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TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis

Oncogene volume 25, pages 650–655 (2006)Cite this article

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.

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Acknowledgements

We thank Marco Di Grappa, David Smookler and Katrina Watson for their technical assistance. This research is supported by funding from the Canadian Institutes of Health Research to RK.

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Authors and Affiliations

  1. Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada

    W Cruz-Muñoz & R Khokha

  2. Department of Medical Biophysics, Ontario Cancer Institute, University of Toronto, Toronto, Ontario, Canada

    I Kim & R Khokha

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  1. W Cruz-Muñoz
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  2. I Kim
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Correspondence to R Khokha.

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Cruz-Muñoz, W., Kim, I. & Khokha, R. TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis. Oncogene 25, 650–655 (2006). https://doi.org/10.1038/sj.onc.1209104

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