While telomere shortening has been thought to be an adverse sign of aging, new research suggests that the shortening of telomeres – the ends of chromosomes – may actually be a mechanism that acts to prevent the development of cancer. These findings are published in eLife and shed light on the complex relationship between telomeres and cancer.
This insight comes from the long-established idea that only cancers capable of activating the enzyme that adds telomeric DNA to the ends of chromosomes – telomerase – are able to overcome the finite telomere reserve and continue dividing. While this idea that shortening telomeres protect against cancer has been proven in mice models, the complexities of such a phenomenon in humans has yet to be fully explained.
"Telomeres protect the genetic material," says Titia de Lange, Leon Hess Professor at Rockefeller. "The DNA in telomeres shortens when cells divide, eventually halting cell division when the telomere reserve is depleted. Most clinically detectable cancers have re-activated telomerase, often through mutations," de Lange explains.
The new study was conducted by analyzing mutations in families with cancer histories in order to understand how telomere length influences tumor suppression. At de Lange's lab in the last decades, researchers have identified a protein called TIN2 that limits telomere length. When the protein is inhibited, telomerase lengthens telomeres without limit. This study focused on deepening the scientific knowledge on TIN2.
From the team’s analyses, de Lange explains: "The data show that if you're born with long telomeres, you are at greater risk of getting cancer. We are seeing how the loss of the telomere tumor suppressor pathway in these families leads to breast cancer, colorectal cancer, melanoma, and thyroid cancers. These cancers would normally have been blocked by telomere shortening. The broad spectrum of cancers in these families shows the power of the telomere tumor suppressor pathway.
How telomeres are regulated is a fundamental problem," de Lange concludes. "And by working on a fundamental problem, we were eventually able to understand the origins of a human disease."