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KAIST, 유전자동의보감사업단(재)

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Cancer Cell, Volume 30, Issue 6, p953-967 | DOI: http://dx.doi.org/10.1016/j.ccell.2016.10.018 Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment

Abstract

Jin-Sung Park,^1,2,10 Il-Kug Kim,^1,10 Sangyeul Han,^2,3,10 Intae Park,^1,2 Chan Kim,¹ Jeomil Bae,² Seung Ja Oh,³ Seungjoo Lee,⁴ Jeong Hoon Kim,⁴ Dong-Cheol Woo,⁵ Yulong He,⁶ Hellmut G. Augustin,⁷ Injune Kim,¹ Doheon Lee,^8,9,* and Gou Young Koh^1,2,11,*

¹Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Republic of Korea
²Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34141, Republic of Korea
³Samsung Advanced Institute of Technology, Suwon 16678, Republic of Korea
⁴Department of Neurosurgery
⁵Asan Institute for Life Sciences
Asan Medical Center, Seoul 05505, Republic of Korea
⁶Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China
⁷Division of Vascular Oncology and Metastasis, German Cancer Research Center Heidelberg (DKFZ-ZMBH Alliance), 69121 Heidelberg, Germany
⁸Department of Bio and Brain Engineering, KAIST, Daejeon 34141, Republic of Korea
⁹Bio-Synergy Research Center, Daejeon 34141, Republic of Korea
¹⁰Co-first author
¹¹Lead Contact

^*Correspondence: Doheon Lee, Gou Young Koh

Summary
A destabilized tumor vasculature leads to limited drug delivery, hypoxia, detrimental tumor microenvironment, and even metastasis. We performed a side-by-side comparison of ABTAA (Ang2-Binding and Tie2-Activating Antibody) and ABA (Ang2-Blocking Antibody) in mice with orthotopically implanted glioma, with subcutaneously implanted Lewis lung carcinoma, and with spontaneous mammary cancer. We found that Tie2 activation induced tumor vascular normalization, leading to enhanced blood perfusion and chemotherapeutic drug delivery, markedly lessened lactate acidosis, and reduced tumor growth and metastasis. Moreover, ABTAA favorably altered the immune cell profile within tumors. Together, our findings establish that simultaneous Tie2 activation and Ang2 inhibition form a powerful therapeutic strategy to elicit a favorable tumor microenvironment and enhanced delivery of a chemotherapeutic agent into tumors.

Keywords : tumor vasculature, Tie2 activation, tumor vessel normalization, tumor microenvironment, enhanced drug delivery, M2-like TAM, angiopoietin-2

논문정보

형식Research article
게재일2016년 12월 (BRIC 등록일 2016-12-16)
연구진국내(교신)+국외 연구진
분야 의약학 > 재생의학
피인용횟수60회 이상 인용된 논문 (상위피인용논문 등록일 2020-03-10)

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