Abstract
Studies have suggested that an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to the malignant phenotype of gliomas. In this study, we have undertaken a detailed analysis of expression of the TIMP family in normal human brain and malignant gliomas at both the mRNA and protein level. Reverse transcription-PCR (RT-PCR) analyses of total RNA from surgical tumour specimens revealed unique expression patterns for the 4 members of the TIMP family, with TIMP-1 and -4 showing positive and negative correlations, respectively, with glioma malignancy. By RT-PCR, TIMP-2 and TIMP-3 expression did not change with tumour grade. In situ hybridization localized TIMP-1 to glial tumour cells and also to the surrounding tumour vasculature. TIMP-4 transcripts were predominantly localized to tumour cells, though minor expression was found in vessels. Recombinant TIMP-4 reduced invasion of U251 glioma cells through Matrigel, and U87 clones overexpressing TIMP-4 showed reduced invasive capacity in vitro. TIMP-4, but not TIMP-1, blocked Membrane Type-1-MMP-mediated progelatinase-A (MMP-2) activation in human umbilical vein endothelial cells. The differential expression and localization of individual TIMPs may contribute to the pathophysiology of human malignant gliomas, particularly with regard to tumour vascularization. © 2001 Cancer Research Campaign http://www.bjcancer.com
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Ahonen M, Baker AH and Kahari VM (1998) Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 58: 2310–2315
Apte S, Olsen BR and Murphy G (1995) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem 270: 14313–14318
Bachman KE, Herman JG, Corn PG and Merlo A (1999) Methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene suggest a suppressor role in kidney, brain, and other human cancers. Cancer Res 59: 798–802
Baker AH, Zaltsman AB, George SJ and Newby AC (1998) Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or-3 overexpression of rat vascular smooth muscle cell invasion, proliferation, and death in vitro. J Clin Invest 101: 1478–1487
Belien AT, Paganetti PA and Schwab ME (1999) Membrane-type 1 matrix metalloproteinase (MT1-MMP) enables invasive migration of glioma cells in central nervous system white matter. J Cell Biol 144: 373–384
Bertaux B, Hornebeck W, Eisen AZ and Dubertret L (1991) Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J Invest Dermatol 97: 679–685
Blavier L, Henriet P, Imren S and Declerck YA (1999) Tissue inhibitors of matrix metalloproteinases in cancer. Ann NY Acad Sci 878: 108–119
Butler GS, Will H, Atkinson SJ and Murphy G (1997) Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. Eur J Biochem 244: 653–657
Chambers AF and Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260–1270
DeClerck YA, Yean TD, Chan D, Shimada H and Langely KE (1991) Inhibition of tumour invasion of smooth muscle cell layers by recombinant human metalloproteinase inhibitor. Cancer Res 51: 2151–2157
DeClerck YA, Perez N, Shimada H, Boon TC, Langley KE and Taylor SM (1992) Inhibition of invasion and metastasis in cells transfected with an inhibitor of metalloproteinases. Cancer Res 52: 701–708
Deryugina EI, Bourdon MA, Reisfeld RA and Strongin A (1998) Remodeling of collagen matrix by human tumor cells requires activation and cell surface association of matrix metalloproteinase-2. Cancer Res 58: 3743–3750
Foda HD, George S, Conner C, Drews M, Tompkins DC and Zucker S (1996) Activation of human umbilical vein endothelial cell progelatinase A by phorbol myristate acetate: a protein kinase C-dependent mechanism involving a membrane-type matrix metalloproteinase. Lab Invest 74: 538–545
Forsyth PA, Wong H, Dickson Laing T, Rewcastle NB and Morris DG (1999) Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer 79: 1828–1835
Gasson JC, Golde DW, Kaufman SE and Westbrook CA (1985) Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 315: 768–771
Greene J, Wang M, Liu YE, Raymond LA, Rosen C and Shi YE (1996) Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 271: 30375–30380
Guedez L, Courtemanch L and Stetler-Stevenson M (1998) Tissue inhibitor of metalloproteinase (TIMP)-1 induces differentiation and an antiapoptotic phenotype in germinal center B cells. Blood 92: 1342–1349
