A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2

Abstract

Tissue inhibitor of metalloproteinases-3 (TIMP3) is one of four members of a family of proteins that were originally classified according to their ability to inhibit matrix metalloproteinases (MMP). TIMP3, which encodes a potent angiogenesis inhibitor, is mutated in Sorsby fundus dystrophy, a macular degenerative disease with submacular choroidal neovascularization. In this study we demonstrate the ability of TIMP3 to inhibit vascular endothelial factor (VEGF)-mediated angiogenesis and identify the potential mechanism by which this occurs: TIMP3 blocks the binding of VEGF to VEGF receptor-2 and inhibits downstream signaling and angiogenesis. This property seems to be independent of its MMP-inhibitory activity, indicating a new function for this molecule.

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

“…The antiangiogenic effect of TIMP3 observed in tumor xenografts suggests a link between frequent increase of angiogenesis and TIMP3 downregulation detected in PTC (Akslen and LiVolsi, 2000;Hu et al, 2006). It has been described that the antiangiogenic effect of TIMP3 is related to its inhibition of VEGFA binding to VEGFR-2, thus attenuating downstream signaling (Qi et al, 2003), and that VEGFR inhibition is responsible for the antitumoral role of TIMP3 in several models (Ahonen et al, 2003;Mahller et al, 2008). Based on the evidence that NIM1 cells produce VEGFA (Melillo et al, 2010), the same mechanism could be responsible for the effects observed in our tumor xenograft model.…”

“…Evidence is emerging that downregulation of TIMP3 expression in tumors can be achieved also through deregulation of microRNAs, as TIMP3 is a target of several microRNAs upregulated in human tumors such as miR21, miR181b, miR221 and 222 (Gabriely et al, 2008;Garofalo et al, 2009;Wang et al, 2010). The tumor-suppressor role of TIMP3 is also documented by a large body of data showing its capability to inhibit growth, invasion and metastasis of several cancers (Anand-Apte et al, 1996;Qi et al, 2003). Treatment of human melanoma, lung, prostate and breast cancer cells and xenografts with recombinant TIMP3 protein reduced cell proliferation, induced caspase-mediated apoptosis, sensitized cells to paclitaxel, and reduced tumor growth and metastasis (Mahller et al, 2008).…”

“…In melanoma cells, TIMP3 is involved in the stabilization of death receptors TNF receptor-1, FAS and TNF-related apoptosis-inducing ligand receptor-1 on the surface of cells, sensitizing them to apoptosis induced by their ligands (Ahonen et al, 2003). Antitumoral effects of TIMP3 are also ascribed to its antiangiogenic properties, based on the ability to block the binding of vascular endothelial growth factor (VEGF) to its receptor (Qi et al, 2003). Reduction of neovascularization was observed in tumor xenografts induced by melanoma, neuroblastoma and malignant peripheral nerve sheath tumor cells in which TIMP3 expression was restored by different approaches (Ahonen et al, 2003;Mahller et al, 2008).…”

Tissue inhibitor of metalloproteinases-3 transfer suppresses malignant behaviors of colorectal cancer cells

“…3 Overexpression of TIMP3 in tumor cell lines blocks cancer cell invasion and metastasis, as well as growth. 4,5 Qi et al 6 demonstrated the ability of TIMP3 to inhibit VEGF-mediated angiogenesis independent of MMP-inhibitor activity. Recently, TIMP3 was found to be a multiple functional molecule in many aspects of physiology and disease development.…”

Reference profiling of the genomic response induced by an antimicrotubule agent, TZT-1027 (Soblidotin), in vitro

“…36 Therefore, TIMP3 is regarded as a potent inhibitor of angiogenesis and tumor growth. 37 Qi et al 38 reported that TIMP3 blocks the binding of VEGF (vascular endothelial growth factor) to the VEGF receptor-2, inhibiting downstream signaling and angiogenesis. TZT-1027 showed antitumor activity in vivo against a hypervascular advanced-stage tumor from a VEGFtransfectant lung cancer cell line, whereas VCR and TXT did not.…”