Complex roles of tissue inhibitors of metalloproteinases in cancer

Jiang, Yangfu; Goldberg, Itzhak D.; Shi, Yan

doi:10.1038/sj.onc.1205291

Cited by 436 publications

(350 citation statements)

References 92 publications

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“…If TIMPs inhibit MMPs in vivo, it should be expected that high levels of these inhibitors would prevent tumour progression and thus be related with good outcome in patients with cancer. 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).…”

Section: Discussionmentioning

confidence: 99%

“…Matrix metalloproteinases may also regulate cancer/related angiogenesis, both positively through their ability to mobilise or activate proangiogenic factors (Stetler-Stevenson, 1999) and negatively via generation of angiogenesis inhibitors, such as angiostatin and endostatin, cleaved from large protein precursors (Cornelius et al, 1998). In addition, it is now assumed that TIMPs are multifactorial proteins also involved in the induction of proliferation and the inhibition of apoptosis (Jiang et al, 2002;Wurtz et al, 2005).…”

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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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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Study of matrix metalloproteinases and their inhibitors in breast cancer

et al. 2007

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“…TIMPs-1, -2, -3, -4 reversibly inhibit MMPs in a 1:1 stoichiometric fashion (Sternlicht and Werb, 2001). The different TIMPs differ in tissue-specific expression and ability to inhibit various MMPs and their capacity to interact or not with pro-MMPs (Jiang et al, 2002;Sternlicht and Werb, 2001 …”

Section: Mmp Structure and Functionsmentioning

confidence: 99%

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis

et al. 2003

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The matrix metalloproteinases (MMPs) constitute a multigene family of over 23 secreted and cell-surface associated enzymes that cleave or degrade various pericellular substrates. In addition to virtually all extracellular matrix (ECM) compounds, their targets include other proteinases, chemotactic molecules, latent growth factors, growth factor-binding proteins and cell surface molecules. The MMP activity is controlled by the physiological tissue inhibitors of MMPs (TIMPs). There is much evidence that MMPs and their inhibitors play a key role during extracellular remodeling in physiological situations and in cancer progression. They have other functions that promoting tumor invasion. Indeed, they regulate early stages of tumor progression such as tumor growth and angiogenesis. Membrane type MMPs (MT-MMPs) constitute a new subset of cell surface-associated MMPs. The present review will focus on MT1-MMP which plays a major role at least, in the ECM remodeling, directly by degrading several of its components, and indirectly by activating pro-MMP2. As our knowledge on the field of MT1-MMP biology has grown, the unforeseen complexities of this enzyme and its interaction with its inhibitor TIMP-2 have emerged, often revealing unexpected mechanisms of action.Keywords: MT1-MMP ; tumoral angiogenesis ; vascular endothelial growth factor ; protease inhibitors ; estradiol MMP structure and functionsMatrix metalloproteinases (MMPs) are a broad family of zinc-binding endopeptidases that play a key role in the extracellular matrix (ECM) degradation associated with cancer cell invasion, metastasis and angiogenesis (Egeblad and Werb, 2002;McCawley and Matrisian, 2000). At present, more than 21 human MMPs and the homologues from other species have been identified (Egeblad and Werb, 2002). The MMP family can be segregated into two groups, the soluble type and the membrane-type MMPs (MT-MMPs and MMP23). Although initially classified according to their substrate specificity (McCawley and Matrisian, 2000), the MMP classification is now based on their structure (Egeblad and Werb, 2002). The 'minimal-domain MMPs' (MMP7 and MMP26) contains (i) a signal peptide that directs them to the endoplasmic reticulum, (ii) a propeptide, with a zinc-interacting thiol (SH) group that maintains the proMMP in a latent form (zymogen), and (iii) a catalytic domain containing the highly conserved Zn 2+ binding site (HEXGHXXGXXHS/T) (Fig. 1). With the exception of MMP23, all other MMPs display a prolinerich hinge region that links the catalytic domain to the hemopexin/vitronectin-like domain. This C-terminal domain influences substrate specificity and the binding to tissue inhibitors of MMPs (TIMPs) and cell surface molecules. The hemopexin-containing MMPs are further distinguished by the presence of specific insert(s). The gelatin-binding MMPs (MMP2 and MMP9 or gelatinases) contain inserts that resemble the collagen-binding type II repeats of fibronectin. The membrane type (MT)-MMPs have a single pass transmembrane domain and a short cytoplasmic...

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“…6 -10 Thus, it has been speculated that TIMP-1 may actually play a dual role in cancer progression and metastasis. 11 Several studies have demonstrated that tumor tissue levels of MMP mRNA and protein are significantly increased in various malignant diseases and that such MMP elevations are correlated with cancer cell invasion, metastasis and short patient survival. 12,13 In addition, many reports have described similar overexpression of TIMP-1 mRNA and protein in several cancer types.…”

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confidence: 99%

Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

Holten-Andersen

Hansen

Brünner³

et al. 2004

Intl Journal of Cancer

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Tissue inhibitor of matrix metalloproteases 1 (TIMP-1) inhibits the proteolytic activity of matrix metalloproteases and hereby prevents cancer invasion. However, TIMP-1 also possesses other functions such as inhibition of apoptosis, induction of malignant transformation and stimulation of cell-growth. We have previously demonstrated that TIMP-1 is elevated in blood from colorectal cancer patients and that high TIMP-1 levels predict poor prognosis. To clarify the role of TIMP-1 in colorectal tumorigenesis, the expression pattern of TIMP-1 in benign and malignant colorectal tumors was studied. In all of 24 cases of colorectal adenocarcinoma TIMP-1 mRNA was detected by in situ hybridization. In all cases TIMP-1 expression was found in fibroblast-like cells located at the invasive front but was seen only sporadically in normal mucosa. No TIMP-1 mRNA was seen in any of the cases in benign or malignant epithelial cells, in vascular cells or smooth muscle cells. Comparison of sections processed for TIMP-1 in situ hybridization with sections immunohistochemically stained with antibodies against TIMP-1 showed good correlation between TIMP-1 mRNA and immunoreactivity. Combining TIMP-1 in situ hybridization with immunohistochemical staining for ␣-smooth muscle actin or CD68 showed TIMP-1 mRNA in myofibroblasts but not in macrophages. TIMP-1 mRNA was detected in 2 of 7 adenomatous polyps in the adenoma area: in both cases associated with focal stromal inflammation at the epithelial-stromal interface. In conclusion, TIMP-1 expression is a rare event in benign human colon tissue but is highly expressed by myofibroblasts in association with invading colon cancer cells.

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Complex roles of tissue inhibitors of metalloproteinases in cancer

Cited by 436 publications

References 92 publications

Study of matrix metalloproteinases and their inhibitors in breast cancer

Study of matrix metalloproteinases and their inhibitors in breast cancer

Membrane type-1 matrix metalloproteinase and TIMP-2 in tumor angiogenesis

Localization of tissue inhibitor of metalloproteinases 1 (TIMP‐1) in human colorectal adenoma and adenocarcinoma

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