Microenvironmental Independence Associated with Tumor Progression

Abstract

Tumor-microenvironment interactions are increasingly recognized to influence tumor progression. To understand the competitive dynamics of tumor cells in diverse microenvironments, we experimentally parameterized a hybrid discretecontinuum mathematical model with phenotypic trait data from a set of related mammary cell lines with normal, transformed, or tumorigenic properties. Surprisingly, in a resource-rich microenvironment, with few limitations on proliferation or migration, transformed (but not tumorigenic) cells were most successful and outcompeted other cell types in heterogeneous tumor simulations. Conversely, constrained microenvironments with limitations on space and/or growth factors gave a selective advantage to phenotypes derived from tumorigenic cell lines. Analysis of the relative performance of each phenotype in constrained versus unconstrained microenvironments revealed that, although all cell types grew more slowly in resource-constrained microenvironments, the most aggressive cells were least affected by microenvironmental constraints. A game theory model testing the relationship between microenvironment resource availability and competitive cellular dynamics supports the concept that microenvironmental independence is an advantageous cellular trait in resource-limited microenvironments. [Cancer Res 2009;69(22):8797-806]

Game theory in the death galaxy: interaction of cancer and stromal cells in tumour microenvironment

“…Thus, we here simply assume the pay-offs to be a linear gradient when a linear drug gradient is applied. We found that, in regions with higher drug concentrations, ST cells grow more slowly while the most resistant cancer cells survive; this is related to the previous discovery that the most aggressive cancer cells are the least limited by environmental constraints [33].…”

The impact of age on oncogenic potential: tumor-initiating cells and the brain microenvironment

“…This may provide a selective advantage to cells that are able to bypass these signals. Computational modeling has predicted that NPCs that are able to proliferate without growth factors could be selected for in this environment, but would have no such competitive advantage in a younger brain with more growth factor availability (Anderson et al ., 2009). Although dysfunction in intracellular signaling as a result of genetic mutation is considered to be the major cause of oncogenic transformation, malignant cells are also able to co-opt the surrounding tissue to create a favorable environment for the growing tumor.…”

Exploiting Evolution To Treat Drug Resistance: Combination Therapy and the Double Bind

“…This framework uses evolutionary game theory (EGT), a mathematical tool that has been traditionally used in evolutionary ecology [4] and more recently in mathematical oncology [5, 6, 7, 8, 9, 10]. This modelling tool has potential to provide insights into the evolutionary dynamics of cancer when a combination therapy is used.…”