The effect of targeted therapy on recruited cancer stem cells in a head and neck carcinoma model.

Abstract

Head and neck cancers (HNC) are known for their repopulation ability driven by cancer stem cells (CSCs). While a small fraction of CSCs proliferates, there are quiescent CSCs that are long-lived and reside outside the cell cycle. Recruitment of quiescent CSCs into the cycle occurs as a response to cell loss and their proliferation may lead to treatment failure. Therefore, CSCs require a more targeted approach to be destroyed. An agent that sensitizes CSC response to treatment is all-trans-retinoic acid (ATRA). The aim of this work is to assess the impact of ATRA combined with radiotherapy on HNC and to analyse the interplay between these agents and cell recruitment. An in silico model is employed to grow a HNC consisting of all cancer cell lineages, with biologically valid kinetic and dynamic parameters. The fate of both cycling and quiescent cancer stem cells is assessed. The Linear Quadratic model is used to simulate radiotherapy, while cellular recruitment and the effects of ATRA on cancer stem cells are modelled based on literature data. A Dose Enhancement Factor (DEF) was determined in order to undertake a quantitative assessment of the effect of ATRA on tumour control. Without recruitment, DEF for the tumour population is 1.06, indicating a slight radiosensitizing effect. Yet, when CSCs are being recruited, the dose enhancement factor is significantly greater (DEF=1.89). Radiation-induced cell arrest and CSC sensitization by ATRA significantly decreases the dose required for CSC eradication in the cycling population. However, the tumour as a whole is not notably affected as the quiescent cells appear to dictate the shape of the survival curve. The model shows that ATRA exhibits a powerful effect on CSCs when combined with radiotherapy. However, the more radioresistant quiescent cell population should not be ignored, as it can be a potential threat to treatment outcome when cells are recruited into the cell cycle.