The evolutionary approach to cancer has been the dominant theory of cancer since it was proposed in the 1970s (1
) and has continued to be developed as a unifying theory for understanding the emergence and progression of cancers (2
). Here we apply evolutionary and ecological theory to understand the transition from benign sedentary cells to invasive and metastatic cells. Dispersal, metabolism, niche modification and resource limitation play central roles in phenotypic change across species. These process have clear parallels in cancer and neoplastic progression, including cell migration/motility (6
), altered metabolism (7
), microenvironment modification (9
) and resource limited conditions such as hypoxia (10
Although it is well understood in the ecology literature that high rates of consumption and subsequent degradation of local environments leads to selection for mobile organisms, this idea has yet to be applied to understanding the relationships among cell metabolism, microenvironment quality and the evolution of motility in somatic cells. In this paper we describe the applicability of ecological dispersal theory to neoplastic progression and report the results of an agent based model designed to test the hypothesis that high rates of cell metabolism promote the evolution of cell motility.
The consumption of resources is a fundamental characteristic of living things, and a process that inevitably affects the local environment. Because resource limitation is an unavoidable consequence of exponential growth, it is a universal limitation on survival and reproduction across all ecological systems. High rates of resource use can generate a tragedy of the commons (12
), a type of social dilemma (14
) that emerges from resource competition (15
) and tends to favor individuals who can escape from resource limitation through dispersal (15
). In neoplastic progression, invasive and metastatic cells may be selected because their dispersal phenotype allows them to gain access to resources in spite of local scarcity. Cancer cells outstrip the local supply of resources, both because they outgrow existing vasculature and because they consume limiting resources at a higher rate than do normal cells (8
). Here we explore whether increased motility of somatic cells is positively selected when cells have high rates of consuming resources in their microenvironments, i.e., high metabolic rates.
Disregulated metabolism, especially in the form of increased glucose metabolism, is a characteristic of neoplastic cells and an important factor in neoplastic progression (8
). A variety of oncogenes have been implicated in the shift to higher glucose metabolism including mutations that affect RAS, AKT
, and MYC
). Mutations in the TP53
) tumor suppressor gene also affect tumor metabolism, in part through downstream effects on SCO2
). Although it is clear that these mutations are associated with neoplastic cells, the causal role of disregulated metabolism in neoplastic progression is not well understood.
Because the nutrient conditions in neoplasms are not well characterized (19
) and it is not yet known how many limiting resources there are to cancer growth (8
), we have made our model general rather than basing it on a particular limiting resource. The applicability of this model depends only on the existence of some limiting resource for cell growth and proliferation.
In order to test the hypothesis that high rates of metabolism of limiting resources leads to the evolution of cell motility, we model populations of cells with varying metabolic rates and explore the evolution of motility rate. We report results from two related agent-based models, one in which the metabolic rate of cells is systematically varied, and one in which a population of normal cells can be invaded by a neoplastic cell type with a higher rate of resource metabolism. We predict that higher resource metabolism will lead to the evolution of higher cell motility. These results suggest that an evolutionary and ecological framework can provide insights into the transition from benign cells to invasive and metastatic cells.