Targeting prion-like protein doppel selectively suppresses tumor angiogenesis
Taslim A. Al-Hilal, Seung Woo Chung, Jeong Uk Choi, Farzana Alam, Jooho Park, Seong Who Kim, Sang Yoon Kim, Fakhrul Ahsan, In-San Kim, Youngro Byun
Taslim A. Al-Hilal, Seung Woo Chung, Jeong Uk Choi, Farzana Alam, Jooho Park, Seong Who Kim, Sang Yoon Kim, Fakhrul Ahsan, In-San Kim, Youngro Byun
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Research Article Oncology

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

Taslim A. Al-Hilal, Seung Woo Chung, Jeong Uk Choi, Farzana Alam, Jooho Park, Seong Who Kim, Sang Yoon Kim, Fakhrul Ahsan, In-San Kim, Youngro Byun

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Figure 9

LHbisD4 targets doppel-expressing vasculatures with broad tumor specificity.

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LHbisD4 targets doppel-expressing vasculatures with broad tumor specific...
Whole-body distribution (A) and organ accumulation (B) of Cy5.5-labeled LHbisD4 in SCC7 tumor–bearing mice 8 hours after oral administration at a dose of 10 mg/kg (n = 3 mice). See also Supplemental Figure 5, A and B. (C) Localization of LHbisD4 in the SCC7 tumor (n = 3 tumors). LHbisD4 was mainly localized in the doppel-expressing blood vessels of tumor sections. Scale bars: 20 μm. (D) LHbisD4 localization in vivo was assessed by IF staining of various organs following oral administration of Cy5.5-labeled LHbisD4 (10 mg/kg) to SCC7 tumor–bearing mice (n = 3 tumors). LHbisD4 is stained in green, blood vessels in red, and nuclei in blue. Scale bars: 50 μm (tumor sections) and 100 μm (other organs). (E) Amount of LHbisD4 in the plasma and in SCC7 tumor at different time points after oral administration at a dose of 10 mg/kg (n = 4 mice). (F and G) Cy5.5-labeled LHbisD4 distribution in 6 different tumor models of different cancer types (breast, head and neck, colorectal, brain, and lung cancers) in mice 8 hours after oral administration at a dose of 10 mg/kg and (H) total photon counts in the tumors at different time points.