Multiscale modeling of tumor growth and angiogenesis: Evaluation of tumor-targeted therapy

PLoS Comput Biol. 2021 Jun 23;17(6):e1009081. doi: 10.1371/journal.pcbi.1009081. eCollection 2021 Jun.

Abstract

The dynamics of tumor growth and associated events cover multiple time and spatial scales, generally including extracellular, cellular and intracellular modifications. The main goal of this study is to model the biological and physical behavior of tumor evolution in presence of normal healthy tissue, considering a variety of events involved in the process. These include hyper and hypoactivation of signaling pathways during tumor growth, vessels' growth, intratumoral vascularization and competition of cancer cells with healthy host tissue. The work addresses two distinctive phases in tumor development-the avascular and vascular phases-and in each stage two cases are considered-with and without normal healthy cells. The tumor growth rate increases considerably as closed vessel loops (anastomoses) form around the tumor cells resulting from tumor induced vascularization. When taking into account the host tissue around the tumor, the results show that competition between normal cells and cancer cells leads to the formation of a hypoxic tumor core within a relatively short period of time. Moreover, a dense intratumoral vascular network is formed throughout the entire lesion as a sign of a high malignancy grade, which is consistent with reported experimental data for several types of solid carcinomas. In comparison with other mathematical models of tumor development, in this work we introduce a multiscale simulation that models the cellular interactions and cell behavior as a consequence of the activation of oncogenes and deactivation of gene signaling pathways within each cell. Simulating a therapy that blocks relevant signaling pathways results in the prevention of further tumor growth and leads to an expressive decrease in its size (82% in the simulation).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Animals
  • Cell Proliferation / physiology
  • Computational Biology
  • Computer Simulation
  • Humans
  • Models, Biological*
  • Molecular Targeted Therapy
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • Neoplasms / blood supply*
  • Neoplasms / pathology*
  • Neoplasms / therapy
  • Neovascularization, Pathologic
  • Signal Transduction / physiology
  • Systems Analysis
  • Tumor Hypoxia / physiology
  • Vascular Endothelial Growth Factor A / physiology

Substances

  • Vascular Endothelial Growth Factor A

Grants and funding

The present research work was financially supported by national funds from FCT – Fundação para a Ciência e a Tecnologia, Instituto Publico, through projects UIDB/04564/2020 and UIDP/04564/2020 (to JC, RT and SJN) and under the project MATIS (CENTRO-01-0145-FEDER-000014) - Process 673289 (to SJN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.