by James DeGregori: Principles of evolution and natural selection drive a radical new approach to drugs and prevention strategies…
This year at least 31,000 men in the U.S. will be diagnosed with prostate cancer that has spread to other parts of their body, such as bones and lymph nodes. Most of them will be treated by highly skilled and experienced oncologists, who have access to 52 drugs approved to treat this condition. Yet eventually more than three quarters of these men will succumb to their illness.
Cancers that have spread, known as metastatic disease, are rarely curable. The reasons that patients die despite effective treatment are many, but they all trace back to an idea popularized in 1859 by Charles Darwin to explain the rise and fall of species of birds and tortoises. Today we call it evolution.
Think of a cancer cell like Darwin’s Galápagos finches, which had slightly different beaks on various islands. Finches eat seeds, and seeds on each island had different shapes or other characteristics. The bird with a beak shape best matched to the local seed got the most food and had the most offspring, which also had that particular beak shape. Birds with less adaptive beaks did not make it. This natural selection ensured that different finch species, with various beaks, evolved on each island. The key is that when two groups of critters compete in the same small space, the one better adapted to the environment wins out.
Cancer cells evolve in a similar manner. In normal tissue, regular noncancer cells thrive because they are a good fit for the biochemical growth signals, nutrients and physical cues they get from surrounding healthy tissue. If a mutation creates a cancer cell poorly adapted for those surroundings, it does not stand much chance initially: normal cells outcompete it for resources. But if the surroundings are further damaged by inflammation—sometimes a growing cancer can cause this itself—or old age, the cancer cell does better and starts to outcompete normal cells that used to crowd it out. The change in the surroundings ultimately determines a cancer cells’ success.
This is a theory we call adaptive oncogenesis, and we have found evidence that supports it in the way cancer takes off when we change its cellular environment in experimental animals, although the internal workings of the cancer cell have not changed. Doctors have also observed this acceleration of cancer in humans with tissue-disturbing ailments such as inflammatory bowel disease. The overall implication is that we can best understand cancer by looking at its surroundings rather than solely focusing on the mutations inside a cell. By reducing tissue alterations caused by processes such as inflammation, we can restore a more normal environment and—as we have shown in animal studies—prevent cancer from gaining a competitive edge.
Our evolutionary perspective also has inspired a different approach to cancer therapy, one that we have successfully tested in small clinical trials. Doctors dump a lot of chemotherapy drugs on a cancer in an effort to kill every last trace of the threat, and at first this often looks like it works. The tumor shrinks or goes away. But then it comes back and is resistant to the drugs that once killed these cells, akin to crop-destroying insects that evolve resistance to pesticides. In a clinical trial with prostate cancer patients, one of us (Gatenby) tried an alternative to the scorched-earth approach, applying only enough chemo to keep the tumor tiny without killing it entirely. The goal was to maintain a small population of vulnerable chemosensitive cells. That population did well enough to prevent cells with an unwanted new trait—chemoresistance—from taking over. In a group of patients in which tumors usually start growing uncontrollably after 13 months, this regimen has kept tumors under control for 34 months on average—with less than half the standard drug dose.
The results of our prevention and therapeutic strategies may point to a way to ward off cancer before it becomes a danger to life and limb and to save many patients for whom a regimen of giant, toxic drug doses has failed.
WHY DO WE GET CANCER?
If you asked almost any doctor or cancer researcher, “Why is aging, smoking or radiation exposure associated with cancer?” you would probably get a short answer: “These things cause mutations.” This assessment is partly true. Exposure to cigarette smoke or radiation does cause mutations in our DNA, and mutations do accumulate in our cells throughout life. The mutations can provide cells with new properties, such as hyperactive growth signals for cell divisions, reduced death rates or even an increased ability to invade surrounding tissue.
Yet this simple explanation, focused on changes within cells, overlooks the fact that a major driver of evolutionary change in any single cell—or in entire collections of them, such as human beings—is outside, in the cell’s environment.
We know that the evolution of species on the earth has been highly dependent on environmental perturbations, including dramatic changes to landmasses, the gases in the air and water, and ambient temperature. These changes led to selection for new adaptive features in organisms, producing amazing diversity. As Darwin wrote in On the Origin of Speciesin 1859, “Owing to this struggle for life, any variation, however slight and from whatever cause proceeding, if it be in any degree profitable to an individual of any species, in its infinitely complex relations to other organic beings and to external nature, will tend to the preservation of that individual, and will generally be inherited by its offspring” (emphasis added). Darwin proposed that competition for limited resources would drive selection for individuals with traits that were best adapted to the environment. And when environments changed, so would these pressures, selecting for new traits that were better tuned to the new surroundings.
Similar Darwinian dynamics should apply to the evolution of cancers in our body. Even though we trained as a molecular biologist (DeGregori) and a physician (Gatenby), evolution and ecology have always fascinated both of us. Our extensive reading in these areas, while initially driven by what we thought was curiosity unrelated to our day jobs, revealed unappreciated parallels between the driving forces of evolution and our observations of cancer development and cancer patients’ responses to therapy.