Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model

Spurbeck, William W.; Ng, Catherine Y.; Strom, Ted S.; Vanin, Elio F.; Davidoff, Andrew M.

doi:10.1182/blood.v100.9.3361

Cited by 95 publications

(85 citation statements)

References 44 publications

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“…Different effects of TIMP3 restoration on tumor cell growth have been reported. No effect on in vitro proliferation of murine neuroblastoma and melanoma cells was observed (Spurbeck et al, 2002); on the contrary, in human melanoma, neuroblastoma and malignant peripheral nerve sheath tumor, TIMP3 was reported to induce apoptosis (Ahonen et al, 2003;Mahller et al, 2008). The lack of effect of TIMP3 on the growth rate of NIM1 cells might be related to their thyroid origin and/or to the advanced tumor stage they represent, being derived from a PTC metastasis.…”

Section: Discussionmentioning

confidence: 91%

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

et al. 2011

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Papillary thyroid carcinoma (PTC) arises from the thyroid follicular epithelium and represents the most frequent thyroid malignancy. PTC is associated with gene rearrangements generating RET/PTC and TRK oncogenes, and to the BRAFV600E activating point mutation. A role of tumor-suppressor genes in the pathogenesis of PTC has not been assessed yet. The tissue inhibitor of metalloproteinase-3 (TIMP3) gene, encoding a metalloproteinases inhibitor and capable of inhibiting growth, angiogenesis, invasion and metastasis of several cancers, was found to be silenced by promoter methylation in a consistent fraction of PTCs, in association with tumor aggressiveness and BRAFV600E mutation, thus suggesting an oncosuppressor role. To explore this possibility, in this study we performed gene expression and functional studies. Analysis of gene expression data produced in our laboratory as well as meta-analysis of publicly available data sets confirmed the downregulation of TIMP3 gene expression in PTC with respect to normal thyroid. The functional consequences of TIMP3 downregulation were investigated in the PTC-derived NIM1 cell line, in which the expression of TIMP3 is silenced. Restoration of TIMP3 expression by exposure to soluble TIMP3 protein or by complementary DNA transfection had no effect on the growth rate of NIM1 cells. Instead, it affected the adhesive, migratory and invasive capabilities of NIM1 cells by modulating several proteins involved in these processes. A striking effect was observed in vivo, as TIMP3 reduced the tumorigenicity of NIM1 cells by repressing angiogenesis and macrophage infiltration. Our data indicate that the loss of TIMP3 expression exerts a functional role in the pathogenesis of PTC.

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Section: Discussionmentioning

confidence: 91%

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

et al. 2011

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“…However, TIMPs are multifunctional proteins that in addition to their MMPinhibitory effect also demonstrate distinct tumour-stimulatory functions (Jiang et al, 2002). Experimental studies have shown that TIMP-3 may show activity to inhibit angiogenesis and induce apoptosis (Ahonen et al, 1998;Spurbeck et al, 2002). It has also been published that high TIMP-3 mRNA levels are associated with a good prognosis in breast cancer (Kotzsch et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Study of matrix metalloproteinases and their inhibitors in breast cancer

et al. 2007

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An immunohistochemical study was performed using tissue microarrays and specific antibodies against matrix metalloproteinases (MMPs) 1, 2, 7, 9, 11, 13, 14, and their tisullar inhibitors (TIMPs) 1, 2, and 3. More than 2600 determinations on cancer specimens from 131 patients with primary ductal invasive tumours of the breast (65 with and 66 without distant metastasis) and controls were performed. Staining results were categorised using a score based on the intensity of the staining and a specific software program calculated the percentage of immunostained cells automatically. We observed a broad variation of the total immunostaining scores and the cell type expressing each protein. There were multiple and significant associations between the expression of the different MMPs and TIMPs evaluated and some parameters indicative of tumour aggressiveness, such as large tumour size, advanced tumour grade, high Nottinham prognostic index, negative oestrogen receptor status, peritumoural inflammation, desmoplastic reaction, and infiltrating tumoural edge. Likewise, the detection of elevated immunohistochemical scores for MMP-9, 11, TIMP-1, and TIMP-2, was significantly associated with a higher rate of distant metastases. The expression of MMP-9 or TIMP-2 by tumour cells, MMP-1, 7, 9, 11, 13, or TIMP-3 by fibroblastic cells, and MMP-7, 9, 11, 13, 14, TIMP-1, or TIMP-2 by mononuclear inflammatory cells, was also significantly associated with a higher rate of distant metastases.

