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S100-A10, thioredoxin, and S100-A6 as biomarkers of papillary thyroid carcinoma with lymph node metastasis identified by MALDI Imaging

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Abstract

In papillary thyroid carcinoma (PTC), metastasis is a feature of an aggressive tumor phenotype. To identify protein biomarkers that distinguish patients with an aggressive tumor behavior, proteomic signatures in metastatic and non-metastatic tumors were investigated comparatively. In particular, matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to analyze primary tumor samples. We investigated a tumor cohort of PTC (n = 118) that were matched for age, tumor stage, and gender. Proteomic screening by MALDI-IMS was performed for a discovery set (n = 29). Proteins related to the discriminating mass peaks were identified by 1D-gel electrophoresis followed by mass spectrometry. The candidate proteins were subsequently validated by immunohistochemistry (IHC) using a tissue microarray for an independent PTC validation set (n = 89). In this study, we found 36 mass-to-charge-ratio (m/z) species that specifically distinguished metastatic from non-metastatic tumors, among which m/z 11,608 was identified as thioredoxin, m/z 11,184 as S100-A10, and m/z 10,094 as S100-A6. Furthermore, using IHC on the validation set, we showed that the overexpression of these three proteins was highly associated with lymph node metastasis in PTC (p < 0.005). For functional analysis of the metastasis-specific proteins, we performed an Ingenuity Pathway Analysis and discovered a strong relationship of all candidates with the TGF-β-dependent EMT pathway. Our results demonstrated the potential application of the MALDI-IMS proteomic approach in identifying protein markers of metastasis in PTC. The novel protein markers identified in this study may be used for risk stratification regarding metastatic potential in PTC.

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References

  1. Davies L, Welch HG (2006) Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 295:2164–2167

    Article  PubMed  CAS  Google Scholar 

  2. Baudin E, Schlumberger M (2007) New therapeutic approaches for metastatic thyroid carcinoma. Lancet Oncol 8:148–156

    Article  PubMed  CAS  Google Scholar 

  3. Mazzaferri EL, Jhiang SM (1994) Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418–428

    Article  PubMed  CAS  Google Scholar 

  4. Shaha AR (2000) Controversies in the management of thyroid nodule. Laryngoscope 110:183–183

    Article  PubMed  CAS  Google Scholar 

  5. Chow S-M, Law SCK, Chan JKC, Au S-K, Yau S, Lau W-H (2003) Papillary microcarcinoma of the thyroid—prognostic significance of lymph node metastasis and multifocality. Cancer 98:31–40

    Article  PubMed  Google Scholar 

  6. Mehta RS, Negin B, Popii V, Langer C (2008) An aggressive radio-resistant papillary thyroid cancer. Clin Adv Hematol Oncol 6:761–767

    PubMed  Google Scholar 

  7. Xing M, Clark D, Guan H, Ji M, Dackiw A, Carson KA, Kim M, Tufaro A, Ladenson P, Zeiger M et al (2009) BRAF Mutation Testing of Thyroid Fine-Needle Aspiration Biopsy Specimens for Preoperative Risk Stratification in Papillary Thyroid Cancer. J Clin Oncol 27:2977–2982

    Article  PubMed  CAS  Google Scholar 

  8. Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA (2003) High prevalence of BRAF mutations in thyroid cancer. Cancer Res 63:1454–1457

    PubMed  CAS  Google Scholar 

  9. Chen G, Gharib TG, Huang C-C, Thomas DG, Shedden KA, Taylor JMG, Kardia SLR, Misek DE, Giordano TJ, Iannettoni MD et al (2002) Proteomic Analysis of Lung Adenocarcinoma. Clinical Cancer Research 8:2298–2305

    PubMed  CAS  Google Scholar 

  10. Reyzer ML, Caldwell RL, Dugger TC, Forbes JT, Ritter CA, Guix M, Arteaga CL, Caprioli RM (2004) Early changes in protein expression detected by mass spectrometry predict tumor response to molecular therapeutics. Cancer Res 64:9093–9100

    Article  PubMed  CAS  Google Scholar 

  11. Cazares LH, Troyer D, Mendrinos S, Lance RA, Nyalwidhe JO, Beydoun HA, Clements MA, Drake RR, Semmes OJ (2009) Imaging mass spectrometry of a specific fragment of mitogen—activated protein kinase/extracellular signal-regulated kinase kinase kinase 2 discriminates cancer from uninvolved prostate tissue. Clin Cancer Res 15:5541–5551

    Article  PubMed  CAS  Google Scholar 

  12. Deininger S-O, Ebert MP, Fütterer A, Gerhard M, Rocken C (2008) MALDI imaging combined with hierarchical clustering as a new tool for the interpretation of complex human cancers. J Proteome Res 7:5230–5236

    Article  PubMed  CAS  Google Scholar 

  13. Hanselmann M, Kirchner M, Renard BY, Amstalden ER, Glunde K, Heeren RMA, Hamprecht FA (2008) Concise representation of mass spectrometry images by probabilistic latent semantic analysis. Anal Chem 80:9649–9658

