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  • Original Paper
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Decorin suppresses tumor cell-mediated angiogenesis

Oncogene volume 21, pages 4765–4777 (2002)Cite this article

Abstract

The progressive growth of most neoplasms is dependent upon the establishment of new blood vessels, a process regulated by tumor-secreted factors and matrix proteins. We examined the in vitro and in vivo angiogenic ability of conditioned media obtained from fibrosarcoma, carcinoma, and osteosarcoma cells and their decorin-transfected counterparts. Human endothelial cells were investigated in vitro by evaluating three essential steps of angiogenesis: migration, attachment, and differentiation. On the whole, wild-type tumor cell-secretions enhanced endothelial cell attachment, migration, and differentiation, whereas their decorin-expressing forms inhibited these processes. Similarly, decorin-containing media suppressed endothelial cell sprouting in an ex vivo aortic ring assay. Since angiogenesis is an important component of tumor expansion, the growth rate of these cells as tumor xenografts was examined by implantation in nude mice. In vivo, the decorin-expressing tumor xenografts grew at markedly lower rates and showed a significant suppression of neovascularization. Immunohistochemical, Northern and Western blot analyses indicated that the decorin-expressing cells produced vascular endothelial growth factor (VEGF) at markedly reduced rates vis-á-vis their wild-type counterparts. Specificity of this process was confirmed by experiments where addition of recombinant decorin to the wild-type tumor cells caused 80–95% suppression of VEGF mRNA and protein. These results provide a novel mechanism of action for decorin, and indicate that decorin could adversely affect in vivo tumor growth by suppressing the endogenous tumor cell production of a powerful angiogenic stimulus.

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Abbreviations

VEGF:

vascular endothelial growth factors

FGF2:

fibroblast growth factor 2 also known as basic FGF

EGFR:

epidermal growth factor receptor

HUVEC:

human umbilical vein endothelial cells

SFM:

serum-free medium

SDS–PAGE:

Na dodecylsulfate polyacrylamide gel electrophoresis

DPBS:

Dulbecco's phosphate buffered saline

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Acknowledgements

We thank J Pope for help with the quantization of the vessels in the mouse tumors, and J Caro, L Fisher and D Mann for providing valuable reagents. This work was supported by grants from the Landenberger Research Foundation and Merck Pharmaceuticals, Rahway N.J. (DS Grant) and from the National Institutes of Health grants RO1 CA39481 and RO1 CA47282, and grants from the Department of the Army, DAMD17-00-1-0663 and DAMD17-00-1-0425 (RV Iozzo), and from the Turkish Scientific Technical and Research Council (TÜBITAK) (C Yenisey).

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Authors and Affiliations

  1. Department of Medicine, Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Room 812 Curtis Building, 1015 Walnut Street, Philadelphia, 19107, Pennsylvania, PA, USA

    Derrick S Grant, Cigdem Yenisey, R Wesley Rose & Mason Tootell

  2. Department of Pathology, Anatomy and Cell Biology, and the Kimmel Cancer Center, Thomas Jefferson University, Room 249 Jefferson Alumni Hall, 1020 Locust Street, Philadelphia, 19107, Pennsylvania, PA, USA

    Manoranjan Santra & Renato V Iozzo

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  1. Derrick S Grant
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Correspondence to Renato V Iozzo.

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Grant, D., Yenisey, C., Rose, R. et al. Decorin suppresses tumor cell-mediated angiogenesis. Oncogene 21, 4765–4777 (2002). https://doi.org/10.1038/sj.onc.1205595

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