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“…Retrovirus-mediated expression of TIMP-3 in tumor cells inhib- 145 MMP-2 Various IFN-a 147 EC proliferation/migration Angiostatin 148,149 Various Endostatin 117,150 MT1-MMP, MMP-2 Various Arresten 151 EC proliferation, migration Canstatin 152 EC viability, migration Tumstatin 153,154 EC viability, migration, protein synthesis Platelet factor 4 155 VEGF and bFGF signaling TIMP-1 156 Broad-range Various effects, including MMP inhibition TIMP-2 157 Broad-range Various effects, including MMP inhibition TIMP-3 138 Broad-range Various effects, including MMP inhibition TIMP-4 136 Broad-range Various effects, including MMP inhibition Exogenous/synthetic TNP-470 158 EC proliferation Squalamine 159 EC proliferation Captopril 160 MMP-2, MMP-9 EC migration Combretastatin-A4 161 EC tubulin CP-547, 632 162 VEGFR-2 and bFGF kinases Vitaxin 163 a v b 3 integrin, EC apoptosis EMD121974 164 a v b 3 and a v b 5 integrin COL-3 83 MMP-2, -9, -14 MMPs Neovastat 165,166 MMP-2, -9, -12 MMPs, designed to avoid sheddases BMS-275291 54 MMP-1, -2, -3, -7, -9, -14 Bevacizumab 167 VEGF ited tumor growth and angiogenesis in vivo. Tumors overexpressing TIMP-3 failed to form a functional vasculature and had reduced pericyte recruitment.…”

Section: Timps As Potential Antiangiogenic Agentsmentioning

confidence: 99%

“…Tumors overexpressing TIMP-3 failed to form a functional vasculature and had reduced pericyte recruitment. 138 Intratumoral adenoviral delivery of TIMP-3 (AdTIMP-3) has been shown to inhibit growth of preestablished tumors and also angiogenesis associated with these tumors, even though only a small percentage of tumor cells expressed TIMP-3 after adenoviral administration. This suggests that TIMP-3 expressed by the AdTIMP-3 tumor cells was having a bystander effect on the untransduced tumor cells, illustrating that in the case of gene transfer systems, secreted proteins such as the TIMPs are advantageous as antiangiogenesis/anticancer agents.…”

Section: Timps As Potential Antiangiogenic Agentsmentioning

confidence: 99%

Metalloproteinases and their inhibitors in tumor angiogenesis

Handsley

Edwards

2005

Intl Journal of Cancer

264

211

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Angiogenesis is the process by which new blood vessels are formed from preexisting vasculature. It is an essential feature of the female reproductive cycle, embryonic development and wound repair. Angiogenesis has also been identified as a causal or contributing factor in several pathologies, including cancer, where it is a rate-limiting step during tumor progression. Matrix metalloproteinases (MMPs) are a family of soluble and membrane-anchored proteolytic enzymes that can degrade components of the extracellular matrix (ECM) as well as a growing number of modulators of cell function. Several of the MMPs, in particular the gelatinases and membrane-type 1 MMP (MT1-MMP), have been linked to angiogenesis. Potential roles for these proteases during the angiogenic process include degradation of the basement membrane and perivascular ECM components, unmasking of cryptic biologically relevant sites in ECM components, modulation of angiogenic factors and production of endogenous angiogenic inhibitors. This review brings together what is currently known about the functions of the MMPs and the closely related ADAM (a disintegrin and metalloproteinase domain) and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families in angiogenesis and considers how this information might be useful in manipulation of the angiogenic process, with a view to constraining tumor progression. ' 2005 Wiley-Liss, Inc.Key words: metalloproteinase; tumor; angiogenesis; tissue inhibitor of metalloproteinases; protease; extracellular matrix Angiogenesis is an essential feature of several physiologic processes such as the developmental growth of organs, wound healing and the female reproductive cycle. 1 It is also particularly significant in cancer progression, being a crucial step in the transition of a tumor from a hyperplastic but contained in situ state to a malignant phenotype. 2,3 To allow its growth beyond a certain critical size, a solid avascular tumor must develop its own blood supply in order to meet its growing metabolic requirements. 1 Vascularization of a tumor also provides a route for dissemination of the tumor cells to different sites around the body.Although angiogenesis appears to be the primary form of tumor vascularization, the malignant cells of a tumor can gain access to a blood supply through other means, such as via tumor-induced vasculogenesis, in which bone marrow-derived precursor endothelial cells contribute to the formation of tumor vessels. 4,5 Vasculogenic mimicry is another form of vessel formation that has been reported in certain tumor types, such as aggressive human uveal melanomas, prostate and breast tumors. [6][7][8] In these cases, networks of tumor cell-lined vascular channels were identified within the tumors. Finally, vessel co-option, implemented by tumor cells as a temporary means of gaining access to a blood supply, involves the tumor cells growing around and thus co-opting existing host vessels to form an initially well-vascularized tumor. 9 This review will highlight new insigh...

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Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model

Cited by 95 publications

References 44 publications

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

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

Study of matrix metalloproteinases and their inhibitors in breast cancer

Metalloproteinases and their inhibitors in tumor angiogenesis

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