Tumor Biology

, Volume 36, Issue 12, pp 9929–9939 | Cite as

Prognostic significance of the tumour-adjacent tissue in head and neck cancers

  • Martina Raudenska
  • Marketa Sztalmachova
  • Jaromir Gumulec
  • Michaela Fojtu
  • Hana Polanska
  • Jan Balvan
  • Marek Feith
  • Hana Binkova
  • Zuzana Horakova
  • Rom Kostrica
  • Rene Kizek
  • Michal Masarik
Research Article

Abstract

Even with significant advances in operative skills and adjuvant therapies, the overall survival of patients suffering with head and neck squamous cancers (HNSCC) is unsatisfactory. Accordingly, no clinically useful prognostic biomarkers have been found yet for HNSCC. Many studies analysed the expression of potential markers in tumour tissues compared to adjacent tissues. Nevertheless, due to the sharing of the same microenvironment, adjacent tissues show molecular similarity to tumour tissues. Thus, gene expression patterns of 94 HNSCC tumorous tissues were compared with 31 adjacent tissues and with 10 tonsillectomy specimens of non-cancer individuals. The genes analysed at RNA level using quantitative RT-PCR and correlated with clinico-pathological conditions were as follows: EGF, EGFR, MKI67, BCL2, BAX, FOS, JUN, TP53, VEGF, FLT1, MMP2, MMP9, MT1A and MT2A. The elevated MT2A, BAX, EGF and JUN expression was associated with the influence of tumour cells on the rearrangement of healthy tissues, as well as a significant shift in the BAX/BCL2 ratio. Our investigation also indicated that adjacent tissues play an important role in cancerogenesis by releasing several tumour-supporting factors such as EGF. A gradual increase in the metallothionein expression, from the lowest one in tonsillectomy samples to the highest ones in tumour samples, suggests that MT expression might be tissue reaction to the presence of tumour cells. The results of this study confirmed the significance of metallothionein in tumori-genesis and gave evidences for its use as a potential HNSCC biomarker. Furthermore, this study highlighted the importance of histologically normal tumour-adjacent tissue in prediction of HNSCC progress.

Keywords

Head and neck neoplasms Biological markers Prognosis Tumour microenvironment Metallothionein Matrix metalloproteinase 9 Gene expression 

Notes

Acknowledgments

This work was supported by the Ministry of Health of the Czech Republic IGA MZ NT 14337-3/2013.

Conflicts of interest

None.

Supplementary material

13277_2015_3755_MOESM1_ESM.pdf (59 kb)
ESM. 1 (PDF 59 kb)

