Frequent Methylation-Associated Silencing of the<i>Tissue Inhibitor of Metalloproteinase-3</i>Gene in Pancreatic Endocrine Tumors

Wild, Anja; Ramaswamy, Annette; Langer, Peter; Çelik, I.; Fendrich, Volker; Chaloupka, Brunhilde; Simon, Babette; Bartsch, Detlef K.

doi:10.1210/jc.2002-021027

Cited by 73 publications

(66 citation statements)

References 22 publications

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“…22,28,29 There seem to be some exceptions, for example, in JB6 tumor cells TIMP-3 overexpression failed to inhibit invasion through reconstituted basement membranes, 30 suggesting a complex function for TIMP-3 in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

Zhang

Zhao

et al. 2009

Cancer Gene Ther

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The destruction of extracellular matrix by matrix metalloproteinases is a key event in cancer progression. The tissue inhibitors of metalloproteinases can restrain tumor growth by inhibiting these enzymes. We sought to determine whether overexpression of tissue inhibitor of metalloproteinase-3 (TIMP-3) could suppress the malignant phenotype of human prostate cancer cell line PC-3M. Stable overexpression of TIMP-3 inhibited cell proliferation significantly by MTT assay. Both early and late apoptosis were observed in TIMP-3 overexpressing cells, and flow cytometry analysis showed S-phase blocking of the cell cycle. Monolayer invasion assay and transwell invasion assay showed significantly decreased invasive potential in TIMP-3 overexpressing cells compared with control cells. Cell adhesion and motility were also lower after TIMP-3 was overexpressed. In vivo, cells stably overexpressing TIMP-3 completely lost the ability to form tumors after injection into nude mice. Transfection of TIMP-3 into established tumors by electroporation also had a significant antitumor effect. TIMP-3-treated tumor tissues had significant apoptosis by TUNEL assay. These results showed that overexpression of TIMP-3 inhibits invasion and proliferation of prostate cancer cells in vitro and inhibits tumor growth in vivo. The experiments suggest a potential use for TIMP-3 in the gene therapy of prostate cancer.

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Section: Discussionmentioning

confidence: 99%

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

Zhang

Zhao

et al. 2009

Cancer Gene Ther

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“…Hypermethylation of the promoter of TIMP-3 (tissue inhibitor of metalloproteinase-3) gene was found in 44% of PanNET in a study performed on 18 PanNET in correlation with protein loss. TIMP-3 alterations were significantly more frequent in metastatic setting (Wild et al 2003). Promoter hyper-methylation of MHL1 and hyper-methylation of IGF2 DMR2 were found exclusively in insulinomas in association with increased malignancy.…”

Section: Pancreatic Netmentioning

confidence: 92%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

102

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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“…TIMP-3 may be relevant considering the putative role in tumor growth inhibition, as it antagonizes primary tumor growth, angiogenesis, apoptosis, tumor invasion, and the development of metastasis [104][105][106][107][108]. Recent studies about the methylation-associated silencing of TIMP-3 also suggest a tumor suppressor role in several tumor types [109][110][111][112][113], which might not be directly related to its effect as an MMP inhibitor. Therefore, the lack of TIMP-3 expression in pure DCIS may be a potential marker of invasive growth.…”

Section: Roles Of Mmps and Timps In Transition From Ductal Carcinoma mentioning

confidence: 99%

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

2013

J Carcinog Mutagen

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Degradation of the stromal connective tissue and basement membrane components are key elements in tumor invasion and metastasis. Some components, particularly the interstitial collagens, are very resistant to proteolytic attacks and can be degraded by specific proteinases like Matrix Metalloproteinases (MMPs). MMPs can also impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, or chemokines/cytokines, and for stimulating angiogenesis. Different molecular expression profiles of MMPs and their inhibitors (TIMPs) have been associated with the main steps in breast cancer progression, such as creating a potential invasive phenotype in Ductal Carcinoma in situ (DCIS), favoring the hematogenous dissemination, and enabling the metastatic progression across the axillary lymphatic system. These associations have clinical interests, as they can contribute to a better characterization of early breast carcinomas (which differ in their both biological and clinical behavior), evaluate microinvasion in resection specimens of breast tumors, provide a more precise prognostic, and predict the tumoral status of non-sentinel lymph nodes in breast cancer. It is also especially remarkable the evidences indicating that MMPs and TIMPs expression in individual cell populations from tumor stroma, such as mononuclear inflammatory cells (MICs) and fibroblast, clearly impacts on the clinical outcome of breast cancer patients. There are several factors linking inflammation, MMP activity and breast cancer. This knowledge will be useful to develop novel therapies and prevention strategies targeting critical components.

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Frequent Methylation-Associated Silencing of theTissue Inhibitor of Metalloproteinase-3Gene in Pancreatic Endocrine Tumors

Cited by 73 publications

References 22 publications

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

Inhibition of tumor growth and induction of apoptosis in prostate cancer cell lines by overexpression of tissue inhibitor of matrix metalloproteinase-3

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Clinical Relevance of Matrix Metalloproteases and their Inhibitors in Breast Cancer

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