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Tissue inhibitor of matrix metalloproteinase-3 has both anti-metastatic and anti-tumourigenic properties

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Abstract

TIMP-3 is one of four tissue inhibitors of matrix metalloproteinases, the endogenous inhibitors of the matrix metalloproteinase enzymes. These enzymes have an important role in metastasis, in the invasion of cancer cells through the basement membrane and extracellular matrix. TIMP-1, -2 and -4 both promote and inhibit tumour development, in a context-dependent manner, however TIMP-3 is consistently anti-tumourigenic. TIMP-3 is also the only insoluble member of the family, being either bound to the extracellular matrix or the low density lipoprotein-related protein-1, through which it can be endocytosed. Levels of TIMP-3 have also been shown to be regulated by micro RNAs and promoter hypermethylation, resulting in frequent silencing in many tumour types, to the extent that its expression has been suggested as a prognostic marker in some tumours, being associated with lower levels of metastasis, or better response to treatment. TIMP-3 has been shown to have anti-metastatic effects, both through inhibition of matrix metalloproteinases and ADAM family members and downregulation of angiogenesis. This occurs via interactions with receptors including VEGF, via modulation of signaling pathways and due to protease inhibition. TIMP-3 has also been shown to reduce tumour growth rate, most often by inducing apoptosis by stabilisation of death receptors. A number of successful mechanisms of delivery of TIMP-3 to tumour or inflammatory sites have been investigated in vitro or in animal studies. It may therefore be worthwhile further exploring the use of TIMP-3 as a potential anti-metastatic or anti-tumorigenic therapy for many tumour types.

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References

  1. 1.

    Gonzalez-Avila G, Sommer B, Mendoza-Posada DA, Ramos C, Garcia-Hernandez AA, Falfan-Valencia R (2019) Matrix metalloproteinases participation in the metastatic process and their diagnostic and therapeutic applications in cancer. Crit Rev Oncol 137:57–83. https://doi.org/10.1016/j.critrevonc.2019.02.010

  2. 2.

    Young D, Das N, Anowai A, Dufour A (2019) Matrix metalloproteases as influencers of the cells’ social media. Int J Mol Sci 20:3847. https://doi.org/10.3390/ijms20163847

  3. 3.

    McCawley LJ, Matrisian LM (2000) Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today 6(4):149–156

  4. 4.

    Isaacson KJ, Jensen MM, Subrahmanyam NB, Ghandehari H (2017) Matrix-metalloproteinases as targets for controlled delivery in cancer: an analysis of upregulation and expression. J Control Release 259:62–75. https://doi.org/10.1016/j.jconrel.2017.01.034

  5. 5.

    Vihinen P, Kahari VM (2002) Matrix metalloproteinases in cancer: prognostic markers and therapeutic targets. Int J Cancer 99:157–166. https://doi.org/10.1002/ijc.10329

  6. 6.

    Talvensaari-Mattila A, Paako P, Turpeenniemi-Hujanen T (1999) MMP-2 positivity and age less than 40 years increases the risk for recurrence in premenopausal patients with node-positive breast carcinoma. Breast Cancer Res Treat 58:287–293

  7. 7.

    Garbisa S, Scagliotti G, Masiero L, Di Francesco C, Caenazzo C, Onisto M, Micela M, Stetler-Stevenson WG, Liotta LA (1992) Correlation of serum metalloproteinase levels with lung cancer metastasis and response to therapy. Cancer Res 15:4548–4549

  8. 8.

    Slaton JW, Inoue K, Perrotte P, El-Naggar AK, Swanson DA, Fidler IJ, Dinney CPN (2001) Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. Am J Pathol 158:735–743. https://doi.org/10.1016/S0002-9440(10)64016-3

  9. 9.

    Fujisawa T, Rubin B, Suzuki A, Patel PS, Gahl WA, Joshi BH, Puri RK (2012) Cysteamine suppresses invasion, metastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer (cysteamine suppresses metastatic pancreatic cancer). PLoS ONE 7(4):e34437. https://doi.org/10.1371/journal.pone.0034437

  10. 10.

