Life history trade-offs in cancer evolution

Abstract

Somatic evolution during cancer progression and therapy results in tumour cells that show a wide range of phenotypes, which include rapid proliferation and quiescence. Evolutionary life history theory may help us to understand the diversity of these phenotypes. Fast life history organisms reproduce rapidly, whereas those with slow life histories show less fecundity and invest more resources in survival. Life history theory also provides an evolutionary framework for phenotypic plasticity, which has potential implications for understanding 'cancer stem cells'. Life history theory suggests that different therapy dosing schedules might select for fast or slow life history cell phenotypes, with important clinical consequences.

Figure 1. Hallmarks of cancer associated with life history selection

Many of the hallmarks and enabling characteristics of cancer evolve under fast or slow life history selection. Environments that are unstable with regard to available resources and threats to cell survival, such as those characterized by wounding, variable blood flow, or rapid changes in the availability of growth factors, will select for fast life history hallmarks (left panel). Environments characterized by less disruption but limited availability of resources, or other population limitations such as immune predation, will select for slow life history hallmarks that increase cell survival or acquisition of resources (right panel). Some cancer hallmarks and enabling characteristics (positioned between the two panels) are associated with both fast and slow life history regimes.

Figure 2. Tumor heterogeneity

The left image is an MRI scan of a glioblastoma multiforme following gadolinium injection at Moffitt Cancer Center. The gray scale image on the left shows blood flow with white corresponding to highest flow and black to little or no flow. This will result in significant variations in many components of the tumor microenvironment including oxygen, glucose, acid, and serum-derived growth factors. In the right image, distinct intratumoral habitats are identified using combinations of images that correspond to vascular flow and cellular density, revealing heterogeneity with regard to resource availability and space competition within the tumor (red = high blood flow, low cell density; blue = low blood flow, high cell density; yellow = high blood flow, high cell density; green = low blood flow, low cell density).

Figure 3. Resource limitation and escape during progression

The second law of ecology states that an exponentially growing population will eventually reach some limit to its growth. In neoplastic progression, there appear to be a series of limitations to the growth of neoplastic cell populations. During progression, the neoplastic cell population evolves mechanisms for escaping each limitation, temporarily releasing the neoplastic cell population with a burst of proliferation such that mutant cells with fast life history strategies have a competitive advantage (red background). However, when those populations reach a new resource limitation, selection shifts from fast to slow life history strategies (blue background), such that cells that can best compete, sequester resources, and avoid death, have an advantage.

Figure 4. Tradeoffs between proliferation and survival during cancer progression

During progression, neoplastic cell lineages go through periods of selection for increased proliferation (vertical movement) and increased survival (horizontal), possibly in phases as resource constraints are reached (selecting for survival) and broken through (selection for proliferation) Early in progression, proliferation and survival can both increase without significant tradeoffs through destruction of various regulatory systems within the cell that otherwise suppress those functions. Later in progression, the capacity of cells to proliferate and survive becomes limited by fundamental tradeoffs, rather than the regulatory machinery of the cell. While some microenvironments may stably select for a particular point along this active edge, leading to cells that specialize on a fixed life history strategy, temporal changes in the microenvironment or cell migration through different microenvironments may select for cells with phenotypic plasticity. In order to proliferate more quickly without sacrificing survival (or vice versa), cells must be able to alter their phenotypes from reproduction specialist (e.g., a proliferating cell) to a survival specialist (e.g., a dormant cell). This selection for phenotypic plasticity or ‘stemness’ (red zone) later in progression may be explained by the fact that clones adopting a conditional phenotype subject to dynamic life history tradeoffs can achieve higher fitness than those constrained to a phenotype with fixed life history strategy.

Figure 5. Effects of treatment on life history strategies

Different treatments select for and induce different life history strategies. A. Traditional high dose therapies cause high levels of cell mortality, initially selecting for survival specialists (light blue) but, afterwards, with an abundance of resources and a paucity of competitors, proliferating specialists (pink) gain an advantage, which may contribute to recurrence. B. A treatment that normalizes and limits resources selects for cells with slow life history strategies, specializing on survival and competition (pink), which may facilitate long-term cancer control. C. Cells with conditional life history strategies may respond to cytotoxic therapies by shifting first into a survival phenotype (blue) and then back into a rapidly proliferating phenotype (red), which may lead relapse. D. When exposed to a therapy that establishes a constant environment with limited yet stable resources, cells with conditional life history strategies may shift into a slow life history phenotype that invests cellular resources into survival and competition (blue), which may enable long-term cancer control.