Hayakawa T, Yamashita K, Tanzawa K, Uchijima E and Iwata K (1992) Growth-promoting activity of tissue inhibitor of metalloproteinase-1 (TIMP-1). FEBS Lett 298: 29–32
Hayakawa T, Yamashita K, Ohuchi E and Shinnagawa A (1994) Cell growth promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci 107: 2373–2379
Hiraoka N, Allen E, Apel IJ, Gyetko MR and Weiss SJ (1998) Matrix metalloproteinases regulate neovascularization by acting as pericellular fibrinolysins. Cell 95: 365–377
Holten-Anderson MN, Murphy G, Nielsen HJ, Pedersen AN, Christensen IJ, Hoyer-Hansen G, Brunner N and Stephens RW (1999) Quantitation of TIMP-1 in plasma of healthy blood donors and patients with advanced cancer. Br J Cancer 80: 495–503
Kachra Z, Beaulieu E, Delbecchi L, Mousseau N and Berthelet R (1999) Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17: 555–566
Khokha R, Waterhouse P, Yagel S, Lala PK and Overall CM (1989) Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 243: 947–950
Kossakowska AE, Urbanski SJ and Edwards DR (1991) Tissue inhibitor of metalloproteinases-1 (TIMP-1) RNA is expressed at elevated levels in malignant non-Hodgkin's lymphomas. Blood 77: 2475–2481
Lampert K, Machein U, Machein MR, Conca W, Peter HH and Volk B (1998) Expression of matrix metalloproteinases and their tissue inhibitors in human brain tumors. Am J Pathol 153: 429–437
Leco KJ, Khokha R, Pavloff N, Hawkes SP and Edwards DR (1994) Tissue inhibitor of metalloproteinase-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 269: 9352–9360
Leco KJ, Apte SS, Taniguchi GT, Hawkes SP and Khokha R (1997) Murine tissue inhibitor of metalloproteinases-4 (TIMP-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett 401: 213–217
Liotta LA, Steeg PS and Stetler-Stevenson WG (1991) Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 54: 327–336
Llano E, Pendas AM, Freije JP, Nakano A and Knauper V (1999) Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase A overexpressed in brain tumors. Cancer Res 59: 2570–2576
Mohanam S, Wang WW, Rayford A, Yamamoto M and Sawaya R (1995) Expression of tissue inhibitors of metalloproteinases: negative regulators of human glioblastoma invasion in vivo. Clin Exp Metastasis 13: 57–62
Murphy A, Unsworth E and Stetler-Stevenson WG (1993) Tissue inhibitor of metalloproteinase-2 (TIMP-2) inhibits bFGF-induced human microvascular endothelial cell proliferation. J Cell Physiol 157: 351–358
Murphy G and Knauper V (1997) Relating matrix metalloproteinase structure to function: why the “hemopexin” domain?. Matrix Biol 15: 511–518
Nagase H and Woessner JFJ (1999) Matrix metalloproteinases. J Biol Chem 274: 21491–21494
Nakada M, Nakamura H, Ikeda E, Fujimoto N and Yamashita J (1999) Expression and tissue localization of membrane-type 1, 2, and 3 matrix metalloproteinases in human astrocytic tumors. Am J Pathol 154: 417–428
Nakano A, Tani E, Miuazaki K, Yamamoto U and Furuyama JI (1995) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in human gliomas. J Neurosurg 83: 298–307
Phillips BW, Sharma R, Leco PA and Edwards DR (1999) A sequence-selective single-strand DNA-binding protein regulates basal transcription of the mouse tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. J Biol Chem 274: 22197–22207
Powe DG, Brough JL, Carter GI, Bailey EM and Stetler-Stevenson WG (1997) TIMP-3 mRNA expression is regionally increased in moderately and poorly differentiated colorectal adenocarcinoma. Br J Cancer 75: 1678–1683
Price A, Shi Q, Morris D, Wilcox M and Brasher PM (1999) Marked inhibition of tumor growth in a malignant glioma tumor model by a novel synthetic matrix metalloproteinase inhibitor AG3340. Cancer Res 5: 845–854
Raithatha SA, Muzik H, Rewcastle NB, Johnston RN, Edwards DR and Forsyth PA (2000). Localization of gelatinase-A and gelatinase-B mRNA and protein in human gliomas, Neuro-Oncol 3
Ritter LM, Garfield SH and Thorgeirsson UP (1999) Tissue inhibitor of metalloproteinases-1 (TIMP-1) binds to the cell surface and translocates to the nucleus of human MCF-7 breast carcinoma cells. Biochem Biophys Res Commun 257: 494–499
Rutka JT, Matsuzawa K, Hubbard SL, Fukuyama K, Becker LE, Stetler-Stevenson W, Edwards DR and Dirks PB (1995) Expression of TIMP-1, TIMP-2, 72-and 92-kDa type IV collagenase transcripts in human astrocytoma cell lines: Correlation with astrocytoma cell invasiveness. Int J Oncol 6: 877–884
