Cancer Cell
Volume 30, Issue 6, 12 December 2016, Pages 953-967
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Article
Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment

https://doi.org/10.1016/j.ccell.2016.10.018Get rights and content
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Highlights

  • ABTAA-induced Tie2 activation and Ang2 inhibition normalize tumor vasculature

  • Tumor vessel normalization leads to enhanced blood perfusion and drug delivery

  • Tumor vessel normalization lessens hypoxia, acidosis, tumor growth, and metastasis

  • Tie2 activation favorably alters the tumor microenvironment and immune infiltration

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

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