Evaluation of Listeria Monocytogenes Based Vaccines for HER-2/neu in Mouse Transgenic Models of Breast Cancer.

摘要

The potential benefits of antiangiogenic therapy have been dramatically shown in mouse tumor models but have been less striking in human clinical trials. A possible explanation for this disparity in treatment outcomes is that the vasculature of human tumors may be more resistant to antiangiogenic therapies. This may be due, at least in part, to extensive pericyte coverage of vessels in many common human cancers, such as breast cancers, compared to a relative deficiency of pericytes surrounding vessels in commonly studied mouse tumors. We have identified two autochthonous mouse mammary tumor models, MMTV-infected and MMTV-neu mice, with high pericyte coverage of tumor vessels that may better recapitulate human breast cancer. The endothelial-specific receptor tyrosine kinase, Tie2, regulates microvessel pericyte coverage and activates endothelial cell (EC) signal transduction pathways that promote their survival (e.g. the PI3 kinase-AKT signaling pathway). Our previous studies using an inducible decoy receptor of Tie2 (Tie2Ex) to inhibit Tie2 activation in K1735 murine melanoma tumors showed a decrease in activated AKT expression in ECs and increased EC apoptosis. Tie2Ex expressing tumors also had decreased pericyte coverage, suggesting Tie2 inhibition in tumors can destabilize vessels. We have generated transgenic MMTV- infected and MMTV-neu mice that express Tie2Ex to inhibit Tie2 activation in mammary tissues. The presence of Tie2Ex does not appear to affect EC pAKT or pERK expression downstream of Tie2 signaling in mammary glands. We are currently awaiting tumors to develop in these transgenic mice to study the effect of Tie2 inhibition in mammary tumors.