    Gialeli C, Theocharis AD, Karamanos NK (2011) Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J 278(1):16–27. https://doi.org/10.1111/j.1742-4658.2010.07919.x

  11. 11.

    Coussens LM, Fingleton B, Matrisian LM (2002) Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science 295(5564):2387–2392. https://doi.org/10.1126/science.1067100

  12. 12.

    Kahari VM, Saarialho-Kere U (1999) Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med 31(1):34–45

  13. 13.

    Arpino V, Brock M, Gill SE (2015) The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol 44–46:247–254. https://doi.org/10.1016/j.matbio.2015.03.005

  14. 14.

    Brew K, Nagase H (2010) The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. BBA Mol Cell Res 1803(1):55–71. https://doi.org/10.1016/j.bbamcr.2010.01.003

  15. 15.

    Bode W, Fernandez-Catalan C, Grams F, Gomis-Rueth FX, Nagase H, Tschesche H, Maskos K (1999) Insights into MMP-TIMP interactions. Ann N Y Acad Sci 878:73–91. https://doi.org/10.1111/j.1749-6632.1999.tb07675.x

  16. 16.

    Murphy G (2011) Tissue inhibitors of metalloproteinases. Genome Biol 12(11):233. https://doi.org/10.1186/gb-2011-12-11-233

  17. 17.

    Jackson HW, Defamie V, Waterhouse P, Khokha R (2017) TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 17(1):38–53. https://doi.org/10.1038/nrc.2016.115

  18. 18.

    Anand-Apte B, Bao L, Smith R, Iwata K, Olsen BR, Zetter B, Apte SS (1996) A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol 74(6):853–862

  19. 19.

    Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516. https://doi.org/10.1146/annurev.cellbio.17.1.463

  20. 20.

    Yu WH, Yu S, Meng Q, Brew K, Woessner JF Jr (2000) TIMP-3 binds to sulfated glycosaminoglycans of the extracellular matrix. J Biol Chem 275(40):31226–31232. https://doi.org/10.1074/jbc.M000907200

  21. 21.

    Destouches D, Huet E, Sader M, Frechault S, Carpentier G, Ayoul F, Briand JP, Menashi S, Courty J (2012) Multivalent pseudopeptides targeting cell surface nucleoproteins inhibit cancer cell invasion through tissue inhibitor of metalloproteinases 3 (TIMP-3) release. J Biol Chem 287(52):43685–43693. https://doi.org/10.1074/jbc.M112.380402

  22. 22.

    Scilabra SD, Troeberg L, Yamamoto K, Emonard H, Thøgersen I, Enghild JJ, Strickland DK, Nagase H (2013) Differential regulation of extracellular tissue inhibitor of metalloproteinases-3 levels by cell membrane-bound and shed low density lipoprotein receptor-related protein 1. J Biol Chem 288(1):332. https://doi.org/10.1074/jbc.M112.393322

  23. 23.

    Yamamoto K, Murphy G, Troeberg L (2015) Extracellular regulation of metalloproteinases. Matrix Biol 44–46:255–263. https://doi.org/10.1016/j.matbio.2015.02.007

  24. 24.

    Scilabra SD, Yamamoto K, Pigoni M, Sakamoto K, Müller SA, Papadopoulou A, Lichtenthaler SF, Troeberg L, Nagase H, Kadomatsu K (2017) Dissecting the interaction between tissue inhibitor of metalloproteinases-3 (TIMP-3) and low density lipoprotein receptor-related protein-1 (LRP-1): development of a “TRAP” to increase levels of TIMP-3 in the tissue. Matrix Biol 59:69–79. https://doi.org/10.1016/j.matbio.2016.07.004

  25. 25.

    Troeberg L, Fushimi K, Scilabra SD, Nakamura H, Dive V, Thøgersen IB, Enghild JJ, Nagase H (2009) The C-terminal domains of ADAMTS-4 and ADAMTS-5 promote association with N-TIMP-3. Matrix Biol 28(8):463–469. https://doi.org/10.1016/j.matbio.2009.07.005

  26. 26.

