A selective tumor microvasculature thrombogen that targets a novel receptor complex in the tumor angiogenic microenvironment.
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 i.t 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.
El-Sheikh
Amr
A
Department of Immunology, The Scripps Research Institute, La Jolla, California 92037, USA.
Borgstrom
Per
P
Bhattacharjee
Gourab
G
Belting
Mattias
M
Edgington
Thomas S
TS
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006493:Heparin / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D018874:Spheroids, Cellular; D013917:Thrombin / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D013927:Thrombosis / Q000139:chemically induced
D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D006493:Heparin; D013925:Thromboplastin; D013917:Thrombin; C478632:Thrombogen