Timp-3 Deficiency in the Host, but Not in the Tumor, Enhances Tumor Growth and Angiogenesis.
From: Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada.
Oncogene
- Publish Date: Jan 2006
- ISSN: 0950-9232
- Volume: 25
- Issue: 4
- Pages: 650-5
- Medium: Print
- Language: English
- Citation (JAMA): Cruz-Muñoz W, Kim I, Khokha R, et al. Timp-3 Deficiency in the Host, but Not in the Tumor, Enhances Tumor Growth and Angiogenesis.. Oncogene Jan 2006;25:650-5
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.
Mesh Headings (Keywords): Animals, Antigens, CD31, Matrix Metalloproteinase 2, Matrix Metalloproteinases, Matrix Metalloproteinases, Membrane-Associated, Melanoma, Experimental, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Neovascularization, Pathologic, Teratoma, Tissue Inhibitor of Metalloproteinase-3
Check for Full Text / PubMed Unique Identifier (PMID): 16186800
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