Tumor microenvironment as a metapopulation model: The effects of angiogenesis, emigration and treatment modalities

Tumors consist of heterogeneous cell subpopulations that may develop differing phenotypes, such as increased cell growth, metastatic potential and treatment sensitivity or resistance. To study the dynamics of cancer development at a single-cell level, we model the tumor microenvironment as a metapopulation, in which habitat patches correspond to possible sites for cell subpopulations. Cancer cells may emigrate into dispersal pool (e.g. circulation system) and spread to new sites (i.e. metastatic disease). In the patches, cells divide and new variants may arise, possibly leading into an invasion provided the aberration promotes the cell growth. To study such adaptive landscape of cancer ecosystem, we consider various evolutionary strategies (phenotypes), such as emigration and angiogenesis, which are important determinants during early stages of tumor development. We use the metapopulation fitness of new variants to investigate how these strategies evolve through natural selection and disease progression. We further study various treatment effects and investigate how different therapy regimens affect the evolution of the cell populations. These aspects are relevant, for example, when examining the dynamic process of a benign tumor becoming cancerous, and what is the best treatment strategy during the early stages of cancer development. It is shown that positive angiogenesis promotes cancer cell growth in the absence of anti-angiogenic treatment, and that the anti-angiogenic treatment reduces the need of cytotoxic treatment when used in a combination. Interestingly, the model predicts that treatment resistance might become a favorable quality to cancer cells when the anti-angiogenic treatment is intensive enough. Thus, the optimal treatment dosage should remain below a patient-specific level to avoid treatment resistance.