A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Standard

A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment. / El-Sheikh, A; Borgstrom, P; Bhattacharjee, G; Belting, Mattias; Edgington, T S.

I: Cancer Research, Vol. 65, Nr. 23, 2005, s. 11109-11117.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Harvard

APA

CBE

MLA

Vancouver

Author

El-Sheikh, A ; Borgstrom, P ; Bhattacharjee, G ; Belting, Mattias ; Edgington, T S. / A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment. I: Cancer Research. 2005 ; Vol. 65, Nr. 23. s. 11109-11117.

RIS

TY - JOUR

T1 - A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment

AU - El-Sheikh, A

AU - Borgstrom, P

AU - Bhattacharjee, G

AU - Belting, Mattias

AU - Edgington, T S

PY - 2005

Y1 - 2005

N2 - We have previously shown that part of the heparin-binding domain of the vascular endothelial growth factor (VEGF), designated HBDt, localizes very selectively to surfaces of the endothelial cells of U blood vessels. Here, we have coupled the HBDt to the extracellular domain of tissue factor (TFt), to locally initiate the thrombogenic cascade. In tumor-bearing mice, infusion of this HBDt.TFt results in rapid occlusive thrombosis selective only for tumor microvasculature with resultant infarctive destruction of tumors. We now show that infusion of an optimal combination of this HBDt.TFt and its requisite cofactor (factor VIIa) in tumor models results in significant tumor eradication. Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment. The HBDt.TFt was also colocalized with the trimolecular receptor complex in endothelial sprouts from tumor tissues, and its binding inhibited the growth of such sprouts. In vitro, we show that the HBDt structure has its highest affinity for chondroitin 6 sulfate. We show the potential of this HBDt.TFt as a candidate therapeutic and elucidate its target in vivo.

AB - We have previously shown that part of the heparin-binding domain of the vascular endothelial growth factor (VEGF), designated HBDt, localizes very selectively to surfaces of the endothelial cells of U blood vessels. Here, we have coupled the HBDt to the extracellular domain of tissue factor (TFt), to locally initiate the thrombogenic cascade. In tumor-bearing mice, infusion of this HBDt.TFt results in rapid occlusive thrombosis selective only for tumor microvasculature with resultant infarctive destruction of tumors. We now show that infusion of an optimal combination of this HBDt.TFt and its requisite cofactor (factor VIIa) in tumor models results in significant tumor eradication. Binding studies and confocal microscopy indicate that the target for the HBDt.TFt seems to be a trimolecular complex of chondroitin C sulfate proteoglycan, neuropilin-1, and VEGF receptor-2, overexpressed together only in highly angiogenic sites of the tumor microenvironment. The HBDt.TFt was also colocalized with the trimolecular receptor complex in endothelial sprouts from tumor tissues, and its binding inhibited the growth of such sprouts. In vitro, we show that the HBDt structure has its highest affinity for chondroitin 6 sulfate. We show the potential of this HBDt.TFt as a candidate therapeutic and elucidate its target in vivo.

U2 - 10.1158/0008-5472.CAN-05-2733

DO - 10.1158/0008-5472.CAN-05-2733

M3 - Article

VL - 65

SP - 11109

EP - 11117

JO - Cancer research. Supplement

JF - Cancer research. Supplement

SN - 1538-7445

IS - 23

ER -