title: In silico study of the impact of cancer stem cell dynamics and radiobiological hypoxia on tumour response to hyperfractionated radiotherapy.
abstract: OBJECTIVE
  Advanced head and neck carcinomas (HNCs) are aggressive tumours, mainly due to hypoxia and a cancer stem cell (CSC) subpopulation. The aim of this study was to simulate tumour growth and behaviour during radiotherapy of three HNC groups (governed by different growth kinetics, hypoxia levels and CSC division pattern) to determine correlation between resistance factors and responses to hyperfractionated radiotherapy.
  
  
  METHODS
  An in silico HNC model was developed based on biologically realistic input parameters. During radiotherapy simulation, three parameters were studied: growth kinetics, hypoxia and probability of CSC symmetrical division. Both independent and combined effects on tumour response to hyperfractionated radiotherapy were assessed.
  
  
  RESULTS
  Oxic and very mildly hypoxic HNCs were revealed to be controlled by hyperfractionated radiotherapy, irrespective of growth kinetics and CSC division pattern. Moderately hypoxic tumours had different responses to radiotherapy: while slowly proliferating HNCs were still controllable, tumours with higher cell turnover were more resistant. In rapidly proliferating tumours, the number of fractions needed for tumour control increased exponentially with the probability of CSC symmetrical division, whereas in moderately growing HNC, this behaviour was linear. Severely hypoxic tumours could not be controlled by radiotherapy alone. Tumours with CSCs in a severely hypoxic niche required adjuvant therapies to be eradicated.
  
  
  CONCLUSIONS
  Growth kinetics strongly influence tumour responses to treatment. Slowly growing tumours showed linear dependence between dose and hypoxia/CSC, whereas rapidly growing tumours followed exponential behaviour.
authors.affiliation: Faculty of Science, University of Oradea, Oradea, 410087, Romania.|School of Physical Sciences, The University of Adelaide, Adelaide, South Australia, 5005, Australia.
authors.forename: L G
authors.initials: LG
authors.lastname: Marcu
authors.affiliation: Faculty of Science, University of Oradea, Oradea, 410087, Romania.
authors.forename: D
authors.initials: D
authors.lastname: Marcu
authors.affiliation: Faculty of Science, University of Oradea, Oradea, 410087, Romania.
authors.forename: S M
authors.initials: SM
authors.lastname: Filip
mesh_terms: D049109:Cell Proliferation; D003198:Computer Simulation; D006258:Head and Neck Neoplasms / Q000150:complications / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D000860:Hypoxia / Q000150:complications / Q000473:pathology / Q000532:radiotherapy*; D008954:Models, Biological; D009010:Monte Carlo Method; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000528:radiation effects*