    Troeberg L, Lazenbatt C, Anower-E-Khuda MF, Freeman C, Federov O, Habuchi H, Habuchi O, Kimata K, Nagase H (2014) Sulfated glycosaminoglycans control the extracellular trafficking and the activity of the metalloprotease inhibitor TIMP-3. Chem Biol 21(10):1300–1309. https://doi.org/10.1016/j.chembiol.2014.07.014

  27. 27.

    Troeberg L, Fushimi K, Khokha R, Emonard H, Ghosh P, Nagase H (2008) Calcium pentosan polysulfate is a multifaceted exosite inhibitor of aggrecanases. FASEB J 22(10):3515–3524. https://doi.org/10.1096/fj.08-112680

  28. 28.

    Garofalo M, Di Leva G, Romano G, Nuovo G, Suh SS, Ngankeu A, Taccioli C, Pichiorri F, Alder H, Secchiero P, Gasparini P, Gonelli A, Costinean S, Acunzo M, Condorelli G, Croce CM (2009) miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16(6):498–509. https://doi.org/10.1016/j.ccr.2009.10.014

  29. 29.

    Dong M, Yang P, Hua F (2015) MiR-191 modulates malignant transformation of endometriosis through regulating TIMP3. Med Sci Monit 21: 915–920. https://doi.org/10.12659/MSM.893872

  30. 30.

    Petrovic N, Sami A, Martinovic J, Zaric M, Nakashidze I, Lukic S, Jovanovic-Cupic S (2017) TIMP-3 mRNA expression levels positively correlates with levels of miR-21 in in situ BC and negatively in PR positive invasive BC. Pathol Res Pract 213(10):1264–1270. https://doi.org/10.1016/j.prp.2017.08.012

  31. 31.

    Bachman KE, Herman JG, Corn PG, Merlo A, Costello JF, Cavenee WK, Baylin SB, Graff JR (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(4):798

  32. 32.

    Brueckl WM, Grombach J, Wein A, Ruckert S, Porzner M, Dietmaier W, Rümmele P, Croner RS, Boxberger F, Kirchner T, Hohenberger W, Hahn EG, Jung A (2005) Alterations in the tissue inhibitor of metalloproteinase-3 (TIMP-3) are found frequently in human colorectal tumours displaying either microsatellite stability (MSS) or instability (MSI). Cancer Lett 223(1):137–142. https://doi.org/10.1016/j.canlet.2004.09.037

  33. 33.

    Cao J, Li Z, Yang L, Liu C, Luan X (2016) Association between tissue inhibitor of metalloproteinase-3 Gene methylation and gastric cancer risk: a meta-analysis. Genet Test Mol Biomark 20(8):427–431. https://doi.org/10.1089/gtmb.2015.0332

  34. 34.

    Gu P, Xing X, Tänzer M, Röcken C, Weichert W, Ivanauskas A, Pross M, Peitz U, Malfertheiner P, Schmid RM, Ebert MP (2008) Frequent loss of TIMP-3 expression in progression of esophageal and gastric adenocarcinomas. Neoplasia 10(6):563. https://doi.org/10.1593/neo.08208

  35. 35.

    Yu JL, Lv P, Han J, Zhu X, Hong LL, Zhu WY, Wang XB, Wu YC, Li P, Ling ZQ (2014) Methylated TIMP-3 DNA in body fluids is an independent prognostic factor for gastric cancer. Arch Pathol Lab Med 138(11):1466–1473. https://doi.org/10.5858/arpa.2013-0285-OA

  36. 36.

    Xu C, Hou Z, Zhan P, Zhao W, Chang C, Zou J, Hu H, Zhang Y, Yao X, Yu L, Yan J (2013) EZH2 regulates cancer cell migration through repressing TIMP-3 in non-small cell lung cancer. Med Oncol 30(4):713. https://doi.org/10.1007/s12032-013-0713-6

  37. 37.

    Wu DW, Tsai LH, Chen PM, Lee MC, Wang L, Chen CY, Cheng YW, Lee H (2012) Loss of TIMP-3 promotes tumor invasion via elevated IL-6 production and predicts poor survival and relapse in HPV-infected non-small cell lung cancer. Am J Pathol 181(5):1796–1806. https://doi.org/10.1016/j.ajpath.2012.07.032

  38. 38.

    van Kempen PM, van Bockel L, Braunius WW, Moelans CB, van Olst M, de Jong R, Stegeman I, van Diest PJ, Grolman W, Willems SM (2014) HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP-3 and CADM-1 promoter hypermethylation. Cancer Med 3(5):1185–1196. https://doi.org/10.1002/cam4.313

  39. 39.

