Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.
Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.
Department of Surgery Division of Surgical Oncology, The James Comprehensive Cancer Center (OSUCCC), The Ohio State University College of Medicine, Columbus, OH, 43210, USA. zhiwei.hu@osumc.edu.|Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA. zhiwei.hu@osumc.edu.
Zhiwei
http://orcid.org/0000-0002-0023-1170
Z
Hu
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA.|Department of Genetics, Yale University, New Haven, CT, USA.
Jijun
J
Cheng
Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, 06520, USA.|Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
Jie
J
Xu
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Wolfram
W
Ruf
Department of Obstetrics and Gynecology, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
Charles J
CJ
Lockwood
D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D058990:Molecular Targeted Therapy; D018919:Neovascularization, Physiologic; D010778:Photochemotherapy; D011485:Protein Binding; D013925:Thromboplastin / Q000378:metabolism*
D005167:Factor VII; D013925:Thromboplastin
Angiogenesis; Factor VII-targeted therapy; Tissue factor; VEGF; Vascular endothelial cells