References

  1. 1.
    Thomas GR, Nadiminti H, Regalado J. Molecular predictors of clinical outcome in patients with head and neck squamous cell carcinoma. Int J Exp Pathol. 2005;86(6):347–63. doi: 10.1111/j.0959-9673.2005.00447.x.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Goldberg HI, Lockwood SA, Wyatt SW, Crossett LS. Trends and differentials in mortality from cancers of the oral cavity and pharynx in the United States, 1973–1987. Cancer. 1994;74(2):565–72. doi: 10.1002/1097-0142(19940715)74:2<565::aid-cncr2820740206>3.0.co;2-i.CrossRefPubMedGoogle Scholar
  3. 3.
    Ghoshal S, Mallick I, Panda N, Sharma SC. Carcinoma of the buccal mucosa: analysis of clinical presentation, outcome and prognostic factors. Oral Oncol. 2006;42(5):533–9. doi: 10.1016/j.oraloncology.2005.10.005.CrossRefPubMedGoogle Scholar
  4. 4.
    Jones KR, Lodgerigal RD, Reddick RL, Tudor GE, Shockley WW. Prognostic factors in the recurrence of stage-I and stage-II squamous-cell cancer of the oral cavity. Arch Otolaryngol Head Neck Surg. 1992;118(5):483–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Goldson TM, Han Y, Knight KB, Weiss HL, Resto VA. Clinicopathological predictors of lymphatic metastasis in HNSCC: implications for molecular mechanisms of metastatic disease. J Exp Ther Oncol. 2010;8(3):211–21.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Fernandez AG, Gimenez N, Fraile M, Gonzalez S, Chabrera C, Torras M, et al. Survival and clinicopathological characteristics of breast cancer patient according to different tumour subtypes as determined by hormone receptor and Her2 immunohistochemistry. A single institution survey spanning 1998 to 2010. Breast. 2012;21(3):366–73. doi: 10.1016/j.breast.2012.03.004.CrossRefGoogle Scholar
  7. 7.
    Wallner LP, Frencher SK, Hsu JWY, Chao CR, Nichol MB, Loo RK, et al. Changes in serum prostate-specific antigen levels and the identification of prostate cancer in a large managed care population. BJU Int. 2013;111(8):1245–52. doi: 10.1111/j.1464-410X.2012.11651.x.CrossRefPubMedGoogle Scholar
  8. 8.
    Polanska H, Raudenska M, Gumulec J, Sztalmachova M, Adam V, Kizek R, et al. Clinical significance of head and neck squamous cell cancer biomarkers. Oral Oncol. 2014;50(3):168–77. doi: 10.1016/j.oraloncology.2013.12.008.CrossRefPubMedGoogle Scholar
  9. 9.
    Chandran UR, Dhir R, Ma CQ, Michalopoulos G, Becich M, Gilbertson J. Differences in gene expression in prostate cancer, normal appearing prostate tissue adjacent to cancer and prostate tissue from cancer free organ donors. BMC Cancer. 2005;5(45). doi: 10.1186/1471-2407-5-45.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Joshi A, Cao DL. TGF-beta signaling, tumor microenvironment and tumor progression: the butterfly effect. Front Biosci Landmark. 2010;15:180–94. doi: 10.2741/3614.CrossRefGoogle Scholar
  11. 11.
    Sanz-Pamplona R, Berenguer A, Cordero D, Mollevi DG, Crous-Bou M, Sole X, et al. Aberrant gene expression in mucosa adjacent to tumor reveals a molecular crosstalk in colon cancer. Mol Cancer. 2014;13:46. doi: 10.1186/1476-4598-13-46.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Strange R, Li F, Saurer S, Burkhardt A, Friis RR. Apoptotic cell-death and tissue remodeling during mouse mammary-gland involution. Development. 1992;115(1):49–58.PubMedGoogle Scholar
  13. 13.
    Le Bitoux MA, Stamenkovic I. Tumor-host interactions: the role of inflammation. Histochem Cell Biol. 2008;130(6):1079–90. doi: 10.1007/s00418-008-0527-3.CrossRefPubMedGoogle Scholar
  14. 14.
    Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer. 2007;121(11):2373–80. doi: 10.1002/ijc.23173.CrossRefPubMedGoogle Scholar
  15. 15.
    Ruttkay-Nedecky B, Nejdl L, Gumulec J, Zitka O, Masarik M, Eckschlager T, et al. The role of metallothionein in oxidative stress. Int J Mol Sci. 2013;14(3):6044–66. doi: 10.3390/ijms14036044.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sato M, Bremner I. Oxygen free-radicals and metallothionein. Free Radic Biol Med. 1993;14(3):325–37. doi: 10.1016/0891-5849(93)90029-t.CrossRefPubMedGoogle Scholar
  17. 17.
