In silico modelling of a cancer stem cell-targeting agent and its effects on tumour control during radiotherapy.

Loredana G Marcu,David Marcu

doi:10.1038/srep32332

Abstract

Head and neck cancers (HNC), like most solid tumours, contain a subpopulation of cancer stem cells (CSC) that are commonly responsible for treatment failure. Conventional therapies are unsuccessful in controlling CSCs, thus novel, targeting therapies are needed. A promising agent is ATRA (All-trans-retinoic acid) that was shown to induce CSC differentiation, cell cycle redistribution and CSCs radiosensitisation. To add to the limited data, this work simulated the effects of ATRA on a virtual HNC and evaluated tumour response to radiotherapy. A Monte Carlo technique was employed to grow a HNC consisting of all lineages of cancer cells. The biologically realistic input parameters led to a pre-treatment CSC population of 5.9%. The Linear Quadratic model was employed to simulate radiotherapy. ATRA-induced differentiation, cell arrest and apoptosis were modelled, based on literature data. While the effect of differentiation was marginal, the strongest influence on CSC subpopulation was displayed by ATRA’s cell arrest effect via an exponential behaviour of the dose-response curve. The apoptotic effect induced by ATRA shows linear correlation between the percentage of apoptotic cells and dose required to eradicate CSCs. In conclusion, ATRA is a potent CSC-targeting agent with viable impact on tumour control when combined with radiotherapy.

Highlights

The current literature is filled with an ever-growing body of evidence towards the existence of cancer stem cells
Based on a study looking at the expression of CSC marker proteins in a head and neck squamous cell carcinoma xenograft mouse model, Geissler et al have assumed that CSCs can be sub-classified into migratory and stationary cancer stem cells[2]
The first section shows the effect of high symmetrical division probabilities on tumour response to radiotherapy alone, while all other sections present the results of All-Trans-Retinoic Acid (ATRA) when combined with hyperfractionated radiotherapy

Summary

Introduction

The current literature is filled with an ever-growing body of evidence towards the existence of cancer stem cells These cells represent a subpopulation of tumour cells that proliferate indefinitely, are tumorigenic and more quiescent than non-cancer stem cells[1]. Since cancer growth is sustained by this small subpopulation of cancer stem cells, their symmetrical division further increases the subpopulation and, resistance to treatment. Experimental studies on the phenotypic heterogeneity of tumours have shown that cancers comprise of various cell subpopulations with heterogeneous molecularity, which confers them distinct biological behaviour[2] Among these varied subpopulations there are cell groups with different features that are linked to invasiveness and metastases, radioresistance, resistance to chemotherapy, etc. This fact is prompting the need for the quantification of the CSC subpopulation

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Conclusion