TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis

Valente, Piera; Fassina, Gianfranco; Melchiori, A; Masiello, Luciana; Cilli, Michele; Vacca, Angelo; Onisto, Maurizio; Santi, Leonardo; Stetler-Stevenson, William G.; Albini, Adriana

doi:10.1002/(sici)1097-0215(19980119)75:2<246::aid-ijc13>3.0.co;2-b

Cited by 248 publications

(187 citation statements)

References 27 publications

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“…Previous studies by our group (Mohanam et al, 1995) and others (DeClerck et al, 1992;Imren et al, 1996;Valente et al, 1998) have established that TIMP expression is downregulated with increasing malignancy and that this downregulation is associated with an imbalance between the production of MMPs and TIMPs and a shift towards a pro-proteolytic state with an invasive phenotype (Fig. 1A).…”

Section: Timp-2 Expression In Normal Tumor and Metastatic Prostate Cmentioning

confidence: 56%

“…All four TIMPs inhibit active forms of most MMPs, but some differences in their inhibitory properties have been reported (Nagase, 1998). TIMPs are involved in diverse biological processes including cell growth, tumor progression, apoptosis, invasion, metastasis and angiogenesis (Gomez et al, 1997;Valente et al, 1998). TIMP-2 is one of the most frequently investigated members of the group due to its involvement in cancer progression and metastasis (DeClerck et al, 1992;Imren et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

“…We have previously demonstrated that the TIMP-2 gene is expressed in normal human tissues, whereas its expression is downregulated in glioblastomas and metastatic lung tumors (Mohanam et al, 1995). Overexpression of TIMP-2 has been shown to restrict the invasiveness of various tumor cell types in vitro (DeClerck et al, 1992;Valente et al, 1998). In addition, TIMP-2 overexpression had inhibitory effects on tumor growth and angiogenesis in a breast cancer mouse model (Hajitou et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

et al. 2007

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Gene silencing via CpG island methylation in the promoter region is one of the mechanisms by which tumor suppressor genes are inactivated in human cancers. Previous studies have shown that the TIMP-2 gene, which is an endogenous inhibitor of matrix metalloproteinases involved in cell invasion and tumorigenesis, is downregulated or silenced in a variety of human cancer cell lines. Here, we investigated the mechanism underlying TIMP-2 expression in prostate cancer cell lines and primary prostate tumor samples. We observed a strong correlation between promoter hypermethylation and lost expression of TIMP-2 gene, which was supported by other results demonstrating that promoter demethylation by 5-aza-2′-deoxycytidine and trichostatin A reactivated TIMP-2 and restored its expression in TIMP-2-silenced metastatic prostate cell lines. These result were further substantiated by a chromatin immunoprecipitation assay, showing the preferential binding of MeCP2 to methylated CpG island in TIMP-2-silenced metastatic prostate cell lines. In vitro Matrigel invasion assays showed that reexpression of TIMP-2 after a combined treatment with 5-aza and TSA in metastatic prostate cells resulted in a significant reduction of tumor cell invasion. Furthermore, CpG methylation of TIMP-2 promoter was also shown in primary prostate tumors that expressed decreased TIMP-2 protein levels. These results suggest that the downregulation of the TIMP-2 gene is associated with promoter methylation and that this may play an important role in prostate cancer progression during the invasive and metastatic stages of the disease.

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Section: Timp-2 Expression In Normal Tumor and Metastatic Prostate Cmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

et al. 2007

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“…Moreover, that increased amounts of TIMP-2 can promote MMP-2 activation and glioblastoma cell invasion is also not surprising. Although TIMP-2 was originally characterized as a suppressor of tumor invasion due to its ability to bind and inhibit MMP-2, 11 and overexpression of TIMP-2 was previously shown to reduce invasion and metastasis in a number of tumor cell models, [25][26][27] it is well known that TIMP-2 TIMP-2 promotes MMP-2 activation in glioblastoma KV Lu et al is also necessary for the efficient activation of proMMP-2. According to the model, a half molar ratio of TIMP-2 to MT1-MMP is theoretically optimal for MMP-2 activation.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Jong

