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Low expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in glioblastoma predicts longer patient survival

  • Clinical Study - Patient Study
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Abstract

In colorectal cancer and breast cancer a high TIMP-1 level has been shown to correlate with a shorter overall patient survival and it has been suggested that TIMP-1 is involved in tumour invasion, proliferation and apoptosis in different types of cancers. TIMP-1 is known to be expressed in gliomas but whether TIMP-1 is a prognostic marker in gliomas has not previously been investigated. In the present study, the TIMP-1 expression was investigated immunohistochemically in 112 formalin-fixed paraffin embedded astrocytomas and related to tumour grade and overall patient survival by scoring the TIMP-1 immunoreactivity of both tumour cells and blood vessels. Moreover, TIMP-1 in situ hybridisation was performed on ten of the glioblastomas. In the vast majority of the tumours TIMP-1 protein was expressed in both tumour cells and blood vessels. In situ hybridisation for TIMP-1 mRNA on glioblastomas confirmed the immunohistochemical expression of TIMP-1. The percentage of TIMP-1 positive tumour cells and blood vessels as well as the staining intensity varied between tumours of the same grade, but the total staining score increased with tumour grade. The multivariate Cox regression test showed that glioblastoma patients with the lowest TIMP-1 expression had a significantly longer overall survival (HR (95% CI) = 3.2 (1.5–6.7), P = 0.004) when compared to the patients with higher TIMP-1 protein expression. In conclusion, this study showed that low TIMP-1 immunohistochemical expression predicts longer overall survival in glioblastoma patients, suggesting a role for TIMP-1 as a biomarker in glioblastoma.

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References

  1. Jiang Y, Goldberg ID, Shi YE (2002) Complex roles of tissue inhibitors of metalloproteinases in cancer. Oncogene 21:2245–2252. doi:10.1038/sj.onc.1205291

    Article  CAS  PubMed  Google Scholar 

  2. Chirco R, Liu XW, Jung KK, Kim HR (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25:99–113. doi:10.1007/s10555-006-7893-x

    Article  CAS  PubMed  Google Scholar 

  3. Carmichael DF, Sommer A, Thompson RC, Anderson DC, Smith CG, Welgus HG, Stricklin GP (1986) Primary structure and cDNA cloning of human fibroblast collagenase inhibitor. Proc Natl Acad Sci USA 83:2407–2411. doi:10.1073/pnas.83.8.2407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Stricklin GP, Welgus HG (1983) Human skin fibroblast collagenase inhibitor. Purification and biochemical characterization. J Biol Chem 258:12252–12258

    CAS  PubMed  Google Scholar 

  5. Welgus HG, Stricklin GP, Eisen AZ, Bauer EA, Cooney RV, Jeffrey JJ (1979) A specific inhibitor of vertebrate collagenase produced by human skin fibroblasts. J Biol Chem 254:1938–1943

    CAS  PubMed  Google Scholar 

  6. Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K (1992) Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett 298:29–32. doi:10.1016/0014-5793(92)80015-9

    Article  CAS  PubMed  Google Scholar 

  7. Chesler L, Golde DW, Bersch N, Johnson MD (1995) Metalloproteinase inhibition and erythroid potentiation are independent activities of tissue inhibitor of metalloproteinases-1. Blood 86:4506–4515

    CAS  PubMed  Google Scholar 

  8. Wang T, Yamashita K, Iwata K, Hayakawa T (2002) Both tissue inhibitors of metalloproteinases-1 (TIMP-1) and TIMP-2 activate Ras but through different pathways. Biochem Biophys Res Commun 296:201–205. doi:10.1016/S0006-291X(02)00741-6

    Article  CAS  PubMed  Google Scholar 

  9. Porter JF, Shen S, Denhardt DT (2004) Tissue inhibitor of metalloproteinase-1 stimulates proliferation of human cancer cells by inhibiting a metalloproteinase. Br J Cancer 90:463–470. doi:10.1038/sj.bjc.6601533

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cornelius LA, Nehring LC, Harding E, Bolanowski M, Welgus HG, Kobayashi DK, Pierce RA, Shapiro SD (1998) Matrix metalloproteinases generate angiostatin: effects on neovascularization. J Immunol 161:6845–6852

    CAS  PubMed  Google Scholar 

  11. Yoshiji H, Harris SR, Raso E, Gomez DE, Lindsay CK, Shibuya M, Sinha CC, Thorgeirsson UP (1998) Mammary carcinoma cells over-expressing tissue inhibitor of metalloproteinases-1 show enhanced vascular endothelial growth factor expression. Int J Cancer 75:81–87. doi:10.1002/(SICI)1097-0215(19980105)75:1<81::AID-IJC13>3.0.CO;2-G

