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Open Access 01-08-2019 | Oropharyngeal Cancer | Original Article

High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer

Authors: Timo Carpén, Timo Sorsa, Lauri Jouhi, Taina Tervahartiala, Caj Haglund, Stina Syrjänen, Jussi Tarkkanen, Hesham Mohamed, Antti Mäkitie, Jaana Hagström, Petri S. Mattila

Published in: Cancer Immunology, Immunotherapy | Issue 8/2019

Abstract

Background

An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC.

Materials and methods

A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS).

Results

High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8–117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3–57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels.

Conclusion

Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.

Mehanna H, Beech T, Nicholson T, El-Hariry I, McConkey C, Paleri V, Roberts S (2013) Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer-systematic review and meta-analysis of trends by time and region. Head Neck 35(5):747–755. https://doi.org/10.1002/hed.22015 CrossRefPubMed

Habbous S, Chu KP, Qiu X, La Delfa A, Harland LT, Fadhel E, Hui A, Perez-Ordonez B, Weinreb I, Liu FF, Waldron J, O’Sullivan B, Goldstein D, Xu W, Huang SH, Liu G (2013) The changing incidence of human papillomavirus-associated oropharyngeal cancer using multiple imputation from 2000 to 2010 at a Comprehensive Cancer Centre. Cancer Epidemiol 37(6):820–829. https://doi.org/10.1016/j.canep.2013.09.011 CrossRefPubMed

Stein AP, Saha S, Kraninger JL, Swick AD, Yu M, Lambert PF, Kimple RJ (2015) Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review. Cancer J 21(3):138–146. https://doi.org/10.1097/PPO.0000000000000115 CrossRefPubMedPubMedCentral

Jouhi L, Halme E, Irjala H, Saarilahti K, Koivunen P, Pukkila M, Hagstrom J, Haglund C, Lindholm P, Hirvikoski P, Vaittinen S, Ellonen A, Tikanto J, Blomster H, Laranne J, Grenman R, Makitie A, Atula T (2018) Epidemiological and treatment-related factors contribute to improved outcome of oropharyngeal squamous cell carcinoma in Finland. Acta Oncol 57(4):541–551. https://doi.org/10.1080/0284186x.2017.1400688 CrossRefPubMed

Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100(6):407–420. https://doi.org/10.1093/jnci/djn025 CrossRefPubMed

Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269. https://doi.org/10.1093/jnci/djn011 CrossRefPubMed

Ragin CC, Taioli E (2007) Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 121(8):1813–1820. https://doi.org/10.1002/ijc.22851 CrossRefPubMed

Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35. https://doi.org/10.1056/NEJMoa0912217 CrossRefPubMedPubMedCentral

Egeblad M, Werb Z (2002) New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2(3):161–174. https://doi.org/10.1038/nrc745 CrossRefPubMed

10.

Lopez-Otin C, Bond JS (2008) Proteases: multifunctional enzymes in life and disease. J Biol Chem 283(45):30433–30437. https://doi.org/10.1074/jbc.R800035200 CrossRefPubMedPubMedCentral

11.

Lempinen M, Lyytinen I, Nordin A, Tervahartiala T, Makisalo H, Sorsa T, Isoniemi H (2013) Prognostic value of serum MMP-8, -9 and TIMP-1 in patients with hepatocellular carcinoma. Ann Med 45(7):482–487. https://doi.org/10.3109/07853890.2013.823779 CrossRefPubMed

12.

Visse R, Nagase H (2003) Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 92(8):827–839. https://doi.org/10.1161/01.RES.0000070112.80711.3D CrossRefPubMed

13.

Karadag A, Fedarko NS, Fisher LW (2005) Dentin matrix protein 1 enhances invasion potential of colon cancer cells by bridging matrix metalloproteinase-9 to integrins and CD44. Cancer Res 65(24):11545–11552. https://doi.org/10.1158/0008-5472.Can-05-2861 CrossRefPubMedPubMedCentral

14.

Chirco R, Liu XW, Jung KK, Kim HR (2006) Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25(1):99–113. https://doi.org/10.1007/s10555-006-7893-x CrossRefPubMed

15.

Liotta LA, Tryggvason K, Garbisa S, Hart I, Foltz CM, Shafie S (1980) Metastatic potential correlates with enzymatic degradation of basement membrane collagen. Nature 284:67. https://doi.org/10.1038/284067a0 CrossRefPubMed

16.

