1. ¹Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada
2. ²Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada

Correspondence: Dr R Khokha, Department of Laboratory Medicine and Pathobiology, 610 University Avenue, Toronto, Ontario, Canada M5G 2M9. E-mail: rkhokha@uhnres.utoronto.ca

Received 13 June 2005; Revised 26 July 2005; Accepted 26 July 2005; Published online 26 September 2005.

Abstract

Tumor cells, stromal cell compartment and the extracellular matrix (ECM) together generate a multifaceted tumor microenvironment. Matrix metalloproteinases and their tissue inhibitors (TIMPs) provide a means for tumor–stromal interaction during tumorigenesis. Among TIMPs, TIMP-3 is uniquely localized to the ECM and is frequently silenced in human cancers. Here, we asked whether the absence of TIMP-3 in the tumor cell or the host affects the process of tumorigenesis. Timp-3^-/- ES-cell clones were generated and used to develop teratomas in nude mice. Timp-3^-/- teratomas showed similar tumor take, growth, and angiogenesis compared to timp-3^+/+ teratomas. To study the effect of TIMP-3 ablation in the host stroma, we measured the growth kinetics of subcutaneous B16F10 melanomas in timp-3^-/- and wild-type littermates. Tumors grew significantly faster in timp-3^-/- than in wild-type mice and their CD31 content was significantly higher indicating increased angiogenesis. Augmented angiogenesis in timp-3^-/- mice was directly tested using Matrigel plug and Gelfoam assays. In response to FGF-2, timp-3^-/- endothelial cells invaded more efficiently, leading to enhanced formation of functional blood vessels. Thus, TIMP-3 deficiency in the host, but not in the tumor per se, leads to enhanced tumor growth and angiogenesis. TIMP-3 located within the tumor microenvironment inhibits tumorigenesis.