Sawaya RE, Yamamoto M, Gokaslan ZL, Wang SW and Mohanam S (1996) Expression and localization of 72 kDa type IV collagenase (MMP-2) in human malignant gliomas in vivo. Clin Exp Metastasis 14: 35–42
Saxena A, Robertson JT, Kufta C, Stetler-Stevenson WG and Ali IU (1995) Increased expression of gelatinase A and TIMP-2 in primary human glioblastomas. Int J Oncology 7: 469–473
Smith MR, Kung H, Durum SK, Colburn NH and Sun Y (1997) TIMP-3 induces cell death by stabilizing TNF-alpha receptors on the surface of human colon carcinoma cells. Cytokine 9: 770–780
Stetler-Stevenson M, Mansoor A, Lim M, Fukushima P and Kehrl J (1997) Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in reactive and neoplastic lymphoid cells. Blood 89: 1708–1715
Uhm JH, Dooley NP, Villemure JG and Yong VW (1996) Glioma invasion in vitro: regulation by matrix metalloprotease-2 and protein kinase C. Clin Exp Metastasis 14: 421–433
Uhm JH, Dooley NP, Villemure JG and Yong VW (1997) Mechanisms of glioma invasion: role of matrix-metalloproteinases. Canadian Journal of Neurological Science 24: 3–15
Velasco G, Cal S, Merlos-Suarez A, Ferrando AA and Alvarez S (2000) Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors. Cancer Res 60: 877–882
Wang M, Liu YE, Greene J, Sheng S and Fuchs A et al (1997) Inhibition of tumor growth and metastasis of human breast cancer cells transfected with tissue inhibitor of metalloproteinase 4. Oncogene 14: 2767–2774
Will H, Atkinson SJ, Butler GS, Smith B and Murphy G (1996) The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propetide of progelatinase A and initiates autoproteolytic activation. J Biol Chem 271: 17119–17123
Wingfield PT, Sax JK, Stahl SJ, Kaufman J, Palmer I, Chung V, Corcoran ML, Kleiner DE and Stetler-Stevenson WG (1999) Biophysical and functional characterization of full length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherischia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. J Biol Chem 274: 21362–21368
Wong H, Anderson WD, Cheng T and Riabowol KT (1994) Monitoring mRNA expression by polymerase chain reaction: the “primer- dropping” method. Anal Biochem 223: 251–258
Yamamoto M, Mohanam S, Sawaya R, Fuller GN and Seiki M (1996) Differential expression of membrane-type matrix metalloproteinase and its correlation with gelatinase A activation in human malignant brain tumors in vivo and in vitro. Cancer Res 56: 384–392
Yong VW, Krekoski CA, Forsyth PA, Bell R and Edwards DR (1998) Matrix metalloproteinases and diseases of the CNS. Trends Neurosci 21: 78–80
Yoshiji H, Harris SR, Raso E, Gomez DE and Lindsay CK (1998) Mammary carcinoma cells over-expressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression. Int J Cancer 75: 81–87
Zeng ZS, Cohen AM, Zhang ZF, Stetler-Stevenson W and Guillem JG (1995) Elevated tissue inhibitor of metalloproteinases-1 RNA in colorectal cancer stroma correlates with lymph node and distant metastases. Clin Cancer Res 1: 899–906
Zhou Z, Apte SS, Soininen R, Cao R and Baaklini GY (2000) Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc Natl Acad Sci USA 97: 4052–4057
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Groft, L., Muzik, H., Rewcastle, N. et al. Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. Br J Cancer 85, 55–63 (2001). https://doi.org/10.1054/bjoc.2001.1854
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1054/bjoc.2001.1854
Keywords
This article is cited by
-
An N6-methyladenosine regulation- and mRNAsi-related prognostic index reveals the distinct immune microenvironment and immunotherapy responses in lower-grade glioma
BMC Bioinformatics (2023)
-
Proteomics analysis of serum from thymoma patients
Scientific Reports (2023)
-
NCX2 Regulates Intracellular Calcium Homeostasis and Translocation of HIF-1α into the Nucleus to Inhibit Glioma Invasion
Biochemical Genetics (2023)
-
An integrative bioinformatics investigation and experimental validation of critically involved genes in high-grade gliomas
Diagnostic Pathology (2022)
-
Serum protein triplet TGF-β1, TIMP-1, and YKL-40 serve as diagnostic and prognostic profile for astrocytoma
Scientific Reports (2021)