Publications [#134142] of Mark W. Dewhirst

Papers Published

1. P Lin, S Sankar, S Shan, MW Dewhirst, PJ Polverini, TQ Quinn, KG Peters, Inhibition of tumor growth by targeting tumor endothelium using a soluble vascular endothelial growth factor receptor., Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research, UNITED STATES, vol. 9 no. 1 (January, 1998), pp. 49-58, ISSN 1044-9523
   (last updated on 2004/03/30)

   Abstract:
   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.

   Keywords:
   Animals • Cell Division* • Cell Movement • Cells, Cultured • Endothelium, Vascular • Neoplasms, Experimental • Neovascularization, Pathologic • Rats • Receptor Protein-Tyrosine Kinases • Receptors, Growth Factor • Receptors, Vascular Endothelial Growth Factor • Recombinant Proteins • blood supply • pathology* • physiology* • prevention & control