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Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor.

Publication ,  Journal Article
Lin, P; Sankar, S; Shan, S; Dewhirst, MW; Polverini, PJ; Quinn, TQ; Peters, KG
Published in: Cell Growth Differ
January 1998

Vascular endothelial growth factor (VEGF) is a leading candidate for an endogenous mediator of tumor angiogenesis. Recently, two endothelial cell surface receptors, flk-1 and flt-1, have been shown to mediate the angiogenic activities of VEGF. In this study, we have evaluated whether a soluble VEGF receptor could suppress tumor angiogenesis and thereby inhibit tumor growth. A soluble VEGF receptor was constructed by fusing the entire extracellular domain of murine flk-1 to a six-histidine tag at the COOH terminus (ExFlk.6His). In vitro, recombinant ExFlk.6His protein bound VEGF with high affinity (Kd, 16 nM) and blocked receptor activation in a dose-dependent manner and inhibited VEGF-induced endothelial cell proliferation and migration. ExFlk.6His bound to endothelial cells only in the presence of VEGF, and cell surface cross-linking yielded a high molecular weight complex consistent with the VEGF-mediated formation of a heterodimer between ExFlk.6His and the endogenous VEGF receptor. In vivo, ExFlk.6His potently inhibited corneal neovascularization induced by conditioned media from a rat mammary carcinoma cell line (R3230AC). Moreover, when ExFlk.6His protein was administered into a cutaneous tumor window chamber concomitantly with R3230AC carcinoma transplants, tumor growth was inhibited by 75% (P < 0.005) and vascular density was reduced by 50% (P < 0.002) compared with control-treated tumors. These results demonstrate the potential of ExFlk.6His to inhibit VEGF action by a potent "dominant-negative" mechanism and suggest that targeting VEGF action using a soluble receptor may be an effective antiangiogenic therapy for cancer and other "angiogenic" diseases.

Duke Scholars

Published In

Cell Growth Differ

ISSN

1044-9523

Publication Date

January 1998

Volume

9

Issue

1

Start / End Page

49 / 58

Location

United States

Related Subject Headings

  • Recombinant Proteins
  • Receptors, Vascular Endothelial Growth Factor
  • Receptors, Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Rats
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Neoplasms, Experimental
  • Endothelium, Vascular
  • Developmental Biology
 

Citation

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MLA
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Lin, P., Sankar, S., Shan, S., Dewhirst, M. W., Polverini, P. J., Quinn, T. Q., & Peters, K. G. (1998). Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ, 9(1), 49–58.
Lin, P., S. Sankar, S. Shan, M. W. Dewhirst, P. J. Polverini, T. Q. Quinn, and K. G. Peters. “Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor.Cell Growth Differ 9, no. 1 (January 1998): 49–58.
Lin P, Sankar S, Shan S, Dewhirst MW, Polverini PJ, Quinn TQ, et al. Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ. 1998 Jan;9(1):49–58.
Lin, P., et al. “Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor.Cell Growth Differ, vol. 9, no. 1, Jan. 1998, pp. 49–58.
Lin P, Sankar S, Shan S, Dewhirst MW, Polverini PJ, Quinn TQ, Peters KG. Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor. Cell Growth Differ. 1998 Jan;9(1):49–58.

Published In

Cell Growth Differ

ISSN

1044-9523

Publication Date

January 1998

Volume

9

Issue

1

Start / End Page

49 / 58

Location

United States

Related Subject Headings

  • Recombinant Proteins
  • Receptors, Vascular Endothelial Growth Factor
  • Receptors, Growth Factor
  • Receptor Protein-Tyrosine Kinases
  • Rats
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Neoplasms, Experimental
  • Endothelium, Vascular
  • Developmental Biology