Cancer is one of our most persistent enemies, but while we now have advanced immune systems to fight the good fight, how did early multicellular life manage to stave it off? A genetic "kill switch" seems to have been the original weapon of choice, and now researchers at Northwestern University believe they've discovered a way to trigger that mechanism. This knowledge could potentially pave the way to a therapy where cancer cells commit suicide, which would be impossible for cancer cells to adapt a resistance to.
Cancer begins to form when regular cells break ranks, growing and multiplying faster than they're supposed to. Eventually the extra cells form a tumor, and soon the cancer attracts the attention of the immune system, which goes in to wipe out the dangerous cells – that's how it should play out, anyway. The immune system doesn't always respond in time, and cancer has some crafty tricks up its sleeve to avoid detection in the first place.
But the immune system is extremely complex, and arose relatively late in the game. So if cancer had the upper hand for millions of years, how did life survive long enough to develop an immune system at all?
"Ever since life became multicellular, which could be more than 2 billion years ago, it had to deal with preventing or fighting cancer," says Marcus Peter, lead author of the study. "So nature must have developed a fail safe mechanism to prevent cancer or fight it the moment it forms. Otherwise, we wouldn't still be here."
So the team set out to find just such a mechanism buried in the genome. It was a tricky search, since any kind of kill switch would only be active in a single cell right at the moment it becomes cancerous. Eventually, the team found the molecular weapons they were looking for, hidden in a tool that scientists currently use to study gene function.
Certain gene sequences, spread throughout the human genome, can be converted into molecules called small interfering RNAs (siRNAs). When these are introduced into cells, they suppress the activity of the genes that they were originally crafted from: in this case, the team developed siRNAs that target three genes that cancer relies on, effectively causing the cells to kill themselves.
Because it affects three different survival genes at once, the molecules trigger several cell death pathways at once, meaning the cancer cannot develop a resistance to the treatment. The researchers call the cell-killing mechanism Death Induced by Survival gene Elimination (DISE).
"This could be a major breakthrough," says Peter. "We think this is how multicellular organisms eliminated cancer before the development of the adaptive immune system, which is about 500 million years old. It could be a fail-safe that forces rogue cells to commit suicide. We believe it is active in every cell protecting us from cancer."
A little unnerving is the fact that the DISE mechanism can be applied to essentially any cell, but Peter's team says that the tests indicate it prefers cancerous cells. The researchers trialled the treatment on mice with ovarian cancer, and found that tumor growth was strongly reduced, with no toxic side effects and no sign of the cancer developing resistance to the molecules.
The researchers are refining the technique in hopes that it might become a viable treatment option. The research was published in the journals eLife and OncoTarget.
Source: Northwestern University
