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Open Access Research article

Developing and applying a gene functional association network for anti-angiogenic kinase inhibitor activity assessment in an angiogenesis co-culture model

Yuefeng Chen1, Tao Wei2, Lei Yan1, Frank Lawrence2, Hui-Rong Qian3, Timothy P Burkholder4, James J Starling1, Jonathan M Yingling1 and Jianyong Shou15*

Author Affiliations

1 Angiogenesis and Tumor Microenvironment Biology, Lilly Research Laboratories, Indianapolis, IN 46285, USA

2 Integrative Biology, Lilly Research Laboratories, Indianapolis, IN 46285, USA

3 Statistics, Lilly Research Laboratories, Indianapolis, IN 46285, USA

4 Discovery Chemistry, Lilly Research Laboratories, Indianapolis, IN 46285, USA

5 Current Address: China Novartis Institutes for BioMedical Research, Shanghai 201203, PR China

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BMC Genomics 2008, 9:264  doi:10.1186/1471-2164-9-264

Published: 2 June 2008

Abstract

Background

Tumor angiogenesis is a highly regulated process involving intercellular communication as well as the interactions of multiple downstream signal transduction pathways. Disrupting one or even a few angiogenesis pathways is often insufficient to achieve sustained therapeutic benefits due to the complexity of angiogenesis. Targeting multiple angiogenic pathways has been increasingly recognized as a viable strategy. However, translation of the polypharmacology of a given compound to its antiangiogenic efficacy remains a major technical challenge. Developing a global functional association network among angiogenesis-related genes is much needed to facilitate holistic understanding of angiogenesis and to aid the development of more effective anti-angiogenesis therapeutics.

Results

We constructed a comprehensive gene functional association network or interactome by transcript profiling an in vitro angiogenesis model, in which human umbilical vein endothelial cells (HUVECs) formed capillary structures when co-cultured with normal human dermal fibroblasts (NHDFs). HUVEC competence and NHDF supportiveness of cord formation were found to be highly cell-passage dependent. An enrichment test of Biological Processes (BP) of differentially expressed genes (DEG) revealed that angiogenesis related BP categories significantly changed with cell passages. Built upon 2012 DEGs identified from two microarray studies, the resulting interactome captured 17226 functional gene associations and displayed characteristics of a scale-free network. The interactome includes the involvement of oncogenes and tumor suppressor genes in angiogenesis. We developed a network walking algorithm to extract connectivity information from the interactome and applied it to simulate the level of network perturbation by three multi-targeted anti-angiogenic kinase inhibitors. Simulated network perturbation correlated with observed anti-angiogenesis activity in a cord formation bioassay.

Conclusion

We established a comprehensive gene functional association network to model in vitro angiogenesis regulation. The present study provided a proof-of-concept pilot of applying network perturbation analysis to drug phenotypic activity assessment.