    Nayak CS, Carvalho AL, Jeronimo C, Henrique R, Kim MM, Hoque MO, Chang S, Jiang WW, Koch W, Westra W, Sidransky D, Califano J (2007) Positive correlation of tissue inhibitor of metalloproteinase-3 and death-associated protein kinase hypermethylation in head and neck squamous cell carcinoma. Laryngoscope 117(8):1376–1380. https://doi.org/10.1097/MLG.0b013e31806865a8

  40. 40.

    Anania M, Sensi M, Radaelli E, Miranda C, Vizioli MG, Pagliardini S, Favini E, Cleris L, Supino R, Formelli F, Borrello MG, Pierotti MA, Greco A (2011) TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene 30(27):3011–3023. https://doi.org/10.1038/onc.2011.18

  41. 41.

    Mitsutoshi N, Ishida E, Shimada K, Kishi M, Nakase H, Sakaki T, Konishi N (2004) Frequent LOH on 22q123 and TIMP-3 inactivation occur in the progression to secondary glioblastomas. Lab Invest 85(2):165. https://doi.org/10.1038/labinvest.3700223

  42. 42.

    Barski D, Wolter M, Reifenberger G, Riemenschneider MJ (2010) Hypermethylation and transcriptional downregulation of the TIMP3 gene is associated with allelic loss on 22q123 and malignancy in meningiomas. Brain Pathol 20(3):623–631. https://doi.org/10.1111/j.1750-3639.2009.00340.x

  43. 43.

    Kang SH, Choi HH, Kim SG, Jong HS, Kim NK, Kim SJ, Bang YJ (2000) Transcriptional inactivation of the tissue inhibitor of metalloproteinase-3 gene by dna hypermethylation of the 5’-CpG island in human gastric cancer cell lines. Int J Cancer 86(5):632. https://doi.org/10.1002/(sici)1097-0215(20000601)86:5%3c632:aid-ijc5%3e3.0.co;2-5

  44. 44.

    Yun J, Park MH, Son DJ, Nam KT, Moon DB, Ju JH, Hwang OK, Choi JS, Kim TH, Jung YS, Hwang DY, Han SB, Yoon DY, Hong JT (2018) IL-32 gamma reduces lung tumour development through upregulation of TIMP-3 overexpression and hypomethylation. Cell Death Dis 9:306. https://doi.org/10.1038/s41419-018-0375-6

  45. 45.

    Allione F, Eisinger F, Parc P, Noguchi T, Sobol H, Birnbaum D (1998) Loss of heterozygosity at loci from chromosome arm 22Q in human sporadic breast carcinomas. Int J Cancer 75(2):181–186. https://doi.org/10.1002/(sici)1097-0215(19980119)75:2%3c181:aid-ijc3%3e3.0.co;2-q

  46. 46.

    Zhou CZ, Peng ZH, Zhang F, Qiu GQ, He L (2002) Loss of heterozygosity on long arm of chromosome 22 in sporadic colorectal carcinoma. World J Gastroenterol 8(4):668–673. https://doi.org/10.3748/wjg.v8.i4.668

  47. 47.

    Ino SY, Silver JS, Blazejewski L, Nishikawa R, Matsutani M, von Deimling A, Louis DN (1999) Common regions of deletion on chromosome 22q12.3–q13.1 and 22q13.2 in human astrocytomas appear related to malignancy grade. J Neuropath Exp Neurol 58(8):881–885. https://doi.org/10.1097/00005072-199908000-00010

  48. 48.

    Wild A, Langer P, Celik I, Chaloupka B, Bartsch DK (2002) Chromosome 22q in pancreatic endocrine tumors: identification of a homozygous deletion and potential prognostic associations of allelic deletions. Eur J Endocrin 147(4):507–513

  49. 49.

