Targeting Tie2 to Increase Breast Cancer Responsiveness to Antiangiogenic Therapy
Abstract
Antiangiogenic therapy of cancers targets tumor blood vessels to deprive malignant cells of oxygen and nutrients. Therapy of human cancers has produced poorer results than therapy of mouse tumors, a disparity that may be explained by more extensive coverage of human tumor vessels (e.g. in breast cancers) by pericytes, which may be rendering vessels more therapy-resistant. Mouse mammary tumor virus (MMTV)- induced mammary carcinomas reproduce the extensive pericyte coverage of tumor vessels seen in human breast cancers and are relatively refractory to antiangiogenic therapy compared to other mouse tumors. This project attempts to decrease pericyte coverage of vessels in these and other tumors by manipulating activity of endothelial cell (EC) Tie2 receptors and improve tumor response to antiangiogenic therapy. We created K1735 tumors and transgenic mice that inducibly express Tie2Ex, an inhibitor of EC Tie2 activation, under doxycycline regulation. Dox-induced Tie2Ex expression in K1735 tumors reduces tumor vessel phospho-AKT and pericyte coverage and causes tumor EC death, vessel regression and tumor stasis. Using Tie2Ex to treat tumors in combination with an antiangiogenic agent, sorafenib, that reduces tumor vessel phospho-ERK expression displayed synergistic effectiveness. We created double transgenic mice that express Tie2Ex in mammary tissue under Dox regulation and are awaiting development of mammary carcinomas in these mice to study the effect of Tie2 inhibition in mammary tumors. We obtained a no-cost extension to finish this project.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 2007
- Accession Number
- ADA475122
Entities
People
- William Lee
Organizations
- University of Pennsylvania