    Sochor J, Hynek D, Krejcova L, Fabrik I, Krizkova S, Gumulec J, et al. Study of metallothionein role in spinocellular carcinoma tissues of head and neck tumours using brdicka reaction. Int J Electrochem Sci. 2012;7(3):2136–52.Google Scholar
  18. 18.
    Ioachim E, Assimakopoulos D, Peschos D, Zissi A, Skevas A, Agnantis NJ. Immunohistochemical expression of metallothionein in benign premalignant and malignant epithelium of the larynx: correlation with p53 and proliferative cell nuclear antigen. Pathol Res Pract. 1999;195(12):809–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Dutsch-Wicherek M, Lazar A, Tomaszewska R, Kazmierczak W, Wicherek L. Analysis of metallothionein and vimentin immunoreactivity in pharyngeal squamous cell carcinoma and its microenvironment. Cell Tissue Res. 2013;352(2):341–9. doi: 10.1007/s00441-013-1566-1.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Gumulec J, Raudenska M, Adam V, Kizek R, Masarik M. Metallothionein—Immunohistochemical cancer biomarker: a meta-analysis. Plos One. 2014;9(1). doi: 10.1371/journal.pone.0085346.
  21. 21.
    Inoue K-i, Takano H, Shimada A, Satoh M. Metallothionein as an anti-inflammatory mediator. Mediat Inflamm. 2009. doi: 10.1155/2009/101659.Google Scholar
  22. 22.
    Inoue KI, Takano H, Yanagisawa R, Sakurai M, Ichinose T, Sadakane K, et al. Role of metallothionein in antigen-related airway inflammation. Exp Biol Med. 2005;230(1):75–81.Google Scholar
  23. 23.
    Tate DJ, Newsome DA, Oliver PD. Metallothionein shows an age-related decrease in human macular retinal-pigment epithelium. Invest Ophthalmol Vis Sci. 1993;34(7):2348–51.PubMedGoogle Scholar
  24. 24.
    Dutsch-Wicherek M, Popiela TJ, Klimek M, Rudnicka-Sosin L, Wicherek L, Oudinet JP, et al. Metallothionein stroma reaction in tumor adjacent healthy tissue in head and neck squamous cell carcinoma and breast adenocarcinoma. Neuroendocrinol Lett. 2005;26(5):567–74.PubMedGoogle Scholar
  25. 25.
    Walentowicz-Sadlecka M, Koper A, Krystyna G, Koper K, Basta P, Mach P, et al. The analysis of metallothionein immunoreactivity in stromal fibroblasts and macrophages in cases of uterine cervical carcinoma with respect to both the local and distant spread of the disease. Am J Reprod Immunol. 2013;70(3):253–61. doi: 10.1111/aji.12120.CrossRefPubMedGoogle Scholar
  26. 26.
    Colella S, Richards KL, Bachinski LL, Baggerly KA, Tsavachidis S, Lang JC, et al. Molecular signatures of metastasis in head and neck cancer. Head Neck J Sci Spec Head Neck. 2008;30(10):1273–83. doi: 10.1002/hed.20871.CrossRefGoogle Scholar
  27. 27.
    Wlostowski T. Involvement of metallothionein and copper in cell-proliferation. Biometals. 1993;6(2):71–6. doi: 10.1007/bf00140106.CrossRefPubMedGoogle Scholar
  28. 28.
    Saadeddin A, Babaei-Jadidi R, Spencer-Dene B, Nateri AS. The links between transcription, beta-catenin/jnk signaling, and carcinogenesis. Mol Cancer Res. 2009;7(8):1189–96. doi: 10.1158/1541-7786.mcr-09-0027.CrossRefPubMedGoogle Scholar
  29. 29.
    Li W, Wu C-L, Febbo PG, Olumi AF. Stromally expressed c-Jun regulates proliferation of prostate epithelial cells. Am J Pathol. 2007;171(4):1189–98. doi: 10.2353/ajpath.2007.070285.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jameson MJ, Beckler AD, Taniguchi LE, Allak A, VanWagner LB, Lee NG, et al. Activation of the insulin-like growth factor-1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells. Mol Cancer Ther. 2011;10(11):2124–34. doi: 10.1158/1535-7163.mct-11-0294.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Buchheit CL, Weigel KJ, Schafer ZT. OPINION cancer cell survival during detachment from the ECM: multiple barriers to tumour progression. Nat Rev Cancer. 2014;14(9):632–41. doi: 10.1038/nrc3789.CrossRefPubMedGoogle Scholar
  32. 32.
    Skvortsov S, Dudas J, Eichberger P, Witsch-Baumgartner M, Loeffler-Ragg J, Pritz C, et al. Rac1 as a potential therapeutic target for chemo-radioresistant head and neck squamous cell carcinomas (HNSCC). Br J Cancer. 2014;110(11):2677–87. doi: 10.1038/bjc.2014.221.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Couture C, Raybaud-Diogene H, Tetu B, Bairati I, Murry D, Allard J, et al. p53 and Ki-67 as markers of radioresistance in head and neck carcinoma. Cancer. 2002;94(3):713–22. doi: 10.1002/cncr.10232.CrossRefPubMedGoogle Scholar