    Hojilla CV, Jackson HW, Khokha R (2011) TIMP3 regulates mammary epithelial apoptosis with immune cell recruitment through differential TNF dependence. PLoS ONE 6(10):e26718. https://doi.org/10.1371/journal.pone.0026718

  50. 50.

    Martin EL, Moyer BZ, Pape MC, Starcher B, Leco KJ, Veldhuizen RA (2003) Negative impact of tissue inhibitor of metalloproteinase-3 null mutation on lung structure and function in response to sepsis. Am J Physiol 285(6):L1222–L1232. https://doi.org/10.1152/ajplung.00141.2003

  51. 51.

    Murthy A, Shao YW, Defamie V, Wedeles C, Smookler D, Khokha R (2012) Stromal TIMP3 regulates liver lymphocyte populations and provides protection against Th1 T cell-driven autoimmune hepatitis. J Immunol 188(6):2876–2883. https://doi.org/10.4049/jimmunol.1102199

  52. 52.

    Gill SE, Huizar I, Bench EM, Nazarian N, Leco KJ, Khokha R, Parks BC (2008) A protective role for TIMP3 in acute lung injury. Matrix Biol. https://doi.org/10.1016/j.matbio.2008.09.362

  53. 53.

    Fiorentino L, Cavalera M, Menini S, Marchetti V, Mavilio M, Fabrizi M, Conserva F, Casagrande V, Menghini R, Pontrelli P, Arisi I, D'Onofrio M, Lauro D, Khokha R, Accili D, Pugliese G, Gesualdo L, Lauro R, Federici M (2013) Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Mol Med 5(3):441–455. https://doi.org/10.1002/emmm.201201475

  54. 54.

    Hewing NJ, Weskamp G, Vermaat J, Farage E, Glomski K, Swendeman S, Chan RVP, Chiang MF, Khokha R, Apte BA, Blobel CP (2013) Intravitreal injection of TIMP3 or the EGFR inhibitor erlotinib offers protection from oxygen-induced retinopathy in mice. Invest Opthalmol Vis Sci 54(1):864–870. https://doi.org/10.1167/iovs.12-10954

  55. 55.

    Menghini R, Menini S, Amoruso R, Fiorentino L, Casagrande V, Marzano V, Tornei F, Bertucci P, Iacobini C, Serino M, Porzio O, Hribal ML, Folli F, Khokha R, Urbani A, Lauro R, Pugliese G, Federici M (2009) Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice. Gastroenterol 136(2):663–672.e4. https://doi.org/10.1053/j.gastro.2008.10.079

  56. 56.

    Baker AH, Edwards DR, Murphy G (2002) Metalloproteinase inhibitors: biological actions and therapeutic opportunities. J Cell Sci 115:3719–3727. https://doi.org/10.1242/jcs.00063

  57. 57.

    Amour A, Slocombe PM, Webster A, Butler M, Knight CG, Smith BJ, Stephens PE, Shelley C, Hutton M, Knauper V, Docherty AJP, Murphy G (1998) TNF-α converting enzyme (TACE) is inhibited by TIMP-3. FEBS Lett 435:39–44. https://doi.org/10.1016/s0014-5793(98)01031-x

  58. 58.

    Amour A, Knight CG, Webster A, Slocombe PM, Stephens PE, Knäuper V, Docherty AJ, Murphy G (2000) The in vitro activity of ADAM-10 is inhibited by TIMP-1 and TIMP-3. FEBS Lett 473(3):275–279. https://doi.org/10.1016/s0014-5793(00)01528-3

  59. 59.

    Lee MH, Maskos K, Knäuper V, Dodds P, Murphy G (2002) Mapping and characterization of the functional epitopes of tissue inhibitor of metalloproteinases (TIMP)-3 using TIMP-1 as the scaffold: a new frontier in TIMP engineering. Protein Sci 11(10):2493–2503. https://doi.org/10.1110/ps.0216202

  60. 60.

