Modeling three-dimensional invasive solid tumor growth in heterogeneous microenvironment under chemotherapy

PLoS One. 2018 Oct 26;13(10):e0206292. doi: 10.1371/journal.pone.0206292. eCollection 2018.

Abstract

A systematic understanding of the evolution and growth dynamics of invasive solid tumors in response to different chemotherapy strategies is crucial for the development of individually optimized oncotherapy. Here, we develop a hybrid three-dimensional (3D) computational model that integrates pharmacokinetic model, continuum diffusion-reaction model and discrete cell automaton model to investigate 3D invasive solid tumor growth in heterogeneous microenvironment under chemotherapy. Specifically, we consider the effects of heterogeneous environment on drug diffusion, tumor growth, invasion and the drug-tumor interaction on individual cell level. We employ the hybrid model to investigate the evolution and growth dynamics of avascular invasive solid tumors under different chemotherapy strategies. Our simulations indicate that constant dosing is generally more effective in suppressing primary tumor growth than periodic dosing, due to the resulting continuous high drug concentration. In highly heterogeneous microenvironment, the malignancy of the tumor is significantly enhanced, leading to inefficiency of chemotherapies. The effects of geometrically-confined microenvironment and non-uniform drug dosing are also investigated. Our computational model, when supplemented with sufficient clinical data, could eventually lead to the development of efficient in silico tools for prognosis and treatment strategy optimization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Proliferation / drug effects
  • Humans
  • Models, Biological*
  • Neoplasm Invasiveness
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Tumor Microenvironment / drug effects*

Substances

  • Antineoplastic Agents

Grants and funding

This work was supported by Grant No. 11474345 and 11674043, and 11604030 issued by the National Natural Science Foundation of China, Grant No. 2013CB837200 issued by the State Key Development Program for Basic Research of China, and the Start-Up fund issued by Arizona State University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.