition of telomere repeats to these mutant chromosomes, which enables their survival, and the progression of the cancer.

A great deal of research has been targeted at developing pharmacological inhibitors of telomerase, with the aim of knocking out the telomerase that enables the cancer cells to survive and replicate. However, these data suggest that removing telomerase function from these cells may lead to their death in some instances, but in cells that are still not near the 'threshold for viability', the removal of telomerase may actually cause them to mutate into more aggressive forms. This suggests that telomerase inhibitors should be used in conjunction with other forms of chemotherapy to ensure the death of all cancer cells.