Format

Send to

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

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

Author information

1
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus.
2
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.
3
Department of Biomedical Engineering, Bucknell University, Lewisburg, PA 17837.
4
Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, 1678 Nicosia, Cyprus; tstylian@ucy.ac.cy jain@steele.mgh.harvard.edu.
5
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114; tstylian@ucy.ac.cy jain@steele.mgh.harvard.edu.

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

PMID:
30700544
PMCID:
PMC6377457
[Available on 2019-07-30]
DOI:
10.1073/pnas.1818322116

Conflict of interest statement

Conflict of interest statement: R.K.J. received an honorarium from Amgen and consultant fees from Merck, Ophthotech, Pfizer, Sun Pharma Advanced Research Corporation (SPARC), SynDevRx, and XTuit; owns equity in Enlight, Ophthotech, and SynDevRx; and serves on the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund. No funding or reagents from these companies were used in these studies. N.D.K. completed the study more than 5 years ago and neither any reagent nor any funding from Novartis was used at the time.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center