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Mol Cell Ther. 2014 Jun 3;2:17. doi: 10.1186/2052-8426-2-17. eCollection 2014.

Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment.

Author information

1
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 USA.
2
Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Advanced Technology Center, 8717 Grovemont Circle, Bethesda, MD 20892-4605 USA.
3
Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 USA ; Department of Urology and Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210 USA.

Abstract

There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review.

KEYWORDS:

Angiogenesis; Matrix metalloproteinase (MMPs); Tissue inhibitor of metalloproteinase-2 (TIMP-2); Tumor microenvironment (TME)

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