Rajasekaran

et al. 2003

Lab Invest

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Local invasiveness is a characteristic feature of glioblastoma that makes surgical resection nearly impossible and accounts in large part for its poor prognosis. To identify mechanisms underlying glioblastoma invasion and motility, we used Transwell invasion chambers to select for a more potently invasive subpopulation of U87MG human glioblastoma cells. The stable population of tumor cells (U87-C1) obtained through this in vitro selection process were three times more invasive than parental U87MG cells and demonstrated faster monolayer wound healing and enhanced radial motility from cell spheroids. This enhanced invasiveness was associated with an 80% increase in matrix metalloproteinase 2 (MMP-2) activation. No differences in expression levels of pro-MMP-2, membrane-type matrix metalloproteinase I (MT1-MMP), or integrin avb3 (mediators of MMP-2 activation) were detected. However, U87-C1 cells exhibited two-fold elevation of tissue inhibitor of metalloproteinases (TIMP)-2 mRNA and protein relative to parental cells. Exogenous addition of comparable levels of purified TIMP-2 to parental U87MG cells increased MMP-2 activation and invasion. Similarly, U87MG cells engineered to overexpress TIMP-2 at the same levels as U87-C1 cells also demonstrated increased MMP-2 activation, indicating that an increase in physiological levels of TIMP-2 can promote MMP-2 activation and invasion in glioblastoma cells. However, exogenous administration or recombinant overexpression of higher amounts of TIMP-2 in U87MG cells resulted in inhibition of MMP-2 activation. These results demonstrate that the complex balance between TIMP-2 and MMP-2 is a critical determinant of glioblastoma invasion, and indicate that increasing TIMP-2 in glioblastoma patients may potentially cause adverse effects, particularly in tumors containing high levels of MT1-MMP and MMP-2.

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“…22 The design of therapies addressed to interfere with this action (by over-expressing TIMP genes) may be of help in the control of metastatic disease. 23 Although the relationship between invasion, matrix degradation, morphogenesis and new vessel formation is not completely clear, it is likely that inhibition of different steps of these processes could have summatory or even synergistic effects.…”

mentioning

confidence: 99%

Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice

Sacco¹,

Catò²,

Ceruti

et al. 2001

Gene Ther

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Tumor growth and metastasis are angiogenesis-dependent. The possibility of inhibiting tumor growth by interfering with the formation of new vessels has recently raised considerable interest. We previously reported that it is possible to inhibit primary tumor growth and metastasis in a transgenic model of spontaneous breast tumor, which shows many similarities to its human counterpart (including ability to metastasize) by intratumoral administration of a DNA conKeywords: gene therapy; breast adenocarcinoma; metastasis; transgenic mice; anti-angiogenesis; liposomesIt is now widely recognized that the development of new blood vessels (angiogenesis) is necessary to sustain tumor growth, invasion and metastasis. At some point during tumor growth, cancer cells acquire the ability to activate the quiescent vasculature to produce new blood vessels via a so-called 'angiogenic switch '. 1,2 Although the need for recruiting new blood vessels to the tumor has been know for more than two decades, the possibility of treating malignancies by acting on their vasculature has become popular only since the isolation of endogenous angiogenesis inhibitors, which dramatically affect cancer growth in experimental murine systems. Highly promising results on experimental tumors in rodents using these inhibitors as purified proteins as well as transduced genes, alone or in combination with traditional therapies have been reported. [3][4][5][6][7] The establishment of a dormancy status, which in some cases persists even after the suspension of therapy, has been obtained with these gene products, 5 and this, together with the absence of drug resistance, 8 raised the possibility that the anti-angiogenic effects could be useful in the treatment of human tumors.The achievement of the inhibition of local tumor growth is the usual end-point of these therapeutical attempts, but in humans it is the metastatic spread that is responsible for the majority of cancer-related deaths. Therefore, to be really useful in the human context, any new approach must be evaluated in its ability to interfere Correspondence: MG Sacco, ITBA CNR, Via F lli Cervi, 93, 20090 Segrate (MI), Italy Received 17 August 2000; accepted 11 October 2000 struct carrying the murine angiostatin cDNA driven by liposomes. Here we report that it is also possible to achieve this goal by a systemic (intraperitoneal) delivery of therapeutic DNA constructs carrying genes coding for mouse and human anti-angiogenic factors which include angiostatin, endostatin and TIMP-2. These findings may be relevant to the design of therapeutic interventions in humans. Gene Therapy (2001) 8, 67-70. with tumor cell invasion and metastasis, a therapeutical target which is rarely, if ever, investigated at the experimental level. Unfortunately, most of the results in experimental oncology have been obtained on transplantable tumors which are usually generated by inoculating highly malignant cultured cells, which rapidly grow in the site of injection and become the target for therapeutic intervention. ...

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TIMP-2 over-expression reduces invasion and angiogenesis and protects B16F10 melanoma cells from apoptosis

Cited by 248 publications

References 27 publications

Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors

Upregulation of tissue inhibitor of metalloproteinases (TIMP)-2 promotes matrix metalloproteinase (MMP)-2 activation and cell invasion in a human glioblastoma cell line

Systemic gene therapy with anti-angiogenic factors inhibits spontaneous breast tumor growth and metastasis in MMTVneu transgenic mice

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