02 February 2015
By Daniela Robles-Espinoza
Cancer cells are crafty. Unlike their healthy neighbours, they never stop growing and dividing; they proliferate uncontrollably and, in some cases, form tumours. They are also masters of disguise, able to evade immune surveillance, and persevering adventurers, travelling through the circulatory system to colonise new tissues, often far away from their site of origin.
Cancer cells have found a myriad of ways to resist death. They are cells gone rogue. But how do they achieve their unique -and often deadly- characteristics?
Well, this is a difficult question, but we do know some of the tricks they have up their sleeves. For example, they can activate proteins that promote cell division, or inactivate those that inhibit growth, or perhaps ignore brake signals from their environment. They can secrete proteins that suppress the immune system, and lower the activity of adhesion proteins that keep them attached to their site of origin.
Cancer cells also need to avoid death, and this is the topic I would like to talk to you about today. It turns out that, perhaps not surprisingly, the length and integrity of chromosomes is central to a cell’s survival.
In normal cells, the ends of chromosomes, referred to as telomeres (from the Greek telos, “end”, and meros, “part”), get progressively shorter with each cell division. This is because the DNA replication machinery runs out of room to do its job at the ends of chromosomes – thus being unable to copy them. You can imagine what would happen then if cell division continued indefinitely: genes and other important elements contained in chromosomes could be damaged. Therefore, when telomere length reaches a critical threshold, cells stop dividing (a state known as senescence).
However, there is a special enzyme that cells produce, called telomerase, which is able to replace some of the DNA sequence lost after each round of division. This system ensures then that cells can continue dividing for longer without the risk of genomic damage, but it is not enough to sustain cell division indefinitely.
As you can imagine, cancer cells have found a way to exploit this system to extend their life. In most cases, they activate telomerase to avoid reaching the critical telomere length threshold, and thus accumulate more mutations in their DNA that might contribute to the acquisition of new characteristics.
However, some cancers arise from normal cells that already have defective telomeres. I study genetic susceptibility to a particular type of skin cancer called melanoma, and, while analysing the exome sequences of affected individuals from many different families, we observed defects in one of the proteins that safeguards the integrity of telomeres and controls their length.
We discovered that affected people that had rare inactivating variants in this protein, aptly called protection of telomeres (POT1), had indeed longer telomeres than melanoma cases without mutations in POT1. Another research group also showed that having a defective POT1 also contributed to telomere damage, and thus genomic instability. These are then two different ways by which rare inactivating variants in this protein might contribute to melanoma development.
But biology is complex, and this is not the end of the story. Having much shorter telomeres can also predispose a person to cancer, because without their protective capping telomeres could fuse with each other, giving rise to genomic instability. Many different cancer-predisposing human conditions have their origins in shorter telomeres: dyskeratosis congenita, aplastic anaemia and the Werner and Bloom syndromes are some examples of these. However, the germline variants in POT1 mentioned above constitute, to the best of my knowledge, the first described hereditary longer-telomere syndrome in humans.
So, yes, cancer cells are crafty, but we are making progress in understanding their tricks. In our team, we are modelling this new class of telomere syndrome in mice and ascertaining novel genetic variants found in more families that might be functioning in a similar manner. Our hope is that these discoveries can be used to detect individuals at risk and advise patients on treatment options.
Daniela Robles-Espinoza is a PhD student in the Experimental Cancer Genetics team under the supervision of Dave Adams.
- Robles-Espinoza, CD et al (2014). POT1 loss-of-function variants predispose to familial melanoma.Nature Genetics. DOI:10.1038/ng.2947
- Robles-Espinoza, CD et al (2014). Telomere-regulating genes and the telomere interactome in familial cancers. Molecular Cancer Research. DOI:10.1158/1541-7786.MCR-14-0305