title: Targeting prion-like protein doppel selectively suppresses tumor angiogenesis.
abstract: Controlled and site-specific regulation of growth factor signaling remains a major challenge for current antiangiogenic therapies, as these antiangiogenic agents target normal vasculature as well tumor vasculature. In this article, we identified the prion-like protein doppel as a potential therapeutic target for tumor angiogenesis. We investigated the interactions between doppel and VEGFR2 and evaluated whether blocking the doppel/VEGFR2 axis suppresses the process of angiogenesis. We discovered that tumor endothelial cells (TECs), but not normal ECs, express doppel; tumors from patients and mouse xenografts expressed doppel in their vasculatures. Induced doppel overexpression in ECs enhanced vascularization, whereas doppel constitutively colocalized and complexed with VEGFR2 in TECs. Doppel inhibition depleted VEGFR2 from the cell membrane, subsequently inducing the internalization and degradation of VEGFR2 and thereby attenuating VEGFR2 signaling. We also synthesized an orally active glycosaminoglycan (LHbisD4) that specifically binds with doppel. We determined that LHbisD4 concentrates over the tumor site and that genetic loss of doppel in TECs decreases LHbisD4 binding and targeting both in vitro and in vivo. Moreover, LHbisD4 eliminated VEGFR2 from the cell membrane, prevented VEGF binding in TECs, and suppressed tumor growth. Together, our results demonstrate that blocking doppel can control VEGF signaling in TECs and selectively inhibit tumor angiogenesis.
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.forename: Jeong Uk
authors.initials: JU
authors.lastname: Choi
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.forename: Jooho
authors.initials: J
authors.lastname: Park
authors.forename: Seong Who
authors.initials: SW
authors.lastname: Kim
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.forename: Fakhrul
authors.initials: F
authors.lastname: Ahsan
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011328:Prions / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D009363:Neoplasm Proteins; C501125:PRND protein, human; D011328:Prions; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2