Phenotypic variation modulates the growth dynamics and response to radiotherapy of solid tumours under normoxia and hypoxia. (21st October 2021)

• Record Type: Journal Article
• Authors: Celora, Giulia L.; Byrne, Helen M.; Zois, Christos E.; Kevrekidis, P.G.
• Is Part Of: Journal of theoretical biology. Volume 527(2021)
• Publication Date: 2021-10-21
• Subjects: Cancer stem cells -- Phenotypic variability -- Radio-resistance; Biology -- Periodicals; Biological Science Disciplines -- Periodicals; Biology -- Periodicals; Biologie -- Périodiques; Theoretische biologie; Biology; Periodicals; 571.05
• DOI: 10.1016/j.jtbi.2021.110792
• Languages: English
• ISSNs: 0022-5193

Abstract

Highlights: Phenotype-structured model of tumour growth developed. Advective and diffusive flux terms included to account for adaptive cancer stem cell plasticity. Impact of oxygen levels on cancer stem cell emergence and persistence assessed. Role of phenotypic heterogeneity on tumour responses to radiotherapy investigated. Validation of simulation results using linear stability analysis. Abstract: In cancer, treatment failure and disease recurrence have been associated with small subpopulations of cancer cells with a stem -like phenotype. In this paper, we develop and investigate a phenotype-structured model of solid tumour growth in which cells are structured by a stemness level, which varies continuously between stem-like and terminally differentiated behaviours. Cell evolution is driven by proliferation and death, as well as advection and diffusion with respect to the stemness structure variable. Here, the magnitude and sign of the advective flux are allowed to vary with the oxygen level. We use the model to investigate how the environment, in particular oxygen levels, affects the tumour's population dynamics and composition, and its response to radiotherapy. We use a combination of numerical and analytical techniques to quantify how under physiological oxygen levels the cells evolve to a differentiated phenotype and under low oxygen level (i.e., hypoxia) they de-differentiate. Under normoxia, the proportion of cancer stem cells is typically negligible and the tumour may ultimately become extinct whereas under hypoxia cancer stem cells comprise a dominant proportion of the tumour volume, enhancing radio-resistance and favouring the tumour's long-term survival. We then investigate how such phenotypic heterogeneity impacts the tumour's response to treatment with radiotherapy under normoxia and hypoxia. Of particular interest is establishing how the presence of radio-resistant cancer stem cells can facilitate a tumour's regrowth following radiotherapy. We also use the model to show how radiation-induced changes in tumour oxygen levels can give rise to complex re-growth dynamics. For example, transient periods of hypoxia induced by damage to tumour blood vessels may rescue the cancer cell population from extinction and drive secondary regrowth.