title: Modelling tumour cell proliferation from vascular structure using tissue decomposition into avascular elements.
abstract: Computer models allow the mechanistically detailed study of tumour proliferation and its dependency on nutrients. However, the computational study of large vascular tumours requires detailed information on the 3-dimensional vessel network and rather high computation times due to complex geometries. This study puts forward the idea of partitioning vascularised tissue into connected avascular elements that can exchange cells and nutrients between each other. Our method is able to rapidly calculate the evolution of proliferating as well as dead and quiescent cells, and hence a proliferative index, from a given amount and distribution of vascularisation of arbitrary complexity. Applying our model, we found that a heterogeneous vessel distribution provoked a higher proliferative index, suggesting increased malignancy, and increased the amount of dead cells compared to a more static tumour environment when a homogenous vessel distribution was assumed. We subsequently demonstrated that under certain amounts of vascularisation, cell proliferation may even increase when vessel density decreases, followed by a subsequent decrease of proliferation. This effect was due to a trade-off between an increase in compensatory proliferation for replacing dead cells and a decrease of cell population due to lack of oxygen supply in lowly vascularised tumours. Findings were illustrated by an ectopic colorectal cancer mouse xenograft model. Our presented approach can be in the future applied to study the effect of cytostatic, cytotoxic and anti-angiogenic chemotherapy and is ideally suited for translational systems biology, where rapid interaction between theory and experiment is essential.
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; Research Centre Pharmaceutical Engineering (RCPE) GmbH, Inffeldgasse 13, 8010 Graz, Austria.
authors.forename: Maximilian O
authors.initials: MO
authors.lastname: Besenhard
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Monika
authors.initials: M
authors.lastname: Jarzabek
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Alice C
authors.initials: AC
authors.lastname: O'Farrell
authors.affiliation: Department of Biomedical Sciences, Ross University School of Veterinary Medicine, St Kitts, West Indies.
authors.forename: John J
authors.initials: JJ
authors.lastname: Callanan
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Jochen Hm
authors.initials: JH
authors.lastname: Prehn
authors.affiliation: Centre for Systems Medicine and Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin 2, Ireland; UCD School of Biomolecular & Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland. Electronic address: annettebyrne@rcsi.ie.
authors.forename: Annette T
authors.initials: AT
authors.lastname: Byrne
authors.affiliation: Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, Box 911, 3000 Leuven, Belgium. Electronic address: Heinrich.huber@kuleuven.be.
authors.forename: Heinrich J
authors.initials: HJ
authors.lastname: Huber
mesh_terms: D000818:Animals; D002452:Cell Count; D016923:Cell Death; D049109:Cell Proliferation; D045325:HCT116 Cells; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000473:pathology; D008954:Models, Biological; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology*