Transfection of an Invasive Human Astrocytoma Cell Line with a TIMP-1 cDNA

Matsuzawa, Kazuhito; Fukuyama, Kouzou; Hubbard, Sherri Lynn; Dirks, Peter B.; Rutka, James T.

doi:10.1097/00005072-199601000-00009

Cited by 53 publications

(28 citation statements)

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“…Third, the purified protein can be recognized immunochemically by an affinity-purified specific anti-TIMP-4 polyclonal antibody. Fourth, the purified protein inhibited tumor cell invasion in the Matrigel invasion assay, and a similar effect was also reported for other TIMPs (21,22).…”

Section: Discussionsupporting

confidence: 74%

“…The most widely appreciated biological function of the TIMPs is their role in the inhibition of cell invasions in vitro (21)(22)(23)(24) and tumorigenesis (25)(26)(27)(28)(29) and metastasis in vivo (25)(26)(27)(28)(29)(30)(31). Since the net MMP activity is the result of the balance between activated enzyme levels and TIMP levels, an increase in the amount of TIMPs relative to MMPs could function to block tumor cell invasion and metastasis.…”

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confidence: 99%

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Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Liu¹,

Wang²,

Greene³

et al. 1997

Journal of Biological Chemistry

129

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MMPs 1 and their inhibitors TIMPs play a critical role in ECM homeostasis. Controlled remodeling of the ECM is an essential aspect of normal development, and deregulated remodeling has been indicated to have a role in the etiology of diseases such as arthritis, periodontal disease, and cancer metastasis (1-5). Four mammalian TIMPs have been identified so far: TIMP-1 (6), TIMP-2 (7), TIMP-3 (8 -11), and the recently cloned TIMP-4 (12, 41). The proteins are classified based on structural similarity to each other, as well as their ability to inhibit metalloproteinases.TIMPs are secreted multifunctional proteins that have anti-MMP activity as well as erythroid-potentiating and cell growth-promoting activities. The stimulating effect on cell growth was initially recognized when TIMP-1 and TIMP-2 were identified as having erythroid-potentiating activities (14,15). It is now clear through several recent reports that TIMP-1 and TIMP-2 are mitogenic for non-erythroid cells, including normal keratinocytes (16), fibroblasts (17), lung adenocarcinoma cells (18), and melanoma cells (18). The involvement of TIMPs in the activation of pro-MMP has also been demonstrated (19). In addition, the recent evidence indicates that the TIMP family may be involved in steroidogenesis of rat testis and ovary indicating the potential role of TIMP in the reproduction (20).The most widely appreciated biological function of the TIMPs is their role in the inhibition of cell invasions in vitro (21-24) and tumorigenesis (25-29) and metastasis in vivo (25-31). Since the net MMP activity is the result of the balance between activated enzyme levels and TIMP levels, an increase in the amount of TIMPs relative to MMPs could function to block tumor cell invasion and metastasis. The tumor-suppressing activity of TIMP on primary tumor growth may be in part due to its anti-angiogenic activity. In fact, both TIMP-1 (32) and TIMP-2 (33, 34) have been demonstrated to have an antiangiogenic activity, and such inhibition of angiogenesis is mediated by inhibition of both endothelial cell proliferation (34) and migration (32). The underlying molecular mechanism for the tumor suppressing activities of TIMPs, nevertheless, is thought to depend on their anti-MMP activities.We had recently cloned and characterized a human TIMP-4 (12). Transfection of TIMP-4 into human breast cancer cells inhibited the invasion potential of the cells in the in vitro invasion assay (13). When injected orthotopically into nude mice, TIMP-4 transfectants were significantly inhibited in their tumor growth and axillary lymph node and lung metastasis as compared with controls (13). These results suggest the therapeutic potential of TIMP-4 in treating cancer malignant progression. These results suggest an important role of TIMP-4 in inhibiting primary tumor growth and progression leading to invasion and metastasis. In the present study, we have produced and purified rTIMP4p from baculovirus infected cells. rTIMP4p was shown to inhibit MMP activity and tumor cell invasion across reconstitute...

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Liu¹,

Wang²,

Greene³

et al. 1997

Journal of Biological Chemistry

129

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“…These results suggest that the inhibitory activity of TIMPs might be important in inhibiting tumor malignant progression leading to invasion and metastasis. In fact, tumor invasion and metastasis can be inhibited by up-regulation of TIMP expression in tumor cells (Albini et al, 1991;Baker et al, 1999;Valente et al, 1998;Matsuzawa et al, 1996;Wang et al, 1997). Intraperitoneal injection of rTIMP-1 and rTIMP-2 has been shown to inhibit lung colonization of B16 melanoma cells (Schultz et al, 1988;Alvarez et al, 1990).…”

Section: Old Paradigm: Inhibition Of Tumorigenesis and Tumor Metastasmentioning

confidence: 99%

Complex roles of tissue inhibitors of metalloproteinases in cancer

2002

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Matrix metalloproteinases (MMPs) is tightly associated with extracellular matrix (ECM) turnover, which plays a very active role in tumor invasion and metastasis. Tissue inhibitors of metalloproteinases (TIMPs) plays a critical role in the homeostasis of ECM by regulating the activity of MMPs. TIMPs are well-known for their ability to inhibit MMP activity thereby inhibiting tumor growth and metastasis. However, many evidences suggest that TIMPs are multifunctional proteins, which regulate cell proliferation, apoptosis, proMMP-2 activation, and angiogenesis. These e ects may be through MMPdependent or MMP-independent pathways. Recent data indicate that TIMPs have many paradoxical roles in tumorigenesis. In particular, both inhibitory e ect and stimulatory e ect on tumorigenesis have been demonstrated in many animal models in which TIMPs were overexpressed in cancer cells or in mice. Elevated TIMP levels are reported in association with cancer progression and identi®ed as poor prognostic indicators in several human tumor types. Herein, we review the complex roles of TIMPs in cancer growth and metastasis.

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“…Despite progress in surgery and adjuvant therapy, glioblastoma patients still have a very poor prognosis due to incomplete resection and resistance to radioand chemotherapy [VandenBerg, 1992;Demuth and Berens, 2004;Lemke, 2004]. The dismal prognosis associated with glioblastomas is largely due to the fact that these tumors are characterized by a highly invasive phenotype with diffuse infiltration into the regions of the normal brain, which limits the effectiveness of current treatments [Matsuzawa et al, 1996]. Novel therapeutic approaches are therefore needed to prolong survival.…”

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confidence: 99%

Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

Lamy

Lafleur

Bédard

et al. 2006

J of Cellular Biochemistry

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Complete resection of malignant glioblastomas is usually impossible because of diffuse and widespread invasion of tumor cells, and complementary approaches need to be developed in order to improve the efficacy of current treatments. Consumption of fruits and berries has been associated with decreased risk of developing cancer and there is great interest in the use of molecules from dietary origin to improve anticancer therapies. In this work, we report that the aglycons of the most abundant anthocyanins in fruits, cyanidin (Cy), delphinidin (Dp), and petunidin (Pt), act as potent inhibitors of glioblastoma cell migration. Dp clearly exhibited the highest inhibitory potency, this effect being related to the ortho-dihydroxyphenyl structure on the B-ring and the presence of a free hydroxyl group at position 3. Dp decreases the expression of both urokinase-type plasminogen activator receptor (uPAR) and the low-density lipoprotein receptor-related protein (LRP), acting at the transcriptional levels. In addition, Dp upregulated urokinase-type plasminogen activator (uPA) and downregulated the plasminogen activator inhibitor-1 (PAI-1) but decreased, in a concentration-dependent manner, the uPA-dependent conversion of plasminogen to plasmin, indicating that the upregulation of uPA observed with these compounds was not associated with induction of the plasminolytic activity. Overall, these results demonstrate that Dp, Pt, and Cy affect plasminogen activation, thus leading to the inhibition of glioblastoma cell migration and therefore they may be helpful for the development of new strategies for cancer prevention and therapy.

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Transfection of an Invasive Human Astrocytoma Cell Line with a TIMP-1 cDNA

Cited by 53 publications

References 0 publications

Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Preparation and Characterization of Recombinant Tissue Inhibitor of Metalloproteinase 4 (TIMP-4)

Complex roles of tissue inhibitors of metalloproteinases in cancer

Anthocyanidins inhibit migration of glioblastoma cells: Structure‐activity relationship and involvement of the plasminolytic system

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