    Article  CAS  PubMed  Google Scholar 

  12. Boudreau N, Sympson CJ, Werb Z, Bissell MJ (1995) Suppression of ICE and apoptosis in mammary epithelial cells by extracellular matrix. Science 267:891–893. doi:10.1126/science.7531366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guedez L, Stetler-Stevenson WG, Wolff L, Wang J, Fukushima P, Mansoor A, Stetler-Stevenson M (1998) In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1. J Clin Invest 102:2002–2010. doi:10.1172/JCI2881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lambert E, Boudot C, Kadri Z, Soula-Rothhut M, Sowa ML, Mayeux P, Hornebeck W, Haye B, Petitfrere E (2003) Tissue inhibitor of metalloproteinases-1 signalling pathway leading to erythroid cell survival. Biochem J 372:767–774. doi:10.1042/BJ20030187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liu XW, Bernardo MM, Fridman R, Kim HR (2003) Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells against intrinsic apoptotic cell death via the focal adhesion kinase/phosphatidylinositol 3-kinase and MAPK signaling pathway. J Biol Chem 278:40364–40372. doi:10.1074/jbc.M302999200

    Article  CAS  PubMed  Google Scholar 

  16. Schrohl AS, Holten-Andersen MN, Peters HA, Look MP, Meijer-van Gelder ME, Klijn JG, Brünner N, Foekens JA (2004) Tumor tissue levels of tissue inhibitor of metalloproteinase-1 as a prognostic marker in primary breast cancer. Clin Cancer Res 10:2289–2298. doi:10.1158/1078-0432.CCR-03-0360

    Article  CAS  PubMed  Google Scholar 

  17. Wu ZS, Wu Q, Yang JH, Wang HQ, Ding XD, Yang F, Xu XC (2008) Prognostic significance of MMP-9 and TIMP-1 serum and tissue expression in breast cancer. Int J Cancer 122:2050–2056

    Article  CAS  PubMed  Google Scholar 

  18. Kuvaja P, Wurtz SO, Talvensaari-Mattila A, Brünner N, Paakko P, Turpeenniemi-Hujanen T (2007) High serum TIMP-1 correlates with poor prognosis in breast carcinoma—a validation study. Cancer Biomark 3:293–300

    Article  CAS  PubMed  Google Scholar 

  19. Holten-Andersen M, Christensen IJ, Nilbert M, Bendahl PO, Nielsen HJ, Brünner N, Fernebro E (2004) Association between preoperative plasma levels of tissue inhibitor of metalloproteinases 1 and rectal cancer patient survival. A validation study. Eur J Cancer 40:64–72. doi:10.1016/j.ejca.2003.09.019

    Article  CAS  PubMed  Google Scholar 

  20. Joo YE, Seo KS, Kim HS, Rew JS, Park CS, Kim SJ (2000) Expression of tissue inhibitors of metalloproteinases (TIMPs) in gastric cancer. Dig Dis Sci 45:114–121. doi:10.1023/A:1005421713137

    Article  CAS  PubMed  Google Scholar 

  21. Yoshikawa T, Tsuburaya A, Kobayashi O, Sairenji M, Miyagi Y (2006) Protein levels of tissue inhibitor of metalloproteinase-1 in tumor extracts as a marker for prognosis and recurrence in patients with gastric cancer. Gastric Cancer 9:106–113. doi:10.1007/s10120-006-0362-y

    Article  CAS  PubMed  Google Scholar 

  22. Rauvala M, Puistola U, Turpeenniemi-Hujanen T (2005) Gelatinases and their tissue inhibitors in ovarian tumors; TIMP-1 is a predictive as well as a prognostic factor. Gynecol Oncol 99:656–663. doi:10.1016/j.ygyno.2005.07.009

    Article  CAS  PubMed  Google Scholar 

  23. Nakagawa T, Kubota T, Kabuto M, Sato K, Kawano H, Hayakawa T, Okada Y (1994) Production of matrix metalloproteinases and tissue inhibitor of metalloproteinases-1 by human brain tumors. J Neurosurg 81:69–77

    Article  CAS  PubMed  Google Scholar 

  24. Kachra Z, Beaulieu E, Delbecchi L, Mousseau N, Berthelet F, Moumdjian R, Del MR, Beliveau R (1999) Expression of matrix metalloproteinases and their inhibitors in human brain tumors. Clin Exp Metastasis 17:555–566. doi:10.1023/A:1006760632766