  34. 34.
    Curry JM, Tuluc M, Whitaker-Menezes D, Ames JA, Anantharaman A, Butera A, et al. Cancer metabolism, stemness and tumor recurrence: MCT1 and MCT4 are functional biomarkers of metabolic symbiosis in head and neck cancer. Cell Cycle. 2013;12(9):1371–84. doi: 10.4161/cc.24092.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Gallo O, Chiarelli I, Boddi V, Bocciolini C, Bruschini L, Porfirio B. Cumulative prognostic value of p53 mutations and bcl-2 protein expression in head-and-neck cancer treated by radiotherapy. Int J Cancer. 1999;84(6):573–9. doi: 10.1002/(sici)1097-0215(19991222)84:6<573::aid-ijc6>3.0.co;2-r.CrossRefPubMedGoogle Scholar
  36. 36.
    Voehringer DW, McConkey DJ, McDonnell TJ, Brisbay S, Meyn RE. Bcl-2 expression causes redistribution of glutathione to the nucleus. Proc Natl Acad Sci U S A. 1998;95(6):2956–60. doi: 10.1073/pnas.95.6.2956.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Chen Q, Chai YC, Mazumder S, Jiang C, Macklis R, Chisolm GM, et al. The late increase in intracellular free radical oxygen species during apoptosis is associated with cytochrome c release, caspase activation, and mitochondrial dysfunction. Cell Death Differ. 2003;10(3):323–34. doi: 10.1038/sj.cdd.4401148.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    DelBufalo D, Biroccio A, Leonetti C, Zupi G. Bcl-2 overexpression enhances the metastatic potential of a human breast cancer line. FASEB J. 1997;11(12):947–53.Google Scholar
  39. 39.
    Wick W, Wagner S, Kerkau S, Dichgans J, Tonn JC, Weller M. BCL-2 promotes migration and invasiveness of human glioma cells. FEBS Lett. 1998;440(3):419–24. doi: 10.1016/s0014-5793(98)01494-x.CrossRefPubMedGoogle Scholar
  40. 40.
    Choi J, Choi K, Benveniste EN, Hong YS, Lee JH, Kim J, et al. Bcl-2 promotes invasion and lung metastasis by inducing matrix metalloproteinase-2. Cancer Res. 2005;65(13):5554–60. doi: 10.1158/0008-5472.can-04-4570.CrossRefPubMedGoogle Scholar
  41. 41.
    Wang F, Arun P, Friedman J, Chen Z, Van Waes C. Current and potential inflammation targeted therapies in head and neck cancer. Curr Opin Pharmacol. 2009;9(4):389–95. doi: 10.1016/j.coph.2009.06.005.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Liu CJ, Chang KW, Lin SC, Cheng HW. Presurgical serum levels of matrix metalloproteinase-9 and vascular endothelial growth factor in oral squamous cell carcinoma. Oral Oncol. 2009;45(10):920–5. doi: 10.1016/j.oraloncology.2009.04.007.CrossRefPubMedGoogle Scholar
  43. 43.
    Yuce I, Bayram A, Cagli S, Canoz O, Bayram S, Guney E. The role of CD44 and matrix metalloproteinase-9 expression in predicting neck metastasis of supraglottic laryngeal carcinoma. Am J Otolaryngol. 2011;32(2):141–6. doi: 10.1016/j.amjoto.2010.01.001.CrossRefPubMedGoogle Scholar
  44. 44.
    Chen CH, Chien CY, Huang CC, Hwang CF, Chuang HC, Fang FM, et al. Expression of FLJ10540 is correlated with aggressiveness of oral cavity squamous cell carcinoma by stimulating cell migration and invasion through increased FOXM1 and MMP-2 activity. Oncogene. 2009;28(30):2723–37. doi: 10.1038/onc.2009.128.CrossRefPubMedGoogle Scholar
  45. 45.
    Yang MH, Chang SY, Chiou SH, Liu CJ, Chi CW, Chen PM, et al. Overexpression of NBS1 induces epithelial-mesenchymal transition and co-expression of NBS1 and Snail predicts metastasis of head and neck cancer. Oncogene. 2007;26(10):1459–67. doi: 10.1038/sj.onc.1209929.CrossRefPubMedGoogle Scholar
  46. 46.
    Thomas GT, Lewis MP, Speight PM. Matrix metalloproteinases and oral cancer. Oral Oncol. 1999;35(3):227–33. doi: 10.1016/s1368-8375(99)00004-4.CrossRefPubMedGoogle Scholar
  47. 47.
    Bjorklund M, Koivunen E. Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta Rev Cancer. 2005;1755(1):37–69. doi: 10.1016/j.bbcan.2005.03.001.CrossRefGoogle Scholar
  48. 48.
