Modeling the VEGF-Bcl-2-CXCL8 pathway in intratumoral agiogenesis

Harsh V. Jain, Jacques E. Nör, Trachette L. Jackson

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Recent experiments show that vascular endothelial growth factor (VEGF) is the crucial mediator of downstream events that ultimately lead to enhanced endothelial cell survival and increased vascular density within many tumors. The newly discovered pathway involves up-regulation of the anti-apoptotic protein Bcl-2, which in turn leads to increased production of interleukin-8 (CXCL8). The VEGF-Bcl-2-CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies including short interfering RNA (siRNA) that silence the CXCL8 gene and small molecule inhibitors of Bcl-2. In this paper, we present and validate a mathematical model designed to predict the effect of the therapeutic blockage of VEGF, CXCL8, and Bcl-2 at different stages of tumor progression. In agreement with experimental observations, the model predicts that curtailing the production of CXCL8 early in development can result in a delay in tumor growth and vascular development; however, it has little effect when applied at late stages of tumor progression. Numerical simulations also show that blocking Bcl-2 up-regulation, either at early stages or after the tumor has fully developed, ensures that both microvascular and tumor cell density stabilize at low values representing growth control. These results provide insight into those aspects of the VEGF-Bcl-2-CXCL8 pathway, which independently and in combination, are crucial mediators of tumor growth and vascular development. Continued quantitative modeling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines to alter tumor progression.

Original languageEnglish (US)
Pages (from-to)89-117
Number of pages29
JournalBulletin of mathematical biology
Volume70
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

Bibliographical note

Funding Information:
The authors thank the National Institute of Health Grant R01DE15948, which supported the experiments on which the paper is based. This research was supported by the Alfred P.

Keywords

  • Angiogenesis
  • Anti-angiogenic therapy
  • Bcl-2
  • CXCL8
  • Mathematical model

Fingerprint

Dive into the research topics of 'Modeling the VEGF-Bcl-2-CXCL8 pathway in intratumoral agiogenesis'. Together they form a unique fingerprint.

Cite this