    Article  CAS  PubMed  Google Scholar 

  25. Nuttall RK, Pennington CJ, Taplin J, Wheal A, Yong VW, Forsyth PA, Edwards DR (2003) Elevated membrane-type matrix metalloproteinases in gliomas revealed by profiling proteases and inhibitors in human cancer cells. Mol Cancer Res 1:333–345

    CAS  PubMed  Google Scholar 

  26. Møller SN, Dowell BL, Stewart KD, Jensen V, Larsen L, Lademann U, Murphy G, Nielsen HJ, Brünner N, Davis GJ (2005) Establishment and characterization of 7 new monoclonal antibodies to tissue inhibitor of metalloproteinases-1. Tumour Biol 26:71–80. doi:10.1159/000085588

    Article  Google Scholar 

  27. Sørensen IV, Fenger C, Winther H, Foged NT, Lademann U, Brünner N, Usher PA (2006) Characterization of anti-TIMP-1 monoclonal antibodies for immunohistochemical localization in formalin-fixed, paraffin-embedded tissue. J Histochem Cytochem 54:1075–1086. doi:10.1369/jhc.5A6896.2006

    Article  PubMed  PubMed Central  Google Scholar 

  28. Aaberg-Jessen C, Christensen K, Schrøder HD, Offenberg H, Brünner N, Kristensen BW (2008) Low tissue inhibitor of metalloproteinases-1 (TIMP-1) protein expression in glioblastoma predicts longer patient survival, AACR Annual Meeting, Abstract # 5541

  29. Graham DI, Lantos PL (2002) Tumours of the nervous system. In: Graham DI, Lantos PL (eds) Greenfield’s Neuropathology, vol 2. Arnold, Great Britain, pp 768–1052

    Google Scholar 

  30. Kleihues P, Cavenee WK (2000) Pathology and genetics of tumours of the nervous system. IARC Press, Lyon

    Google Scholar 

  31. Neckelmann K, Kristensen BW, Schrøder HD (2004) Improved histopathological evaluation of gliomas using tissue fragments obtained by ultrasonic aspiration. Clin Neuropathol 23:47–52

    CAS  PubMed  Google Scholar 

  32. Silverman JF, Jones FD, Unverferth M, Berns L (1989) Cytopathology of neoplasms of the central nervous system in specimens obtained by the Cavitron Ultrasonic Surgical Aspirator. Acta Cytol 33:576–582

    CAS  PubMed  Google Scholar 

  33. Malhotra V, Malik R, Gondal R, Beohar PC, Parkash B (1986) Evaluation of histological appearance of tissues removed by cavitron ultrasonic surgical aspirator (CUSA). Acta Neurochir (Wien) 81:132–134. doi:10.1007/BF01401235

    Article  CAS  Google Scholar 

  34. Shi SR, Liu C, Pootrakul L, Tang L, Young A, Chen R, Cote RJ, Taylor CR (2008) Evaluation of the value of frozen tissue section used as “gold standard” for immunohistochemistry. Am J Clin Pathol 129:358–366. doi:10.1309/7CXUYXT23E5AL8KQ

    Article  CAS  PubMed  Google Scholar 

  35. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (2007) WHO Classification of Tumours of the Central Nervous System. International Agency for Research on Cancer, Lyon

    Google Scholar 

  36. Usher PA, Sieuwerts AM, Bartels A, Lademann U, Nielsen HJ, Holten-Andersen L, Foekens JA, Brünner N, Offenberg H (2007) Identification of alternatively spliced TIMP-1 mRNA in cancer cell lines and colon cancer tissue. Mol oncol 1:205–215

    Article  CAS  PubMed  Google Scholar 

  37. Vizoso FJ, Gonzalez LO, Corte MD, Rodriguez JC, Vazquez J, Lamelas ML, Junquera S, Merino AM, Garcia-Muniz JL (2007) Study of matrix metalloproteinases and their inhibitors in breast cancer. Br J Cancer 96:903–911. doi:10.1038/sj.bjc.6603666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Holten-Andersen MN, Stephens RW, Nielsen HJ, Murphy G, Christensen IJ, Stetler-Stevenson W, Brünner N (2000) High preoperative plasma tissue inhibitor of metalloproteinase-1 levels are associated with short survival of patients with colorectal cancer. Clin Cancer Res 6:4292–4299

    CAS  PubMed  Google Scholar 

  39. Yukawa N, Yoshikawa T, Akaike M, Sugimasa Y, Rino Y, Masuda M, Imada T (2007) Impact of plasma tissue inhibitor of matrix metalloproteinase-1 on long-term survival in patients with colorectal cancer. Oncology 72:205–208. doi:10.1159/000112827

