Motif mimetic of epsin perturbs tumor growth and metastasis
Yunzhou Dong, … , R. Sathish Srinivasan, Hong Chen
Yunzhou Dong, … , R. Sathish Srinivasan, Hong Chen
Published November 16, 2015
Citation Information: J Clin Invest. 2015;125(12):4349-4364. https://doi.org/10.1172/JCI80349.
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Research Article Angiogenesis Cardiology Oncology Therapeutics Vascular biology

Motif mimetic of epsin perturbs tumor growth and metastasis

Abstract

Tumor angiogenesis is critical for cancer progression. In multiple murine models, endothelium-specific epsin deficiency abrogates tumor progression by shifting the balance of VEGFR2 signaling toward uncontrolled tumor angiogenesis, resulting in dysfunctional tumor vasculature. Here, we designed a tumor endothelium–targeting chimeric peptide (UPI) for the purpose of inhibiting endogenous tumor endothelial epsins by competitively binding activated VEGFR2. We determined that the UPI peptide specifically targets tumor endothelial VEGFR2 through an unconventional binding mechanism that is driven by unique residues present only in the epsin ubiquitin–interacting motif (UIM) and the VEGFR2 kinase domain. In murine models of neoangiogenesis, UPI peptide increased VEGF-driven angiogenesis and neovascularization but spared quiescent vascular beds. Further, in tumor-bearing mice, UPI peptide markedly impaired functional tumor angiogenesis, tumor growth, and metastasis, resulting in a notable increase in survival. Coadministration of UPI peptide with cytotoxic chemotherapeutics further sustained tumor inhibition. Equipped with localized tumor endothelium–specific targeting, our UPI peptide provides potential for an effective and alternative cancer therapy.

Authors

Yunzhou Dong, Hao Wu, H.N. Ashiqur Rahman, Yanjun Liu, Satish Pasula, Kandice L. Tessneer, Xiaofeng Cai, Xiaolei Liu, Baojun Chang, John McManus, Scott Hahn, Jiali Dong, Megan L. Brophy, Lili Yu, Kai Song, Robert Silasi-Mansat, Debra Saunders, Charity Njoku, Hoogeun Song, Padmaja Mehta-D’Souza, Rheal Towner, Florea Lupu, Rodger P. McEver, Lijun Xia, Derek Boerboom, R. Sathish Srinivasan, Hong Chen

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Figure 2

UPI mimetic inhibits tumor growth.

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UPI mimetic inhibits tumor growth. (A) Tumor volumes from s.c. LLC tumor...
(A) Tumor volumes from s.c. LLC tumor–bearing mice treated i.v. with UPI peptide (2.5 mg/kg, n = 8; 5 mg/kg, n = 8; and 10 mg/kg, n = 10) every other day. Control peptide was administered i.v. at 10 mg/kg (n = 10). *P < 0.05, **P < 0.05, ***P < 0.01. (B) Tumor volumes from s.c. B16 tumor–bearing mice treated i.v. with 10 mg/kg UPI peptide (n = 10) every other day. Control peptide was administered i.v. at 10 mg/kg (n = 10). *P < 0.05. (C) Tumor volumes from s.c. U87 glioma tumor–bearing immunodeficient SCID mice treated i.v. with 10 mg/kg UPI peptide (n = 10) every other day. Control peptide was administered i.v. at 10 mg/kg (n = 8). (A–C) *P < 0.05, by 2-tailed Student’s t test and by Bonferroni’s multiple comparisons test. (D) Genitourinary tracts were isolated from TRAMP mice treated i.p. with control or UPI peptides (20 mg/kg, every other day starting at week 20) and weighed (n = 15). P < 0.001, by 2-tailed Student’s t test. Right panel is a representative image.