Kessenbrock K, Plaks V, Werb Z (2010) Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1):52–67. https://doi.org/10.1016/j.cell.2010.03.015 CrossRefPubMedPubMedCentral

17.

Imanishi Y, Fujii M, Tokumaru Y, Tomita T, Kanke M, Kanzaki J, Kameyama K, Otani Y, Sato H (2000) Clinical significance of expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 in human head and neck squamous cell carcinoma. Hum Pathol 31(8):895–904. https://doi.org/10.1053/hupa.2000.9756 CrossRefPubMed

18.

Ahmed Haji Omar A, Haglund C, Virolainen S, Hayry V, Atula T, Kontio R, Salo T, Sorsa T, Hagstrom J (2015) MMP-7, MMP-8, and MMP-9 in oral and cutaneous squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol 119(4):459–467. https://doi.org/10.1016/j.oooo.2014.12.019 CrossRefPubMed

19.

Moilanen M, Pirila E, Grenman R, Sorsa T, Salo T (2002) Expression and regulation of collagenase-2 (MMP-8) in head and neck squamous cell carcinomas. J Pathol 197(1):72–81. https://doi.org/10.1002/path.1078 CrossRefPubMed

20.

Decock J, Hendrickx W, Vanleeuw U, Van Belle V, Van Huffel S, Christiaens MR, Ye S, Paridaens R (2008) Plasma MMP1 and MMP8 expression in breast cancer: protective role of MMP8 against lymph node metastasis. BMC Cancer 8:77. https://doi.org/10.1186/1471-2407-8-77 CrossRefPubMedPubMedCentral

21.

Korpi JT, Kervinen V, Mäklin H, Väänänen A, Lahtinen M, Läärä E, Ristimäki A, Thomas G, Ylipalosaari M, Åström P, Lopez-Otin C, Sorsa T, Kantola S, Pirilä E, Salo T (2008) Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer. Br J Cancer 98(4):766–775. https://doi.org/10.1038/sj.bjc.6604239 CrossRefPubMedPubMedCentral

22.

Vayrynen JP, Vornanen J, Tervahartiala T, Sorsa T, Bloigu R, Salo T, Tuomisto A, Makinen MJ (2012) Serum MMP-8 levels increase in colorectal cancer and correlate with disease course and inflammatory properties of primary tumors. Int J Cancer 131(4):E463–E474. https://doi.org/10.1002/ijc.26435 CrossRefPubMed

23.

Gutierrez-Fernandez A, Fueyo A, Folgueras AR, Garabaya C, Pennington CJ, Pilgrim S, Edwards DR, Holliday DL, Jones JL, Span PN, Sweep FC, Puente XS, Lopez-Otin C (2008) Matrix metalloproteinase-8 functions as a metastasis suppressor through modulation of tumor cell adhesion and invasion. Can Res 68(8):2755–2763. https://doi.org/10.1158/0008-5472.can-07-5154 CrossRef

24.

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(1):29–32. https://doi.org/10.1016/0014-5793(92)80015-9 CrossRefPubMed

25.

Moore CS, Crocker SJ (2012) An alternate perspective on the roles of TIMPs and MMPs in pathology. Am J Pathol 180(1):12–16. https://doi.org/10.1016/j.ajpath.2011.09.008 CrossRefPubMed

26.

Gouyer V, Conti M, Devos P, Zerimech F, Copin MC, Créme E, Wurtz A, Porte H, Huet G (2005) Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer 103(8):1676–1684. https://doi.org/10.1002/cncr.20965 CrossRefPubMed

27.

Ruokolainen H, Pääkkö P, Turpeenniemi-Hujanen T (2005) Tissue inhibitor of matrix metalloproteinase-1 Is prognostic in head and neck squamous cell carcinoma: comparison of the circulating and tissue immunoreactive protein. Clin Cancer Res 11(9):3257CrossRefPubMed

28.

Pradhan-Palikhe P, Vesterinen T, Tarkkanen J, Leivo I, Sorsa T, Salo T, Mattila PS (2010) Plasma level of tissue inhibitor of matrix metalloproteinase-1 but not that of matrix metalloproteinase-8 predicts survival in head and neck squamous cell cancer. Oral Oncol 46(7):514–518. https://doi.org/10.1016/j.oraloncology.2010.03.002 CrossRefPubMed

29.

