Experimental and computational analyses reveal dynamics of tumor vessel cooption and optimal treatment strategies

Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2662-2671. doi: 10.1073/pnas.1818322116. Epub 2019 Jan 30.

Abstract

Cooption of the host vasculature is a strategy that some cancers use to sustain tumor progression without-or before-angiogenesis or in response to antiangiogenic therapy. Facilitated by certain growth factors, cooption can mediate tumor infiltration and confer resistance to antiangiogenic drugs. Unfortunately, this mode of tumor progression is difficult to target because the underlying mechanisms are not fully understood. Here, we analyzed the dynamics of vessel cooption during tumor progression and in response to antiangiogenic treatment in gliomas and brain metastases. We followed tumor evolution during escape from antiangiogenic treatment as cancer cells coopted, and apparently mechanically compressed, host vessels. To gain deeper understanding, we developed a mathematical model, which incorporated compression of coopted vessels, resulting in hypoxia and formation of new vessels by angiogenesis. Even if antiangiogenic therapy can block such secondary angiogenesis, the tumor can sustain itself by coopting existing vessels. Hence, tumor progression can only be stopped by combination therapies that judiciously block both angiogenesis and cooption. Furthermore, the model suggests that sequential blockade is likely to be more beneficial than simultaneous blockade.

Keywords: Ang2; VEGF; antiangiogenic treatment; glioblastoma; hypoxia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / therapeutic use
  • Angiopoietin-2 / metabolism
  • Animals
  • Brain Neoplasms / blood supply*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Brain Neoplasms / secondary
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Glioblastoma / blood supply*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Mice
  • Microscopy / methods
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / pathology*
  • Neovascularization, Pathologic / prevention & control
  • Oxygen / metabolism
  • Rats
  • Reproducibility of Results
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiogenesis Inhibitors
  • Angiopoietin-2
  • Vascular Endothelial Growth Factor A
  • Oxygen