Normalization of Tumor Vessels by Tie2 Activation and Ang2 Inhibition Enhances Drug Delivery and Produces a Favorable Tumor Microenvironment

Abstract

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.

BMP9, but not BMP10, acts as a quiescence factor on tumor growth, vessel normalization and metastasis in a mouse model of breast cancer

“…“Normalization” of the tumor vasculature through the Angiopoietin-Tie2 axis, for example, decreases vessel density, increases vessel coverage and perfusion while decreasing permeability. As a consequence of this vessel normalization, tumor growth is decreased as well as tumor necrosis and metastasis [46]. Our results on E0771 tumor growth, necrosis, metastasis and tumor perfusion are in accordance with this concept.…”

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…Interestingly, metastatic dissemination could be prevented by treatment of the mice with an ANG2-neutralizing antibody 32 . In other mouse tumour models, anti-ANG2 therapy has been shown to prevent metastasis through the inhibition of tumour cell dissemination to tumour-draining lymph nodes and distant tissues 47,48 , and has therapeutic inhibitory effects on the growth of established metastatic lesions 47 . Similarly, inhibition of vascular endothelial protein tyrosine phosphatase (VEPTP; also known as PTPRβ), which sustains endogenous activation of TIE2, also inhibited extravasation of metastatic breast cancer cells into the lungs and subsequent metastatic foci formation, and thus extended survival durations, in animal models of mammary cancer when added to adjuvant doxorubicin chemotherapy 49 .…”

Impaired angiopoietin/Tie2 signaling compromises Schlemm’s canal integrity and induces glaucoma

“…The cultured hDLECs were incubated with siPROX1, siTIE2, or siControl according to the aforementioned protocol, and RNA-seq of the incubated cells was performed as previously described (59). In brief, 2 μg total RNA was isolated and incubated with magnetic beads coated with oligo-dT.…”