Outsmarting One of Cancer’s Slyest Tricks

How cancer cells use the protective tips of your chromosomes to cheat death – and why this matters for treatment

drawing of telomeres

At the tips of our chromosomes are protective structures called telomeres – acting much like the plastic bits at the ends of shoelaces.

Deep inside our cells, genetic information, encoded in DNA, is coiled into bundles wrapped around proteins. These tidy parcels of genetic material are called chromosomes. At the tips of our chromosomes are protective structures called telomeres – acting much like the plastic bits at the ends of shoelaces.

But telomeres don’t work forever. As we grow older, our telomeres get shorter. If they are too short, they can no longer protect our genetic information. Shortened telomeres are linked to aging and various diseases, including cancer.

Telomeres get shorter each time a cell divides. After a certain number of divisions, when the telomeres become too short, an alarm is tripped in the cell. This alarm causes normal cells to take themselves out of action, so they don’t end up causing harm. Cells will either die off or go into a permanent sleep state.

Cancer cells, however, are tricky. They can short-circuit the alarm. One way they do this is by preventing their telomeres from getting too short. Cancer cells divide a lot – they are completely out of control. Since they are dividing so much, their telomeres should be getting super short very quickly. But they don’t. The cancer cells hijack the body’s own telomere-lengthening tools to force their telomeres to stay long. This lets the cancer cells continue to grow and divide – escaping death.    

“When the tumor loses any kind of control, and the cells become immortal, this is when the problems start. The tumors can become very big and can start invading,” says telomere researcher Eros Lazzerini Denchi, Ph.D., associate professor of molecular medicine at The Scripps Research Institute.

Lazzerini Denchi is trying to find a way to stop cancer cells from using telomere lengthening to remain immortal. 

Scientists thought they already knew everything about telomeres – they were wrong

When Lazzerini Denchi started his lab, nearly 8 years ago, most scientists believed they understood everything about how telomeres work. When he applied for grants to further explore telomere biology, he was met with skepticism. But that changed when, with a grant from the American Cancer Society, Lazzerini Denchi made an important discovery. “I am truly fortunate that the American Cancer Society believed in this project and believed that there was still more to find,” he said.

Lazzerini Denchi and his team wanted to figure out what proteins were attached to telomeres and what those proteins were up to. One such protein, named TZAP (Telomeric Zinc-Finger Associated Protein), caught their attention. They found that TZAP was only present on really long telomeres, but absent from short ones. “That was the first clue that [this protein] was different. All the other proteins bind to the telomere no matter what its length. So, we thought, OK maybe this [protein] is acting like a measuring tape…A way for each species to say how long their telomeres should be,” explained Lazzerini Denchi.

His measuring tape theory turned out to be correct. When TZAP attaches to telomeres, it acts as a signal, telling the cell that because the telomere is a certain length it needs to be “trimmed.” Lazzerini Denchi and his team conducted a series of experiments that showed that putting TZAP into cells caused the telomeres to shorten, while removing TZAP caused the telomeres to lengthen. Their findings were published in the February 2017 issue of the journal Science.

Turning the discovery into a potential cancer-fighting tactic

Since TZAP tells cells to shorten their telomeres, Lazzerini Denchi realized that he could use TZAP to stop cancer cells from tricking their telomeres into staying long and keeping them alive. He and his team tested the idea on cells in the lab. They increased the amount of TZAP in the cancer cells. It worked. The TZAP infusion killed the cancer cells.

The type of cancer cells they did this experiment on use a mechanism to trick telomeres that is linked to about 30% of cancers, according to Lazzerini Denchi. This includes some of the most difficult-to-treat cancers, such as glioblastoma, a type of brain cancer.

Much more to learn, but researchers “can imagine” telomere-tied treatments

Lazzerini Denchi is cautious when speculating about future applications of his TZAP findings, especially since there is still much to learn. But, he is hopeful. “You can imagine that a molecule [drug] that could regulate expression of this protein [TZAP] could potentially kill cancer cells [in patients],” he said. 

The lab continues to push forward with their research with an eye towards one day helping to develop new cancer treatments.

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