A Validated Multiscale In-Silico Model for Mechano-sensitive Tumour Angiogenesis and Growth

PLoS Comput Biol. 2017 Jan 26;13(1):e1005259. doi: 10.1371/journal.pcbi.1005259. eCollection 2017 Jan.

Abstract

Vascularisation is a key feature of cancer growth, invasion and metastasis. To better understand the governing biophysical processes and their relative importance, it is instructive to develop physiologically representative mathematical models with which to compare to experimental data. Previous studies have successfully applied this approach to test the effect of various biochemical factors on tumour growth and angiogenesis. However, these models do not account for the experimentally observed dependency of angiogenic network evolution on growth-induced solid stresses. This work introduces two novel features: the effects of hapto- and mechanotaxis on vessel sprouting, and mechano-sensitive dynamic vascular remodelling. The proposed three-dimensional, multiscale, in-silico model of dynamically coupled angiogenic tumour growth is specified to in-vivo and in-vitro data, chosen, where possible, to provide a physiologically consistent description. The model is then validated against in-vivo data from murine mammary carcinomas, with particular focus placed on identifying the influence of mechanical factors. Crucially, we find that it is necessary to include hapto- and mechanotaxis to recapitulate observed time-varying spatial distributions of angiogenic vasculature.

Publication types

  • Evaluation Study
  • Validation Study

MeSH terms

  • Animals
  • Blood Flow Velocity*
  • Blood Pressure
  • Cell Proliferation*
  • Computer Simulation
  • Humans
  • Mechanotransduction, Cellular*
  • Models, Biological*
  • Neoplasms / pathology
  • Neoplasms / physiopathology*
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / physiopathology*
  • Shear Strength
  • Stress, Mechanical
  • Tumor Microenvironment / physiology

Grants and funding

VV is supported by a Marie Curie Intra-European Fellowship grant (FP7-PEOPLE-2013-IEF, 627025). PAW and DJH were supported by a European FP7 project (FP7-ICT-2011-9, 601040) and an Engineering & Physical Sciences Research Council-UK grant (EPSRC, EP/K020439/1). TS is supported by a European Research Council Starting Grant (336839-ReEngineeringCancer). RS and ML received no specific funding for this work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.