It is well-known in bowel cancer research that because of inherent “chromosomal instability”, cancer cells manage to retain the upper hand by being able to “reshuffle” their genetic pack of cards, the chromosomes that hold the cells’ DNA information, thus increasing cell diversity in tumors, which makes them difficult to treat. Now new research reveals that if bowel cancer cells lack one of three genes they can do this genetic reshuffling very quickly.
The researchers, led by Charles Swanton, a professor based at Cancer Research UK’s London Research Institute and the UCL Cancer Institute, write about their findings in the 27 February online issue of Nature.
Recent work from Cancer Research UK and other groups shows that the genetic landscape of a tumor is complex, and is beginning to change the way scientists understand the disease.
One explanation is that being able to continually shuffle their genetic pack, cancer cells deal themselves a better hand: by increasing their genetic diversity they can adapt to new environments, spur tumor growth, or help resist treatment.
Swanton says in a statement that by uncovering how cancer cells manage to continually shuffle their genetic pack, it may be possible to turn their strength into a weakness, and create so much instability that the cells can’t function normally and die.
“We’re now looking for ways in which this process can be targeted in order to tip cancer cells over the edge,” he explains.
Chromosomal instability is a defining characteristic of most human cancers.
Normal cells have 46 chromosomes, each comprising a long string of DNA. Each time cancer cells divide, they gain or lose whole or large fractions of chromosomes, resulting in an imbalance in the number of chromosomes per cell (a state known as “aneuploidy”).
This means that a tumor can contain cells of enormous genetic diversity, making them increasingly difficult to treat.
Chromosome instability is a well-known problem in bowel cancer, and patients whose bowel cancer cells contain particularly unstable chromosomes are known to do worse.
Researchers are beginning to find out what drives chromosome instability and this study sheds further light in that area.
Cancer cells are no different to normal cells in that cell-division is a two-stage process: first the cell must copy its chromosomes, and then split them between two new daughter cells.
What Swanton and colleagues found was that loss of any one of three particular genes on a chromosome region known as 18q, interfered with the normal copying process, which led to mistakes in chromosome separation.
This is the first time the three genes, PIGN (also known as MCD4), MEX3C (RKHD2) and ZNF516 (KIAA0222), have been implicated in chromosome instability.
By adding basic building blocks of DNA, or nucleosides, to bowel cancer cells lacking all three of the genes, Swanton and colleagues found they could dramatically reduce chromosomal instability, and prevent further copying errors and the genetic shuffling.
Nic Jones, professor and chief scientist at Cancer Research UK, says it is not just in bowel cancer that 18q is missing, suggesting perhaps this process is common to other types of cancer.
“By understanding how cancer cheats at life’s card-game, we can see how an individual person’s cancer can be so complex and varied,” says Jones, adding that:
“Scientists can now start looking for ways to prevent this happening in the first place or turning this instability against cancers.”
In February 2012, a team from Jefferson University in the US, published a study that showed a particular breast cancer subtype may respond to drugs targeting chromosomal instability.
Written by Catharine Paddock PhD
