Robert Axelrod*,, David E. Axelrod, and Kenneth J. Pienta
*Gerald R. Ford School of Public Policy and Department of Political Science, University of Michigan, Ann Arbor, MI 48109; Department of Genetics and Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ 08854; and Departments of Internal Medicine and Urology, University of Michigan Medical School, Ann Arbor, MI 48109
Contributed by Robert Axelrod, July 19, 2006
The evolution of cooperation has a well established theoreticalframework based on game theory. This approach has made valuablecontributions to a wide variety of disciplines, including politicalscience, economics, and evolutionary biology. Existing cancertheory suggests that individual clones of cancer cells evolveindependently from one another, acquiring all of the genetictraits or hallmarks necessary to form a malignant tumor. Itis also now recognized that tumors are heterotypic, with cancercells interacting with normal stromal cells within the tissuemicroenvironment, including endothelial, stromal, and nervecells. This tumor cell–stromal cell interaction in itselfis a form of commensalism, because it has been demonstratedthat these nonmalignant cells support and even enable tumorgrowth. Here, we add to this theory by regarding tumor cellsas game players whose interactions help to determine their Darwinianfitness. We marshal evidence that tumor cells overcome certainhost defenses by means of diffusible products. Our originalcontribution is to raise the possibility that two nearby cellscan protect each other from a set of host defenses that neithercould survive alone. Cooperation can evolve as by-product mutualismamong genetically diverse tumor cells. Our hypothesis supplements,but does not supplant, the traditional view of carcinogenesisin which one clonal population of cells develops all of thenecessary genetic traits independently to form a tumor. Cooperationthrough the sharing of diffusible products raises new questionsabout tumorigenesis and has implications for understanding observedphenomena, designing new experiments, and developing new therapeuticapproaches.
carcinogenesis | hallmarks | tumorigenesis | cancer
PNAS | September 5, 2006 | vol. 103 | no. 36 | 13474-13479. OPEN ACCESS ARTICLE.
The evolution of cooperation has a well established theoreticalframework based on game theory (1–6). This approach hasmade valuable contributions to a wide variety of disciplines,including political science, economics, and evolutionary biology.Two kinds of cooperation have been recognized: commensalism,in which one individual of a pair benefits but not the other;and mutualism, in which both benefit, resulting in synergy.In each case, new properties may emerge in a cooperating groupthat the individuals do not exhibit.
Existing cancer theory suggests that tumors are monoclonal,i.e., they develop from a single cell that starts to divideto form a tumor mass because of an initiating carcinogenic event.The initiated cell does not have all of the necessary mutations(genetic and epigenetic) to form a population of fully malignantcancer cells. As these cells are exposed to further promotionalevents and divide, errors in DNA replication result in daughtercells, or subclones, that are genetically different from eachother, resulting in tumor cell heterogeneity. Prevailing theorysuggests that, as these distinct subclonal populations of cancercells continue to divide, they evolve independently from oneanother, and one subclone acquiring all of the genetic traitsor hallmarks necessary to form a population of fully malignantcancer cells. It is well recognized that this is an inefficientprocess, with many of the subclones dying because they are geneticallyunstable or do not contain a set of mutations that sustain viabilityin the face of host defenses.
Here, we add to this theory by regarding tumor cells as gameplayers whose interactions help to determine their Darwinianfitness. We marshal evidence that genetically distinct tumorcells cooperate to overcome certain host defenses by exchangingdifferent diffusible products. Our original contribution isto raise the possibility that two nearby subclones can protecteach other from a set of host defenses that neither could survivealone, potentially speeding the process of tumorigenesis throughthe more rapid emergence of malignant populations of cells thatcontain all of the necessary hallmarks of cancer (Fig. 1). Wetherefore propose that tumor progression may be facilitatedby the evolution of cooperation in the form of by-product mutualismamong genetically diverse tumor cells. Our hypothesis supplements,but does not supplant, the traditional view of carcinogenesis,in which one subclone of cells evolves independently to acquireall of the necessary genetic traits to form a tumor. Cooperationthrough the sharing of diffusible products raises new questionsabout tumorigenesis and has implications for observed phenomena,designing new experiments, and developing new therapeutic approaches.
Examples of cooperation have been found among a wide range oforganisms, from viruses to animals to humans (1–4). Itis important to realize that cooperation is not limited to sentientorganisms. Cooperation may occur among organisms such as virusesand cells that do not have intent, emotions, sophisticated memory,or any of the other attributes unique to humans or even mammals.A player’s strategy is what it does as a function of whatit can respond to (although, as will be shown, even this contingentaction is not always needed). Two or more players interact,and the payoff for each is influenced by what they all do.
Evolutionary biology now uses game theory to understand theorigin, spread, and maintenance of cooperation. The evolutionaryinterpretation of game theory uses standard Darwinian principles:individuals that interact with each other and their environment,phenotypes that are heritable, change in heritable genotypesby mutation and other mechanisms, competition among individualsfor limited resources, and selection. The criterion for selectionis fitness, i.e., an increase in the number of progeny by sexualor asexual (clonal) reproduction.
Most studies of the evolution of cooperation deal with the apparentlyparadoxical situation of altruism, i.e., cases in which thebenefits to the recipient are costly to the donor. The classicsetting for the study of cooperation with altruism is the "Prisoner’sDilemma." In scenarios such as the Prisoner’s Dilemma,individual "defectors" have a competitive advantage over cooperators,so the evolution and maintenance of cooperation represent apuzzle to be explained. This puzzle has most often been resolvedby pointing to the individual’s ability to make its cooperationcontingent in a manner that favors either close relatives orthose who reciprocate help (6, 7).
Not all forms of cooperation require altruism. For example,in by-product mutualism, two or more individuals provide helpto each other simply as a consequence of each maximizing itsown fitness. We hypothesize that mutualism exists between differentpartially or fully transformed tumor cells in a heterogeneousmixture of cells.