McCarthy K, Maguire T, McGreal G, McDermott E, O’Higgins N, Duffy Michael J (1999) High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. Int J Cancer 84(1):44–48. https://doi.org/10.1002/(SICI)1097-0215(19990219)84:1%3c44:AID-IJC9%3e3.0.CO;2-P CrossRefPubMed

30.

Manenti L, Paganoni P, Floriani I, Landoni F, Torri V, Buda A, Taraboletti G, Labianca R, Belotti D, Giavazzi R (2003) Expression levels of vascular endothelial growth factor, matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 and 2 in the plasma of patients with ovarian carcinoma. Eur J Cancer 39(13):1948–1956. https://doi.org/10.1016/S0959-8049(03)00427-1 CrossRefPubMed

31.

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(17):3934–3942. https://doi.org/10.1038/sj.emboj.7601281 CrossRefPubMedPubMedCentral

32.

Stetler-Stevenson WG (2008) Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signaling 1(27):re6. https://doi.org/10.1126/scisignal.127re6 CrossRef

33.

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(41):40364–40372. https://doi.org/10.1074/jbc.M302999200 CrossRefPubMed

34.

Song G, Xu S, Zhang H, Wang Y, Xiao C, Jiang T, Wu L, Zhang T, Sun X, Zhong L, Zhou C, Wang Z, Peng Z, Chen J, Wang X (2016) TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway. J Exp Clin Cancer Res 35(1):148. https://doi.org/10.1186/s13046-016-0427-7 CrossRefPubMedPubMedCentral

35.

Carpen T, Saarilahti K, Haglund C, Markkola A, Tarkkanen J, Hagstrom J, Mattila P, Makitie A (2018) Tumor volume as a prognostic marker in p16-positive and p16-negative oropharyngeal cancer patients treated with definitive intensity-modulated radiotherapy. Strahlenther Onkol 194(8):759–770. https://doi.org/10.1007/s00066-018-1309-z CrossRefPubMed

36.

Carpen T, Sjoblom A, Lundberg M, Haglund C, Markkola A, Syrjanen S, Tarkkanen J, Makitie A, Hagstrom J, Mattila P (2018) Presenting symptoms and clinical findings in HPV-positive and HPV-negative oropharyngeal cancer patients. Acta Otolaryngol 138(5):513–518. https://doi.org/10.1080/00016489.2017.1405279 CrossRefPubMed

37.

Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, Gershenwald JE, Compton CC, Hess KR, Sullivan DC, Jessup JM, Brierley JD, Gaspar LE, Schilsky RL, Balch CM, Winchester DP, Asare EA, Madera M, Gress DM, Meyer LR (2017) AJCC cancer staging manual, 8th edn. Springer, New York, p 2017CrossRef

38.

Hanemaaijer R, Sorsa T, Konttinen YT, Ding Y, Sutinen M, Visser H, van Hinsbergh VWM, Helaakoski T, Kainulainen T, Rönkä H, Tschesche H, Salo T (1997) Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells: regulation by tumor necrosis factor-α and doxycycline. J Biol Chem 272(50):31504–31509CrossRefPubMed

39.

Tuomainen AM, Nyyssonen K, Laukkanen JA, Tervahartiala T, Tuomainen TP, Salonen JT, Sorsa T, Pussinen PJ (2007) Serum matrix metalloproteinase-8 concentrations are associated with cardiovascular outcome in men. Arterioscler Thromb Vasc Biol 27(12):2722–2728. https://doi.org/10.1161/ATVBAHA.107.154831 CrossRefPubMed

40.

Makinen LK, Hayry V, Atula T, Haglund C, Keski-Santti H, Leivo I, Makitie A, Passador-Santos F, Bockelman C, Salo T, Sorsa T, Hagstrom J (2012) Prognostic significance of matrix metalloproteinase-2, -8, -9, and -13 in oral tongue cancer. J Oral Pathol Med 41(5):394–399. https://doi.org/10.1111/j.1600-0714.2011.01110.x CrossRefPubMed

41.