    Article  CAS  PubMed  Google Scholar 

  40. Waas ET, Hendriks T, Lomme RM, Wobbes T (2005) Plasma levels of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 correlate with disease stage and survival in colorectal cancer patients. Dis Colon Rectum 48:700–710. doi:10.1007/s10350-004-0854-y

    Article  PubMed  Google Scholar 

  41. Tomita T (1997) Matrix metalloproteinases and tissue inhibitors of metalloproteinases in thyroid C-cells and medullary thyroid carcinomas. Histopathology 31:150–156. doi:10.1046/j.1365-2559.1997.2160834.x

    Article  CAS  PubMed  Google Scholar 

  42. Massi D, Franchi A, Ketabchi S, Paglierani M, Pimpinelli N, Santucci M (2003) Expression and prognostic significance of matrix metalloproteinases and their tissue inhibitors in primary neuroendocrine carcinoma of the skin. Hum Pathol 34:80–88. doi:10.1053/hupa.2003.51

    Article  CAS  PubMed  Google Scholar 

  43. Holten-Andersen MN, Hansen U, Brünner N, Nielsen HJ, Illemann M, Nielsen BS (2005) Localization of tissue inhibitor of metalloproteinases 1 (TIMP-1) in human colorectal adenoma and adenocarcinoma. Int J Cancer 113:198–206. doi:10.1002/ijc.20566

    Article  CAS  PubMed  Google Scholar 

  44. Jones JL, Glynn P, Walker RA (1999) Expression of MMP-2 and MMP-9, their inhibitors, and the activator MT1-MMP in primary breast carcinomas. J Pathol 189:161–168. doi:10.1002/(SICI)1096-9896(199910)189:2<161::AID-PATH406>3.0.CO;2-2

    Article  CAS  PubMed  Google Scholar 

  45. Sawatsubashi M, Mizokami H, Tokunaga O, Shin T (1998) Expression of MMP-1, TIMP-1, and type I collagen in laryngeal carcinoma. Mod Pathol 11:878–885

    CAS  PubMed  Google Scholar 

  46. Maeta H, Ohgi S, Terada T (2001) Protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in papillary thyroid carcinomas. Virchows Arch 438:121–128. doi:10.1007/s004280000286

    Article  CAS  PubMed  Google Scholar 

  47. Liu XW, Taube ME, Jung KK, Dong Z, Lee YJ, Roshy S, Sloane BF, Fridman R, Kim HR (2005) Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells from extrinsic cell death: a potential oncogenic activity of tissue inhibitor of metalloproteinase-1. Cancer Res 65:898–906

    CAS  PubMed  Google Scholar 

  48. Davidsen ML, Wurtz S, Rømer MU, Sørensen NM, Johansen SK, Christensen IJ, Larsen JK, Offenberg H, Brünner N, Lademann U (2006) TIMP-1 gene deficiency increases tumour cell sensitivity to chemotherapy-induced apoptosis. Br J Cancer 95:1114–1120. doi:10.1038/sj.bjc.6603378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Li G, Fridman R, Kim HR (1999) Tissue inhibitor of metalloproteinase-1 inhibits apoptosis of human breast epithelial cells. Cancer Res 59:6267–6275

    CAS  PubMed  Google Scholar 

  50. Jung KK, Liu XW, Chirco R, Fridman R, Kim HR (2006) Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 25:3934–3942. doi:10.1038/sj.emboj.7601281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We are grateful to Ole Nielsen for collaboration on the immunohistochemical protocol. Thanks are also due to Professor Werner Vach for help with the statistical survival analysis.

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Authors and Affiliations

  1. Department of Pathology, Odense University Hospital, Odense, Denmark

    Charlotte Aaberg-Jessen, Karina Christensen, Tanja Dreehsen, Henrik Daa Schrøder & Bjarne Winther Kristensen

  2. Department of Veterinary Pathobiology, University of Copenhagen, Copenhagen, Denmark

    Hanne Offenberg, Annette Bartels & Nils Brünner

  3. Department of Oncology, Odense University Hospital, Odense, Denmark

    Steinbjørn Hansen

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  1. Charlotte Aaberg-Jessen
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  2. Karina Christensen
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  3. Hanne Offenberg
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Correspondence to Charlotte Aaberg-Jessen.

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Aaberg-Jessen, C., Christensen, K., Offenberg, H. et al. Low expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in glioblastoma predicts longer patient survival. J Neurooncol 95, 117–128 (2009). https://doi.org/10.1007/s11060-009-9910-8

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  • DOI: https://doi.org/10.1007/s11060-009-9910-8

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