    Fullar A, Kovalszky I, Bitsche M, Romani A, Schartinger VH, Sprinzl GM, et al. Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma. Exp Cell Res. 2012;318(13):1517–27. doi: 10.1016/j.yexcr.2012.03.023.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Koontongkaew S. The tumor microenvironment contribution to development, growth, invasion and metastasis of head and neck squamous cell carcinomas. J Cancer. 2013;4(1):66–83. doi: 10.7150/jca.5112.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    London CA, Sekhon HS, Arora V, Stein DA, Iversen PL, Devi GR. A novel antisense inhibitor of MMP-9 attenuates angiogenesis, human prostate cancer cell invasion and tumorigenicity. Cancer Gene Ther. 2003;10(11):823–32. doi: 10.1038/sj.cgt.7700642.CrossRefPubMedGoogle Scholar
  51. 51.
    Farina AR, Mackay AR. Gelatinase B/MMP-9 in tumour pathogenesis and progression. Cancers (Basel). 2014;6(1):240–96. doi: 10.3390/cancers6010240.CrossRefGoogle Scholar
  52. 52.
    Ebos JML, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, Kerbel RS. Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell. 2009;15(3):232–9. doi: 10.1016/j.ccr.2009.01.021.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Vinals F, et al. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell. 2009;15(3):220–31. doi: 10.1016/j.ccr.2009.01.027.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Van Limbergen EJ, Zabrocki P, Porcu M, Hauben E, Cools J, Nuyts S. FLT1 kinase is a mediator of radioresistance and survival in head and neck squamous cell carcinoma. Acta Oncol. 2014;53(5):637–45. doi: 10.3109/0284186x.2013.835493.CrossRefPubMedGoogle Scholar
  55. 55.
    Ito TK, Ishii G, Chiba H, Ochiai A. The VEGF angiogenic switch of fibroblasts is regulated by MMP-7 from cancer cells. Oncogene. 2007;26(51):7194–203. doi: 10.1038/sj.onc.1210535.CrossRefPubMedGoogle Scholar
  56. 56.
    Lucas JT, Salimath BP, Slomiany MG, Rosenzweig SA. Regulation of invasive behavior by vascular endothelial growth factor is HEF1-dependent. Oncogene. 2010;29(31):4449–59. doi: 10.1038/onc.2010.185.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Smirnova T, Adomako A, Locker J, Van Rooijen N, Prystowsky MB, Segall JE. In vivo invasion of head and neck squamous cell carcinoma cells does not require macrophages. Am J Pathol. 2011;178(6):2857–65. doi: 10.1016/j.ajpath.2011.02.030.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006;24(17):2666–72. doi: 10.1200/jco2005.04.8306.CrossRefPubMedGoogle Scholar
  59. 59.
    Grandis JR, Tweardy DJ. Elevated levels of transforming growth-factor-alpha and epidermal growth-factor receptor messenger-RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res. 1993;53(15):3579–84.PubMedGoogle Scholar
  60. 60.
    Grandis JR, Tweardy DJ, Melhem MF. Asynchronous modulation of transforming growth factor alpha and epidermal growth factor receptor protein expression in progression of premalignant lesions to head and neck squamous cell carcinoma. Clin Cancer Res. 1998;4(1):13–20.Google Scholar
  61. 61.
    Ang KK, Berkey BA, Tu XY, Zhang HZ, Katz R, Hammond EH, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6.PubMedGoogle Scholar
  62. 62.
    Park BJ, Chiosea SI, Grandis JR. Molecular changes in the multistage pathogenesis of head and neck cancer. Cancer Biomark. 2011;9(1–6):325–39. doi: 10.3233/cbm-2011-0163.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Martina Raudenska
    • 1
    • 2
  • Marketa Sztalmachova
    • 1
    • 2
  • Jaromir Gumulec
    • 1
    • 2
  • Michaela Fojtu
    • 1
    • 2
    • 3
  • Hana Polanska
    • 1
    • 2
  • Jan Balvan
    • 1
    • 2
  • Marek Feith
    • 1
  • Hana Binkova
    • 4
  • Zuzana Horakova
    • 4
  • Rom Kostrica
    • 4
  • Rene Kizek
    • 2
    • 5
  • Michal Masarik
    • 1
    • 2
  1. 1.Department of Pathological Physiology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  2. 2.Central European Institute of TechnologyBrno University of TechnologyBrnoCzech Republic
  3. 3.Department of Physiology, Faculty of MedicineMasaryk UniversityBrnoCzech Republic
  4. 4.Department of Otorhinolaryngology and Head and Neck SurgerySt. Anne’s Faculty HospitalBrnoCzech Republic
  5. 5.Department of Chemistry and BiochemistryMendel University in BrnoBrnoCzech Republic

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