Maatta M, Tervahartiala T, Vesti E, Airaksinen J, Sorsa T (2006) Levels and activation of matrix metalloproteinases in aqueous humor are elevated in uveitis-related secondary glaucoma. J Glaucoma 15(3):229–237. https://doi.org/10.1097/01.ijg.0000212229.57922.72 CrossRefPubMed

42.

Prikk K, Maisi P, Pirilä E, Reintam M-A, Salo T, Sorsa T, Sepper R (2002) Airway obstruction correlates with collagenase-2 (MMP-8) expression and activation in bronchial asthma. Lab Invest 82(11):1535–1545. https://doi.org/10.1097/01.Lab.0000035023.53893.B6 CrossRefPubMed

43.

Sorsa T, Mantyla P, Ronka H, Kallio P, Kallis GB, Lundqvist C, Kinane DF, Salo T, Golub LM, Teronen O, Tikanoja S (1999) Scientific basis of a matrix metalloproteinase-8 specific chair-side test for monitoring periodontal and peri-implant health and disease. Ann N Y Acad Sci 878:130–140CrossRefPubMed

44.

Smeets SJ, Hesselink AT, Speel E-JM, Haesevoets A, Snijders PJF, Pawlita M, Meijer CJLM, Braakhuis BJM, Leemans CR, Brakenhoff RH (2007) A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer 121(11):2465–2472. https://doi.org/10.1002/ijc.22980 CrossRefPubMed

45.

Prigge E-S, Arbyn M, von Knebel Doeberitz M, Reuschenbach M (2017) Diagnostic accuracy of p16INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis. Int J Cancer 140(5):1186–1198. https://doi.org/10.1002/ijc.30516 CrossRefPubMed

46.

Gronhoj C, Jakobsen KK, Jensen DH, Rasmussen J, Andersen E, Friborg J, von Buchwald C (2018) Pattern of and survival following loco-regional and distant recurrence in patients with HPV + and HPV- oropharyngeal squamous cell carcinoma: a population-based study. Oral Oncol 83:127–133. https://doi.org/10.1016/j.oraloncology.2018.06.012 CrossRefPubMed

47.

Serrels B, McGivern N, Canel M, Byron A, Johnson SC, McSorley HJ, Quinn N, Taggart D, Von Kreigsheim A, Anderton SM, Serrels A, Frame MC (2017) IL-33 and ST2 mediate FAK-dependent antitumor immune evasion through transcriptional networks. Sci Signal. https://doi.org/10.1126/scisignal.aan8355 CrossRefPubMedPubMedCentral

48.

McLean GW, Carragher NO, Avizienyte E, Evans J, Brunton VG, Frame MC (2005) The role of focal-adhesion kinase in cancer—a new therapeutic opportunity. Nat Rev Cancer 5:505. https://doi.org/10.1038/nrc1647 CrossRefPubMed

49.

Klussmann JP, Mooren JJ, Lehnen M, Claessen SMH, Stenner M, Huebbers CU, Weissenborn SJ, Wedemeyer I, Preuss SF, Straetmans JMJAA, Manni JJ, Hopman AHN, Speel E-JM (2009) Genetic signatures of HPV-related and unrelated oropharyngeal carcinoma and their prognostic implications. Clin Cancer Res 15(5):1779–1786. https://doi.org/10.1158/1078-0432.ccr-08-1463 CrossRefPubMed

50.

Hayes DN, Van Waes C, Seiwert TY (2015) Genetic landscape of human papillomavirus-associated head and neck cancer and comparison to tobacco-related tumors. J Clin Oncol 33(29):3227–3234. https://doi.org/10.1200/JCO.2015.62.1086 CrossRefPubMedPubMedCentral

51.

Lawrence MSea (2015) Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 517(7536):576–582. https://doi.org/10.1038/nature14129 CrossRef

Title: High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer
Authors: Timo Carpén
Timo Sorsa
Lauri Jouhi
Taina Tervahartiala
Caj Haglund
Stina Syrjänen
Jussi Tarkkanen
Hesham Mohamed
Antti Mäkitie
Jaana Hagström
Petri S. Mattila
Publication date: 01-08-2019
Publisher: Springer Berlin Heidelberg
Keyword: Oropharyngeal Cancer
Published in: Cancer Immunology, Immunotherapy / Issue 8/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-019-02362-4

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