Cell illustration by Clemens Habicht

Cancer treatment: where DNA, stem cells and cell immortality meet

3 September 2021

Future cancer treatments could reach beyond the cancer itself

All cancers begin as a particular cellular mishap involving DNA. Researchers are working on treatments for all of them. But what if there was a way to prevent that original and universal cellular mishap from happening at all?

Google ‘telomeres’ and you’ll quickly fall down a rabbit hole of ideas about dramatically improving longevity or even reversing the aging process itself.

There is no shortage of snake oil on offer, but a cohort of international researchers are working on telomeres to understand what potential they truly have in terms of delaying the onset of old age, and more than that, how they might be manipulated to control many of the cancers we currently wrestle with.

Professor Tony Cesare is Head of the Genome Integrity Unit at CMRI.

One of that cohort is Associate Professor Tony Cesare, “I set out as a PhD student in 2000, working on telomeres,” Cesare says in his bright and amiable American accent. He and his wife, also American, are about to become Australian citizens. “There was a time when I wanted to be a baseball coach. Then I found cell biology and genetics. It just kind of clicked.”

Despite the ‘fountain of youth’ associations, telomeres have not fully gripped the public imagination probably because it is hard to describe what they do in a punchy sentence or two, though what telomeres do is vitally important.

“Telomeres are caps of inactive DNA material at the end of all our chromosomes,” says Cesare. “Put too simply, they are involved in the important process of cell division. If there’s no cell division to create new cells, there’s no way for kids to get bigger, or cuts to heal, or damaged cells to be replaced.”

Still, it is a reality that with every cell division, a little bit of each DNA molecule is lost, a scenario called ‘the end of replication problem’. But because of telomeres, the active DNA material is protected. It is the inactive telomere material that is lost.

Long telomeres suggest a cell is well equipped for many future cell divisions. Short telomeres suggest a cell has nearly run its race and may be producing damaged copies. In time, the proportion of cells in the body with short telomeres increases, which is a harbinger of the onset of age-related conditions.

So, what if there was a way of keeping telomeres long? In fact, there is, through a set of obscure behaviours with names like exercise, balanced eating, no smoking and low alcohol intake.

Then there are the telomeres we all have that are naturally and permanently long, making the cells that house them effectively immortal. It is in the understanding this group of immortals that Cesare has made huge strides is recent years.

As a young researcher, Cesare was first drawn to Australia in 2006 by the work happening at the Children’s Medical Research Institute (CMRI) in Westmead; specifically, the work of Professor Roger Reddel AO, who is now CMRI Director and lauded head of its cancer research unit. Reddel introduced many of the earliest ideas around the immortalisation of cells and how that relates to cancer.

With new technologies promising dramatically more pathways to information, and encouraged by Reddel, Cesare started his own lab within the CMRI in 2013. Every time research opens a door, three more doors are revealed. But the mystery of the immortals is being chipped away.

Associate Professor Tony Cesare with members of his lab team at CMRI. Follow the lab on Twitter @TheCesareLab

Harnessing immortal cells for good

The immortals we all carry are stem cells that are like universal patches that convert into whatever cells are needed at that moment – skin cells, bone, hair, gut. Stem cells must be ever ready, so their telomeres are kept permanently long by an enzyme called telomerase. Stem cells are the only cells in the body that get this telomerase attention.

“That means, once a stem cell becomes a specific type of cell, it no longer has a way to keep its telomeres long,” says Cesare. “From then on, the telomeres shorten every time it divides.”

The internet snake oil sellers have grabbed onto the telomerase enzyme as a possible doorway to health and extended longevity, recommending it as a supplement to keep telomeres long, but as one of the world’s most knowledgeable people on the subject, Cesare advises against.

“By giving a cell telomerase, and artificially extending its life, you're interfering in how telomeres prevent damaged cells multiplying and how they prevent tumours from happening,” he says. “Use telomerase in this way, and I believe the result could be cancer.” To underscore the point, consider this: there is one other group of cells unexpectedly kept immortal by telomerase: cancer cells.

Cancer is a wily adversary: evading the immune system; hijacking the body’s nutrition sources to feed itself; riding the bloodstream to other parts of the body. And yes, cancer tricks telomerase into elongating telomeres, thereby allowing its cells to replicate ad infinitum.

“We don't study specifics like pancreatic cancer or breast cancer,” says Cesare. “We're interested in what damage occurs with the DNA that allows a cell to become cancerous, to become immortal.”

The crossroads of telomerase, cancer and stem cells is proving to be a rich source of new insights, not just about cancer and longevity, but also for the burgeoning field of regenerative medicine; the idea being that if stem cells can transform into almost any other cell in the body, could they be used to generate body tissues for transplantation?

Much of Cesare’s research is now focused on how telomeres control the delicate balance between allowing and preventing cell division.

It is a strange contradiction of short telomeres that while they are associated with the conditions of aging, they are also critically important in preventing cancer. Cesare was the first to understand a critical step in this cancer prevention mechanism and how it relates to cell division.

When actual DNA is damaged (as opposed to the telomeres), a signal stops cell division from happening until the DNA is repaired. Then cell division starts again. Cesare found that short telomeres can turn on the damage signal to stop cell division, while also preventing repair from happening. In effect, permanently retiring the cell.

Allowing that cells with short telomeres are reaching the end of their usefulness, and may indeed be making poor copies of themselves, preventing these cells from multiplying reduces the possibility of cancers developing.

Cesare's lab (The Genome Integrity Unit) investigates how cells maintain their DNA health with specific interests in cancer and early development.

An unexpected stem cell discovery

Another key insight concerned a mechanism called the “telomere-loop”, which is literally a loop at the end of the telomere. It has been known to exist for some years, but its function was a mystery until Cesare’s team used super resolution fluorescent imaging to uncover more detail.

They found that the opening and closing of the telomere loop controls those signals allowing or preventing cell division. It is also an extra safety feature intended to keep the end of the telomere hidden from the body’s repair system which would see it as broken DNA to be fixed by stitching to another piece of DNA, with possibly serious consequences.

This “telomere loop” is created by a protein called TRF2. Demonstrating its importance, if you remove TRF2 from adult cells, the telomere loops fail to form, the ends are exposed and the chromosomes become stitched together into one long string, which is incompatible with life. But in a surprise turn of events, it turns out, this is not true of stem cells.

Remove TRF2 from stem cells and almost nothing happens, no effect on the chromosomes, telomere-loops or cell division. Cesare still has a sense of wonder and excitement talking about it, “I've been in the field for 20 years, and this was the single most surprising thing I've ever seen. Hands down.”

This outcome suggests that stem cells have a whole other system of telomere protection yet to be discovered, a system that may provide a deeper understanding of the mechanics of aging and cancer. Or indeed provide tools to manipulate stem cells in regenerative and life-saving ways.

Still, many of the roads that Cesare is exploring point back to the traditional ideas of how to live a long and healthy life, “When people ask me about longevity, I always tell them their mum is probably right,” he says with a smile. “Eat your vegetables. Go to bed at a reasonable hour. Don't smoke. Reduce stress.”

Tony Cesare's work is partially donor funded. Contact our donor team who can help you decide how to show your support through a donation. Banner image: Illustration by Clemens Habicht


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