James DeGregori studies how leukemias and lymphomas begin. The focus of his recent research centers on the fitness of progenitor cells and how damage — whether it be from exposure to carcinogens, aging, or a bad diet — can cause the selection of adaptive oncogenic events. This has led him to propose an evolutionary theory of cancer. Prof. DeGregori graciously set aside time to answer some of our questions.
SCIENTIFIC INQUIRER: For starters, what is the mutation accumulation theory of oncogenesis and how has it informed how cancer therapy is approached?
JAMES DE GREGORI: The mutation accumulation theory holds that the main limiting factor for cancer causation is the accumulation of sufficient numbers of oncogenic mutations. So aging is thought to cause cancer due to the time required to accumulate sufficient mutations. Similarly, smoking is thought to cause cancer by causing mutations. As you can see in the attached, I have argued that there is abundant evidence, and evolution theory, to argue against this theory.
SI: You are proposing something different, an evolutionary theory of cancer. Can you explain what that entails?
JD: Basically, connecting cancer to its causes (like aging and smoking) requires an understanding for how these causes alter tissue microenvironments, which will substantially change selective pressures acting on oncogenic mutations. So an oncogenic mutation that might be advantageous in a smoker’s lung could actually be disadvantageous to cells in a young healthy lung. This new theory is similar to how evolution works – evolutionary change is driven by selection for genetic changes that are adaptive to altered environments.
SI: What was it in the mutation accumulation theory to question it?
JD: Basically, mutation occurrence correlates very poorly with cancer risk across lifetimes, across different tissues, across different species.
SI: Can you discuss some of the evidence in support of cancer being dependent on micro environments within the body?
JD: We have shown that the same oncogenic mutations that provide an advantage to blood cell stem cells in an old mouse can fail to provide such an advantage in the stem cells in a young mouse. If we eliminate one factor in the aged microenvironment – inflammation – we can now prevent selection for the oncogenic mutation. So while we may not be able to avoid mutations as we age, we can change the odds that these mutations (the oncogenic ones) can contribute to a cancer. Some other evidence (including from other labs) is in the attached.
SI: Does the evolutionary theory hold true for the majority of cancers or only ones that develop later in life or after a trauma, e.g. Exposure to carcinogens?
JD: We think that the theory definitely holds true for carcinogen induced cancers, and we have published evidence for how radiation exposure selects for adaptive oncogenic events. Others have shown similar selection acting following UV exposure to skin.
SI: Let’s assume the evolutionary theory is correct, what does this mean for the significant body of research conducted with the mutation accumulation theory as their underlying basis? Is the evolutionary theory a completely new path or is it an adjustment?
JD: Under the umbrella of the mutation theory, the field has still made a lot of progress, often focusing on how particular oncogenic mutations can promote cancer traits (phenotypes). However, I think that the field needs to better understand how the effects of these oncogenic mutations are highly context dependent. We need to worry less about avoiding the mutations, and more about mitigating the ability of these mutations to be selected for (and thus contribute to cancers). So I think that the evolutionary theory is a major revision to the mutation theory.
SI: How can the evolutionary theory be utilized in the drug development field? What therapeutic lines of inquiry open up?
JD: Instead of just designing drugs to target cancer cells, we need to develop interventions that modify tissue (and cancer) environments so that the more aggressive and dangerous cancer phenotypes are disfavored. Basically, we should seek to generate microenvironments that better favor the “normal” cellular type.
SI: What is next for you in terms of research?
JD: We are trying to understand how aging and cigarette smoke exposure alter lung tissue to favor particular oncogenic mutations, why these oncogenic mutations are adaptive in these aged or damaged lungs, and how we can intervene to prevent this adaptation (and thus reduce lung cancer risk).
SI: On a more personal level, what brought you to a life in science? Did you always want to be a scientist?
JD: I have always been a naturalist at heart, even as a child. I really got hooked on research as an undergraduate – I found the difficulties in making new discoveries about how cells and tissues work gratifyingly challenging. I’ve also seen the impact that cancer can make on individuals and their friends and families, and I’d like to do my part to help limit the costs of cancer.
SI: Do you believe in science for science’s sake or should science serve a purpose?
JD: Both. We should always strive to know more about the world around us, from subatomic particles to organisms and their ecosystems. These studies must be supported independent of potential benefit. Still, we know from experience that the more we know, the better we can find ways to manipulate systems for the betterment of humankind.
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