James DeGregori is a Professor in the Department of Biochemistry and Molecular Genetics at the University of Colorado School of Medicine and the Deputy Director of the University of Colorado Cancer Center. His lab studies the evolution of cancer, in the context of their Adaptive Oncogenesis model, with a focus on how aging and other insults influence cancer initiation. His lab has developed this cancer model based on classic evolutionary principles and substantiated this model by theoretical, experimental, and computational studies. This model is described in his recent book, Adaptive Oncogenesis: A New Understanding of How Cancer Evolves inside Us (Harvard University Press). The following is the introduction to that book. Matt Young will serve as moderator of this thread.
Why do we get diseases like cancer, and why do we get them mostly when we are old? Why do children get cancer? Why do we age? These may seem like existential questions, but there are answers, even if we do not know all of them. If you go to your doctor, you will get proximate explanations, which consider the causes of processes and diseases like aging and cancer within us. You may be told that aging is the result of a lifelong accumulation of damage to your tissues, both from errors that occur as your body maintains itself and from the damaging exposures that we experience during life. Analogously, you will be told that cancer is the result of a lifetime’s accumulation of genetic alterations (mutations) and that the accumulation by chance of a certain set of cancer-promoting mutations explains the increased risk of cancer late in life. Similarly, exposures to carcinogens, such as through smoking, are said to cause cancer by inducing mutations that change normal cells into cancer cells. But the more informative and more useful answers lie in an evolutionary understanding of life history and disease. As the great evolutionary biologist Ernst Mayr said, “No biological problem is solved until both the proximate and the evolutionary causation has been elucidated.”
Cancer is the second leading cause of death in industrialized countries: about 40 percent of people in those countries will develop cancer, and close to half of these individuals will die from their disease. Cancer is largely a disease of old age, with over 90 percent of cancers occurring in individuals over fifty. Other causes of cancer include cigarette smoking, alcohol consumption, sun exposure, pollution exposure, infections, and obesity. The medical and research communities have primarily ascribed associations between aging or exposures and cancer to enhanced mutation accumulation, despite strong evidence challenging such simple relationships.
This book will describe how the risk for cancer, like risks for other diseases, is inexorably tied to the life strategies that we and other animals evolved. These evolutionary strategies involve different investments in the maintenance of our tissues, resulting in very different potential life spans across the animal kingdom. Old age is not just the result of the passage of time; it is also the period when we experience physiological decline. The book will discuss the varied mechanisms that humans and other animals have evolved to avoid cancer, innovations required for the evolution of bigger bodies and longer lives. In particular, it will focus on how the maintenance of the body delays cancer until old age. Accordingly, this book will introduce a new theory: adaptive oncogenesis. This theory seeks to provide an explanation for why we and other animals are able to largely avoid cancer through periods of likely reproductive success. The theory postulates that animals have evolved stem cells that are well adapted to specialized niches within tissues (referred to as the microenvironment). Stem cells maintain a tissue for life, and thus they are the ultimate reservoirs of a tissue’s genetic information for a lifetime. The maintenance of tissues during youth creates local environments that are unfavorable to change in the resident stem cells, including oncogenic changes that can contribute to cancer formation. In much the same way as stable environments on Earth limit selection for genetic change in organismal populations, healthy tissues suppress evolutionary change in constituent cells.
Unfortunately, humans and other animals do develop cancer. A primary reason is an unavoidable one—we get old. While the dominant explanation for the aging link is that substantial time is required for cells to accumulate sufficient numbers of mutations to cause cancer, this book will explore alternative explanations that are more in line with evolutionary theory. It will first consider how the force of natural selection to prevent cancer, other disease, or organ dysfunction diminishes in old age, as the odds of successful reproduction decline. Adaptive oncogenesis proposes that tissue decline during aging leads to selection for new cellular characteristics adaptive to this altered tissue landscape. Furthermore, the environmental exposures that our bodies experience can have substantial impacts on cancer risk, as clearly shown in the case of cigarette smoking. Drawing parallels with how changes in the environments of Earth have led to bursts of speciation, we will discuss how exposures like smoking perturb microenvironments for stem cells, leading to selection for oncogenic mutations that are adaptive in this damaged landscape.
This book will reevaluate clinical data within the adaptive oncogenesis framework, providing explanations for why cancer occurs in young children and why the detection of oncogenic mutations far outpaces incidence rates of cancers. It will discuss evolutionary theory‒based strategies to modulate tissue microenvironments as a way to control the fate of precancer and cancer cells, and thus to prevent and treat cancers. The reductions in cancer mortality after almost half a century of the war on cancer have been real but disappointingly inadequate. Greater focus on tissue landscapes and how they affect the evolutionary dynamics of both noncancer and cancer cells may be necessary to limit the pernicious impacts of this disease. All of these discussions will be framed in the light of evolution, as urged by the great evolutionary biologist and geneticist Theodosius Dobzhansky. For better or worse, we and all other animals are products of the forces that shaped our evolution. Thus, we will start with an understanding of life histories among different animals, and how and why they evolved.
Excerpted from ADAPTIVE ONCOGENESIS: A NEW UNDERSTANDING OF HOW CANCER EVOLVES INSIDE US by James DeGregori, published by Harvard University Press. Copyright © 2018 by the President and Fellows of Harvard College. Used by permission. All rights reserved.