    Lee MH, Verma V, Maskos K, Nath D, Knäuper V, Dodds P, Amour A, Murphy G (2002) Engineering N-terminal domain of tissue inhibitor of metalloproteinase (TIMP)-3 to be a better inhibitor against tumour necrosis factor-alpha-converting enzyme. Biochem J 364(Pt 1):227–234. https://doi.org/10.1042/bj3640227

  61. 61.

    Wisniewska M, Goettig P, Maskos K, Belouski E, Winters D, Hecht R, Black R, Bode W (2008) Structural determinants of the ADAM inhibition by TIMP-3: crystal structure of the TACE-N-TIMP-3 complex. J Mol Biol 381(5):1307–1319. https://doi.org/10.1016/j.jmb.2008.06.088

  62. 62.

    Lim NH, Kashiwagi M, Visse R, Jones J, Enghild JJ, Brew K, Nagase H (2010) Reactive-site mutants of N-TIMP-3 that selectively inhibit ADAMTS-4 and ADAMTS-5: biological and structural implications. Biochem J 431(Pt 1):113–122. https://doi.org/10.1042/BJ20100725

  63. 63.

    Loechel F, Fox JW, Murphy G, Albechtsen R, Wewer UM (2000) ADAM 12-S cleaves IGFBP-3 and IGFBP-5 and is inhibited by TIMP-3. Biochem Biophys Res Commun 278:511–515. https://doi.org/10.1006/bbrc.2000.3835

  64. 64.

    Kunte M, Desai K (2018) The protein extract of chlorella minutissima inhibits the expression of MMP-1, MMP-2 and MMP-9 in cancer cells through upregulation of TIMP-3 and down regulation of c-jun. Cell J 20(2):211–219. https://doi.org/10.22074/cellj.2018.5277

  65. 65.

    Kuskunović-Vlahovljak S, Čamdžić N, Radović S, Dorić M, Babić M, Salčin EL, Džananović L (2017) Is the expression of matrix metalloproteinases (MMP-2, -9) and tissue inhibitors of metalloproteinases (TIMP-1, -2, and -3) associated with angiogenesis and clinicopathological features for breast cancer. J Health Sci 7(3):158–168. https://doi.org/10.17532/jhsci.2017.460

  66. 66.

    Das AM, Bolkestein M, van der Klok T, Oude Ophuis CM, Vermeulen CE, Rens JA, Dinjens WN, Atmodimedjo PN, Verhoef C, Koljenović S, Smits R, Ten Hagen TL, Eggermont AM (2016) Tissue inhibitor of metalloproteinase-3 (TIMP3) expression decreases during melanoma progression and inhibits melanoma cell migration. Eur J Cancer 66:34–46. https://doi.org/10.1016/j.ejca.2016.06.020

  67. 67.

    Ahonen M, Baker AH, Kaehaeri VM (1998) Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 58(11):2310–2315

  68. 68.

    Roy R, Wewer UM, Zurakowski D, Pories SE, Moses MA (2004) ADAM12 cleaves extracellular matrix proteins and correlates with cancer status and stage. J Biol Chem 279:51323–51330. https://doi.org/10.1074/jbc.M409565200

  69. 69.

    Mahller YY, Vaikunth SS, Ripberger MC, Baird WH, Saeki Y, Cancelas JA, Crombleholme TM, Cripe TP (2008) Tissue inhibitor of metalloproteinase-3 via oncolytic herpesvirus inhibits tumor growth and vascular progenitors. Cancer Res 68(4):1170–1179. https://doi.org/10.1158/0008-5472.CAN-07-2734

  70. 70.

    Anand-Apte B, Pepper MS, Voest E, Montesano R, Olsen B, Murphy G, Apte SS, Zetter B (1997) Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Opthal Vis Sci 38(5):817–823

  71. 71.

    Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, Baker A, Anand-Apte B (2003) A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med 9(4):407–415. https://doi.org/10.1038/nm846

  72. 72.

    Chen YY, Brown NJ, Jones R, Lewis CE, Mujamammi AH, Muthana M, Seed MP, Barker MD (2014) A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice. Angiogenesis 17(1):207–219. https://doi.org/10.1007/s10456-013-9389-y

  73. 73.

