Telomeres and Cancer

• Telomerase

Telomerase does not cause cancer.

The statement is accurate, but it’s not that simple nor is it a naïve concern.

Telomerase and cancer are clearly linked – telomerase has been called “the two-edged sword” with aging being one edge and cancer the other – and the question thus deserves a more complete and more sophisticated answer. As always, discussions that involve causation tend to miss the point, resulting in misconceptions and errors. Instead of asking about causation, consider a few questions that are far more practical and clinically useful:

• If we increase telomerase in somatic cells, would the incidence of cancer rise in an average group of healthy patients?
• If a patient already has cancer and we increase telomerase in their somatic cells, would that patient get better or worse?
• If we have a population of healthy patients and we wish to decrease the overall incidence of cancer, would it be better to increase or decrease telomerase activity?

These sort of questions are much closer to the nub of what we actually want to know, as they constitute useful clinical information, information that is useful to both the physician and the average patient. Putting it bluntly, if I want to be healthy, do I want telomerase or not? To answer just as bluntly, you generally want more telomerase rather than less, or to put it more accurately, you generally want longer telomeres rather than shorter telomeres.

The reason the answer is “generally” true is that elongating your telomeres – like almost every function in biology and every therapy in medicine – has both an upside and a downside. The upside is that longer telomeres stabilize your genome, and hence lower the probability of cancer. The downside is that – once you have a cancerous cell – cancer needs to maintain telomeres just to survive. In other words, long telomeres prevent cancer, but cancers require telomeres or they may spontaneously go into remission.

There is a balance of risk. If you don’t have cancer, you definitely want long telomeres. If you already have cancer, you would prefer it if the telomeres in your cancer cells would continue shortening and kill the cancer cell before the cancer cell kills the rest of you.

Consider why this balance occurs. In normal cells, the repair and recycling of cellular elements – in this case we can focus on DNA repair – depend on changes in telomere length: as telomeres shorten, DNA repair slows down. In the young cell, DNA maintenance is stunningly accurate and efficient. In the aging cell, DNA maintenance has become slipshod, showing decreasing accuracy and efficiency. In old cells, the genome is no longer defended as competently and the outcome is an increasing number of mutations and errors, leading to cancer. To put it simply, the longer your telomeres, the more stable your genome. As telomeres shorten, genomic stability falls and cancer incidence rises.

On the other hand, once a cell’s genome has accrued enough errors to become cancerous, there are still three internal cellular obstacles: DNA repair, the cell-cycle braking system, and telomere loss. If DNA repair fails (which occurs as the telomere shortens), then cell division is generally halted as the cell detects DNA errors. However, as the telomere shortens, the cell also becomes sloppier in applying the “brakes”: the aging cell is more prone to continue dividing even in the face of DNA damage that would halt a younger cell. This leaves the telomere as a final defense. In normal aging cells, shortened telomeres result in a failure to divide (or to put it more accurately: a slower rate of division, a decreased likelihood of continued division, and an increased likelihood of apoptosis or even necrosis). If the cancer cell no longer divides, then it isn’t a clinical problem. If it can’t grow, it can’t kill you. Unfortunately, there are a number of ways that cancer cells elude the problem of telomere loss, at least for a while, and almost all of them involve maintaining telomere length. Not surprisingly, telomerase is expressed in about 85% of human cancers and telomerase inhibitors are seen as potential cancer therapies. If we have cancer cells, then we would prefer it if their telomeres would be entirely lost, resulting in dead cancer cells. If you already have cancer and we re-extend your telomeres, that wouldn’t cause cancer, but it might increase the ability of your cancer to survive and metastasize.

In short, telomere extension might increase mortality in patients with a pre-existing cancer, but if patients don’t already have cancer, then telomere extension would prevent cancer from occurring in the first place. Neither telomerase nor long telomeres cause cancer, but either telomerase or long telomeres could permit cancer to grow once it gets a foothold.

To return to our practical questions, let’s construct some evidence-based, rational clinical advice for a hypothetical patient population. If a patient comes to us with a known prostate cancer, we would probably recommend against a telomerase therapy. This recommendation is not because telomerase causes cancer, but because telomerase therapy might increase the likelihood that the cancer would continue to grow and would metastasize. On the other hand, if a patient comes to us with no known cancer, we would recommend telomerase therapy to prevent getting cancer in the first place.

This is not a new therapeutic dilemma: it’s actually true of a great many other clinical options. Consider exercise: does it cause heart attacks or is exercise good for you? Most of us – both physicians and the general public – are in favor of exercise as a preventative action: patients who exercise are considered to be less likely to get a heart attack, for example. On the other hand, if a patient has just had a heart attack this morning, we certainly don’t recommend that they run a marathon this afternoon. Does exercise “cause” heart attacks or does it prevent heart attacks? Exercise doesn’t actually cause heart attacks, but it can contribute to them or trigger them if you already have enough atherosclerotic disease. Most of us, however, think of exercise as healthy, and with good reason.

Overall, telomerase therapy is – like exercise and with similar caveats – a beneficial clinical intervention, but one that must be discussed in context.