MMP-3 and MMP-9 Gene Transfer Decrease Growth and Angiogenesis in Breast Cancer Xenografts In Vivo.

Abstract

Abstract Matrix metalloproteinases (MMPs) are largely implicated in tumor angiogenesis and metastasis due to their extracellular matrix (ECM) degrading capacities. Although MMP activity generally is discussed in terms of facilitating tumor invasion, MMP inhibition in clinical trials has failed. Moreover, increasing amounts of data show that MMPs may inhibit tumor progression by generation of potent anti-angiogenic factors such as endostatin from the tumoral stroma. We have previously shown that intratumoral gene transfer of MMP-9 induced tumor regression and reduced angiogenesis of breast cancer in vivo. If MMP activity induces tumor progression or regression may depend on type of MMP or expression levels of MMP in the tumor tissue. In this study we treated established breast cancers in nude mice with adenovirus vectors carrying the human genes of MMP-3 or MMP-9 in a dose response manner. Microdialysis was used to sample endostatin in situ and tumor growth was monitored for 35 days. Tumors in mice treated with low-dose of either MMP-3 or MMP-9 vectors exhibited tumor stasis throughout the experiment whereas high-dose gene transfer of either MMP-3 or MMP-9 induced significant tumor regression compared to controls treated with empty adenovirus vectors. The extracellular in vivo levels of endostatin were significantly increased in tumors treated with adenovirus carrying the MMP genes compared to controls. Tumors treated with high-dose MMP vectors also exhibited decreased microvessel area. Our results propose that increased expression of MMP-3 and MMP-9 have therapeutic effects of established breast cancer in a dose dependent manner where a slight increase of MMP expression results in tumor stasis and a high expression of either MMP-3 or MMP-9 by gene transfer results in a potent tumor regression. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4164.