    Kang KH, Park SY, Rho SB, Lee JH (2008) Tissue inhibitor of metalloproteinases-3 interacts with angiotensin II type 2 receptor and additively inhibits angiogenesis. Cardiovasc Res 79(1):150. https://doi.org/10.1093/cvr/cvn072

  74. 74.

    Finan KM, Hodge G, Reynolds AM, Hodge S, Holmes MD, Baker AH, Reynolds PN (2006) In vitro susceptibility to the pro-apoptotic effects of TIMP-3 gene delivery translates to greater in vivo efficacy versus gene delivery for TIMPs-1 or -2. Lung Cancer 53(3):273–284. https://doi.org/10.1016/j.lungcan.2006.06.006

  75. 75.

    Koers-Wunrau C, Wehmeyer C, Hillmann A, Pap T, Dankbar B (2013) Cell surface-bound TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival pathways. PLoS ONE 8(7):e70709. https://doi.org/10.1371/journal.pone.0070709

  76. 76.

    Qi JH, Anand-Apte B (2015) Tissue inhibitor of metalloproteinase-3 (TIMP3) promotes endothelial apoptosis via a caspase-independent mechanism. Apoptosis 20(4):523–534. https://doi.org/10.1007/s10495-014-1076-y

  77. 77.

    English WR, Ireland-Zecchini H, Baker AH, Littlewood TD, Bennett MR, Murphy G (2018) Tissue Inhibitor of Metalloproteinase-3 (TIMP-3) induces FAS dependent apoptosis in human vascular smooth muscle cells. PLoS ONE 13(4):e0195116. https://doi.org/10.1371/journal.pone.0195116

  78. 78.

    Strand S, Vollmer P, van den Abeelen L, Gottfried D, Alla V, Heid H, Kuball J, Theobald M, Galle PR, Strand D (2004) Cleavage of CD95 by matrix metalloproteinase-7 induces apoptosis resistance in tumour cells. Oncogene 23:3732–3736. https://doi.org/10.1038/sj.onc.1207387

  79. 79.

    Mitsiades N, Yu WH, Poulaki V, Tsokos M, Stamenkovic I (2001) Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res 61:577–581

  80. 80.

    Jones SE, Jomary C, Neal MJ (1994) Expression of TIMP3 mRNA is elevated in retinas affected by simplex retinitis pigmentosa. FEBS Lett 352(2):171–174. https://doi.org/10.1016/0014-5793(94)00951-1

  81. 81.

    Bian J, Wang Y, Smith MR, Kim H, Jacobs C, Jackman J, Kung HF, Colburn NH, Sun Y (1996) Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. Carcinogenesis 17(9):1805–1811. https://doi.org/10.1093/carcin/17.9.1805

  82. 82.

    Smith MR, Kung H, Durum SK, Colburn NH, Sun Y (1997) TIMP-3 induces cell death by stabilizing TNF-α receptors ion the surface of human colon carcinoma cells. Cytokine 9(10):770–780

  83. 83.

    Baker AH, Zaltsman AB, George SJ, Newby AC (1998) Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro. TIMP-3 promotes apoptosis. J Clin Invest 101(6):1478–1487. https://doi.org/10.1172/JCI1584

  84. 84.

    Baker AH, George SJ, Zaltsman AB, Murphy G, Newby AC (1999) Inhibition of invasion and induction of apoptotic cell death of cancer cell lines by overexpression of TIMP-3. Br J Cancer 79(9–10):1347. https://doi.org/10.1038/sj.bjc.6690217

  85. 85.

    Bond M, Murphy G, Bennett MR, Amour A, Knauper V, Newby AC, Baker AH (2000) Localization of the death domain of tissue inhibitor of metalloproteinase-3 to the N terminus. Metalloproteinase inhibition is associated with proapoptotic activity. J Biol Chem 275(52):41358–41363. https://doi.org/10.1074/jbc.M007929200

  86. 86.

    Ahonen M, Poukkula M, Baker AH, Kashiwagi M, Nagase H, Eriksson JE, Kähäri VM (2003) Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilisation of death receptors. Oncogene 22:2121–2134. https://doi.org/10.1038/sj.onc.1206292

  87. 87.

