Skip to main content
Top
Published in: Tumor Biology 12/2015

01-12-2015 | Research Article

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

Authors: Martina Raudenska, Marketa Sztalmachova, Jaromir Gumulec, Michaela Fojtu, Hana Polanska, Jan Balvan, Marek Feith, Hana Binkova, Zuzana Horakova, Rom Kostrica, Rene Kizek, Michal Masarik

Published in: Tumor Biology | Issue 12/2015

Login to get access

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.
Appendix
Available only for authorised users
Literature
4.
go back to reference 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.PubMed 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.PubMed
5.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
6.
go back to reference 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. 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.
7.
go back to reference 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.PubMed 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.PubMed
9.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
10.
go back to reference 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. 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.
12.
go back to reference 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.PubMed 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.PubMed
17.
go back to reference 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. 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.
18.
go back to reference 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.PubMed 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.PubMed
19.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
22.
go back to reference 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. 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.
23.
go back to reference 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.PubMed 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.PubMed
24.
go back to reference 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.PubMed 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.PubMed
25.
go back to reference 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.PubMed 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.PubMed
26.
go back to reference 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. 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.
30.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
31.
go back to reference 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.PubMed 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.PubMed
32.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
33.
go back to reference 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.PubMed 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.PubMed
34.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
37.
go back to reference 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.PubMed 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.PubMed
38.
go back to reference 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. 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.
43.
go back to reference 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.PubMed 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.PubMed
44.
go back to reference 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.PubMed 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.PubMed
45.
go back to reference 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.PubMed 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.PubMed
48.
go back to reference 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.PubMedPubMedCentral 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.PubMedPubMedCentral
50.
go back to reference 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.PubMed 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.PubMed
54.
go back to reference 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.PubMed 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.PubMed
59.
go back to reference 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.PubMed 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.PubMed
60.
go back to reference 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. 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.
61.
go back to reference 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.PubMed 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.PubMed
62.
go back to reference 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. 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.
Metadata
Title
Prognostic significance of the tumour-adjacent tissue in head and neck cancers
Authors
Martina Raudenska
Marketa Sztalmachova
Jaromir Gumulec
Michaela Fojtu
Hana Polanska
Jan Balvan
Marek Feith
Hana Binkova
Zuzana Horakova
Rom Kostrica
Rene Kizek
Michal Masarik
Publication date
01-12-2015
Publisher
Springer Netherlands
Published in
Tumor Biology / Issue 12/2015
Print ISSN: 1010-4283
Electronic ISSN: 1423-0380
DOI
https://doi.org/10.1007/s13277-015-3755-x

Other articles of this Issue 12/2015

Tumor Biology 12/2015 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine