A mathematical study of the influence of hypoxia and acidity on the evolutionary dynamics of cancer

TL;DR

This paper develops a mathematical model to understand how hypoxia and acidity influence the evolution and heterogeneity of cancer cells within tumors, highlighting the role of environmental gradients and nonlinear interactions.

Contribution

It introduces a novel system of partial integro-differential equations modeling tumor microenvironment effects on cancer cell evolution, supported by numerical simulations with real data.

Findings

Tumor cell phenotypes vary with distance from blood vessels.

Environmental gradients promote intra-tumor heterogeneity.

Order of resistance development depends on environmental stressor interactions.

Abstract

Hypoxia and acidity act as environmental stressors promoting selection for cancer cells with a more aggressive phenotype. As a result, a deeper theoretical understanding of the spatio-temporal processes that drive the adaptation of tumour cells to hypoxic and acidic microenvironments may open up new avenues of research in oncology and cancer treatment. We present a mathematical model to study the influence of hypoxia and acidity on the evolutionary dynamics of cancer cells in vascularised tumours. The model is formulated as a system of partial integro-differential equations that describe the phenotypic evolution of cancer cells in response to dynamic variations in the spatial distribution of three abiotic factors that are key players in tumour metabolism: oxygen, glucose and lactate. The results of numerical simulations of a calibrated version of the model based on real data recapitulate the eco-evolutionary spatial dynamics of tumour cells and their adaptation to hypoxic and acidic microenvironments. Moreover, such results demonstrate how nonlinear interactions between tumour cells and abiotic factors can lead to the formation of environmental gradients which select for cells with phenotypic characteristics that vary with distance from intra-tumour blood vessels, thus promoting the emergence of intra-tumour phenotypic heterogeneity. Finally, our theoretical findings reconcile the conclusions of earlier studies by showing that the order in which resistance to hypoxia and resistance to acidity arise in tumours depend on the ways in which oxygen and lactate act as environmental stressors in the evolutionary dynamics of cancer cells.