TIMP-3 deficiency in the host, but not in the tumor, enhances tumor growth and angiogenesis.
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.
Cruz-Muñoz
W
W
Department of Laboratory Medicine and Pathobiology, Toronto, Ontario, Canada.
Kim
I
I
Khokha
R
R
D000818:Animals; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020782:Matrix Metalloproteinases / Q000502:physiology; D053504:Matrix Metalloproteinases, Membrane-Associated; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000209:etiology / Q000517:prevention & control*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D013724:Teratoma / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000172:deficiency / Q000502:physiology*
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2