    King KE, Reddi DM, Ponnamperuma RM, Gerdes M, Weinberg WC (2014) Dysregulated [Delta]Np63[alpha] negatively regulates the maspin promoter in keratinocytes via blocking endogenous p73 binding. Mol Carcinog 53(9):698–710. https://doi.org/10.1002/mc.22022

  88. 88.

    Deb G, Shankar E, Thakur VS, Ponsky LE, Bodner DR, Fu P, Gupta S (2019) Green tea-induced epigenetic reactivation of tissue inhibitor of matrix metalloproteinase-3 suppresses prostate cancer progression through histone-modifying enzymes. Mol Carcinog 58(7):1194–1207. https://doi.org/10.1002/mc.23003

  89. 89.

    Maturi V, Enroth S, Heldin CH, Moustakas A (2018) Genome-wide binding of transcription factor ZEB1 in triple-negative breast cancer cells. J Cell Physiol 233(10):7113–7127. https://doi.org/10.1002/jcp.26634

  90. 90.

    Liu Z, Ren Y, Zhu F (2018) Expression of MMP-2 and TIMP-3 with incidence and prognosis of giant-cell tumor of the bone. Oncol Lett 16(1):721–726. https://doi.org/10.3892/ol.2018.8696

  91. 91.

    Hilska M, Roberts PJ, Collan YU, Laine VJ, Kössi J, Hirsimäki P, Rahkonen O, Laato M (2007) Prognostic significance of matrix metalloproteinases-1, -2, -7 and -13 and tissue inhibitors of metalloproteinases-1, -2, -3 and -4 in colorectal cancer. Int J Cancer 121(4):714–723. https://doi.org/10.1002/ijc.22747

  92. 92.

    Bodnar M, Szelberg L, Kazmierczak W, Marszalek A (2015) Tumor progression driven by pathways activating matrix metalloproteinaeses and their inhibitors. J Oral Pathol Med 44(6):437–443. https://doi.org/10.1111/jop.12270

  93. 93.

    Span PN, Lindberg RL, Manders P, Tjan-Heijnen VC, Heuvel JJ, Beex LV, Sweep CG (2004) Tissue inhibitors of metalloproteinase expression in human breast cancer: TIMP-3 is associated with adjuvant endocrine therapy success. J Pathol 202:395–402. https://doi.org/10.1002/path.1528

  94. 94.

    Alberts BM, Sacre SM, Bush PG, Mullen LM (2019) Engeineering of TIMP-3 as a LAP-fusion protein for targeting to sites of inflammation. J Cell Mol Med 23:1617–1621. https://doi.org/10.1111/jcmm.14019

  95. 95.

    Purcell BP, Barlow SC, Perreault PE, Freeburg L, Doviak H, Jacobs J, Hoenes A, Zellars KN, Khakoo AY, Lee T, Burdick JA, Spinale FG (2018) Delivery of a matrix metalloproteinase-responsive hydrogel releasing TIMP-3 after myocardial infarction: effects on left ventricular remodeling. Am J Physiol Heart Circ Physiol 315(4):H814. https://doi.org/10.1152/ajpheart.00076.2018

  96. 96.

    Tian H, Huang ML, Liu KY, Jia ZB, Sun L, Jiang SL, Liu W, McDonald Kinkaid HY, Wu J, Li RK (2012) Inhibiting matrix metalloproteinase by cell-based TIMP-3 gene transfer effectively treats acute and chronic ischemic cardiomyopathy. Cell Transplant 21(5):1039–1053. https://doi.org/10.3727/096368911X601000

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Acknowledgements

This work was funded by the School of Biomedical Sciences’ Dean’s Bequest Fund of the University of Otago and a University of Otago Research Grant.

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Correspondence to Sarah K. Baird.

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Rai, G.P., Baird, S.K. Tissue inhibitor of matrix metalloproteinase-3 has both anti-metastatic and anti-tumourigenic properties. Clin Exp Metastasis 37, 69–76 (2020). https://doi.org/10.1007/s10585-019-10017-y

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Keywords

  • Matrix metalloproteinase
  • Tissue inhibitor of matrix metalloproteinase
  • Metastasis
  • Apoptosis
  • ADAM