Blood vessel tortuosity selects against evolution of aggressive tumor cells in confined tissue environments: A modeling approach

PLoS Comput Biol. 2017 Jul 17;13(7):e1005635. doi: 10.1371/journal.pcbi.1005635. eCollection 2017 Jul.

Abstract

Cancer is a disease of cellular regulation, often initiated by genetic mutation within cells, and leading to a heterogeneous cell population within tissues. In the competition for nutrients and growth space within the tumors the phenotype of each cell determines its success. Selection in this process is imposed by both the microenvironment (neighboring cells, extracellular matrix, and diffusing substances), and the whole of the organism through for example the blood supply. In this view, the development of tumor cells is in close interaction with their increasingly changing environment: the more cells can change, the more their environment will change. Furthermore, instabilities are also introduced on the organism level: blood supply can be blocked by increased tissue pressure or the tortuosity of the tumor-neovascular vessels. This coupling between cell, microenvironment, and organism results in behavior that is hard to predict. Here we introduce a cell-based computational model to study the effect of blood flow obstruction on the micro-evolution of cells within a cancerous tissue. We demonstrate that stages of tumor development emerge naturally, without the need for sequential mutation of specific genes. Secondly, we show that instabilities in blood supply can impact the overall development of tumors and lead to the extinction of the dominant aggressive phenotype, showing a clear distinction between the fitness at the cell level and survival of the population. This provides new insights into potential side effects of recent tumor vasculature normalization approaches.

MeSH terms

  • Animals
  • Computational Biology
  • Computer Simulation
  • Humans
  • Mice
  • Models, Biological*
  • Mutation
  • Neoplasms / physiopathology*
  • Neovascularization, Pathologic / physiopathology*
  • Tumor Microenvironment / physiology*

Grants and funding

This work was cofinanced by the Netherlands Consortium for Systems Biology (NCSB), which is part of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (NWO). The work is also part of the research programme “Innovational Research Incentives Scheme Vidi Cross-divisional 2010 ALW” with project number 864.10.009, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.