Just as some mutations in the genome of cancer cells actively spur tumor growth, it would appear there are also some that do the reverse, and act to slow it down or even stop it, according to a new US study led by MIT.
Senior author, Leonid Mirny, an associate professor of physics and health sciences and technology at MIT,and colleagues, write about this surprise finding in a paper to be published online this week in the Proceedings of the National Academy of Sciences.
In a statement released on Monday, Mirny tells the press:
“Cancer may not be a sequence of inevitable accumulation of driver events, but may be actually a delicate balance between drivers and passengers.”
“Spontaneous remissions or remissions triggered by drugs may actually be mediated by the load of deleterious passenger mutations,” he suggests.
Your average cancer cell has a genome littered with thousands of mutations and hundreds of mutated genes. But only a handful of these mutated genes are drivers that are responsible for the uncontrolled growth that leads to tumors.
Up until this study, cancer researchers have mostly not paid much attention to the “passenger” mutations, believing that because they were not “drivers”, they had little effect on cancer progression.
Now Mirny and colleagues have discovered, to their surprise, that the “passengers” aren’t there just for the ride. In sufficient numbers, they can slow down, and even stop, the cancer cells from growing and replicating as tumors.
Cancer can take years to develop, sometimes decades. This is because it takes time for the cells to gradually acquire more and more driver mutations, which then switch on genes like Ras that spur tumor growth, and switch off genes like p53 that suppress tumor growth.
Instead of viewing cancer growth as the result of unimpeded driver mutations, Mirny says we should perhaps be looking at it as an evolutionary process where a “delicate balance” develops between growth fuelled by driver mutations and the gradual accumulation of passenger mutations that damage cancer cells.
He and his colleagues are excited by this because it suggests a possible approach for designing new cancer drugs that tip the balance of an existing process in favour of the passenger mutations. It would be like beating the cancer with its own weapon, mutations, they say.
On its own, a passenger mutation has little effect compared to that of a driver, but when you get enough of them together, says Mirny, they can have “a profound effect”.
“If a drug can make them a little bit more deleterious, it’s still a tiny effect for each passenger, but collectively this can build up,” he explains.
Mirny and colleagues made a computer model that simulates the evolutionary growth of cancer to test their idea.
The model follows millions of cells as they divide, keeping track of each random mutation they acquire, and also each cell death.
They discovered that between the long periods between acquiring new driver mutations, the cells were quietly accumulating many passenger mutations.
Also, when a cancerous cell acquired a new driver mutation, that cell and its offspring became dominant, and all the passenger mutations that the original dominant cell contained, got carried along down the line.
Mirny says this was how the passenger cells get passed on, otherwise they would never spread in the population: “they essentially hitchhike on the driver,” he explains.
As they continued to run the simulation, the researchers found this process repeats about 5 to 10 times during cancer development. Each repetition brings a new cohort of potentially damaging (ie bad news for cancer cells) passenger mutations.
And the simulations also showed that when enough of the passenger mutations accumulated, they slowed cancer growth.
In the model, they could see tumors becoming dormant, but then spurred into growth again, as new drivers mutations were acquired.
When they looked at passenger mutations in the genomes of cancer cells from human patients, the researchers found similar patterns (large numbers of accumulated slightly deleterious, passenger mutations), to those predicted by their computer model.
The researchers then tested, using the model, what would happen if they tipped the balance slightly in favor of the passengers.
Their first simulation showed that the effect of each potentially damaging passenger mutation was to reduce the fitness of the cancer cell by around 0.1%. So they ran a simulation where they boosted that effect to 0.3%. And the tumors shrank, as they felt the effect of their own deleterious mutations.
The researchers suggest the model shows what might be achieved in real cancer with drugs that disrupt chaperone proteins. These proteins help building block proteins to fold into the right shapes after they have been synthesized. In cancer cells, chaperone proteins help even mutated proteins fold into the right shape, overcoming the passenger proteins’ tendency to suppress this.
Although there are already several drugs in development that target the effect of chaperone proteins in cancer, they are aiming to suppress driver mutations.
Recently, biochemists at the University of Massachusetts Amherst , “trapped” a chaperone in action, providing a dynamic snapshot of its mechanism as a way to help development of new drugs that target drivers.
But Mirny and colleagues say there is now another option: developing drugs that target the same chaperoning process, but their aim would be to encourage the suppressive effect of the passenger mutations.
They are now comparing cells with identical driver mutations but different passenger mutations, to see which have the strongest effect on growth.
They are also inserting the cells into mice to see which are the most likely to lead to secondary tumors (metastasize).
Funds from the National Institutes of Health, and the National Cancer Institute Physical Sciences Oncology Center at MIT, are helping to finance the research.
Written by Catharine Paddock PhD