    Article  PubMed  CAS  Google Scholar 

  14. Hanselmann M, Köthe U, Kirchner M, Renard BY, Amstalden ER, Glunde K, Heeren RMA, Hamprecht FA (2009) Toward digital staining using imaging mass spectrometry and random forests. J Proteome Res 8:3558–3567

    Article  PubMed  CAS  Google Scholar 

  15. Schwamborn K, Krieg RC, Reska M, Jakse G, Knueche lR, Wellmann A (2007) Identifying prostate carcinoma by MALDI-imaging. Int J Mol Med 20(2):155–159

    PubMed  CAS  Google Scholar 

  16. Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A et al (2007) American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. J Clin Oncol 25:118–145

    Article  PubMed  CAS  Google Scholar 

  17. Villanueva J, Shaffer DR, Philip J, Chaparro CA, Erdjument-Bromage H, Olshen AB, Fleisher M, Lilja H, Brogi E, Boyd J et al (2006) Differential exoprotease activities confer tumor-specific serum peptidome patterns. The Journal of clinical investigation 116:271–284

    Article  PubMed  CAS  Google Scholar 

  18. Bauer JA, Chakravarthy AB, Rosenbluth JM, Mi D, Seeley EH, Matos Granja-Ingram N, Olivares MG, Kelley MC, Mayer IA, Meszoely IM et al (2010) Identification of Markers of Taxane Sensitivity Using Proteomic and Genomic Analyses of Breast Tumors from Patients Receiving Neoadjuvant Paclitaxel and Radiation. Clinical Cancer Research 16:681–690

    Article  PubMed  CAS  Google Scholar 

  19. UICC (2002) In: Sobin LH, Wittekind C (eds) TNM classification of malignant tumours (German edition). Wiley, New York, pp. 59–62

  20. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage. Nature 227:680–685

    Article  PubMed  CAS  Google Scholar 

  21. Hellman U, Wernstedt C, Gonez J, Heldin C-H (1995) Improvement of an “in-gel” digestion procedure for the micropreparation of internal protein fragments for amino acid sequencing. Anal Biochem 224:451–455

    Article  PubMed  CAS  Google Scholar 

  22. Powell N, Jeremiah S, Morishita M, Dudley E, Bethel J, Bogdanova T, Tronko M, Thomas G (2005) Frequency of BRAF T1796A mutation in papillary thyroid carcinoma relates to age of patient at diagnosis and not to radiation exposure. J Pathol 205:558–564

    Article  PubMed  CAS  Google Scholar 

  23. Rauser S, Marquardt C, Balluff B, Deininger Sr-O, Albers C, Belau E, Hartmer R, Suckau D, Specht K, Ebert MP et al (2010) Classification of HER2 Receptor Status in Breast Cancer Tissues by MALDI Imaging Mass Spectrometry. Journal of Proteome Research 9:1854–1863

    Article  PubMed  CAS  Google Scholar 

  24. Sanders ME, Dias EC, Xu BJ, Mobley JA, Billheimer D, Roder H, Grigorieva J, Dowsett M, Arteaga CL, Caprioli RM (2008) Differentiating Proteomic biomarkers in breast cancer by laser capture microdissection and MALDI MS. J Proteome Res 7:1500–1507

    Article  PubMed  CAS  Google Scholar 

  25. Hay ID, Thompson GB, Grant CS, Bergstralh EJ, Dvorak CE, Gorman CA, Maurer MS, McIver B, Mullan BP, Oberg AL et al (2002) Papillary thyroid carcinoma managed at the mayo clinic during six decades (1940–1999): temporal trends in initial therapy and long-term outcome in 2444 consecutively treated patients. World J Surg 26:879–885

    Article  PubMed  Google Scholar 

  26. Beasley NJP, Lee J, Eski S, Walfish P, Witterick I, Freeman JL (2002) Impact of nodal metastases on prognosis in patients with well-differentiated thyroid cancer. Arch Otolaryngol Head Neck Surg 128:825–828

    PubMed  Google Scholar 

  27. Nucera C, Porrello A, Antonello ZA, Mekel M, Nehs MA, Giordano TJ, Gerald D, Benjamin LE, Priolo C, Puxeddu E et al (2010) B-RafV600E and thrombospondin-1 promote thyroid cancer progression. Proceedings of the National Academy of Sciences 107:10649–10654

    Article  CAS  Google Scholar 

  28. Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, Janakiraman M, Solit D, Knauf JA, Tuttle RM et al (2009) Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1. Cancer Research 69:4885–4893

    Article  PubMed  CAS  Google Scholar 

  29. Knauf JA, Sartor MA, Medvedovic M, Lundsmith E, Ryder M, Salzano M, Nikiforov YE, Giordano TJ, Ghossein RA, Fagin JA (2011) Progression of BRAF-induced thyroid cancer is associated with epithelial–mesenchymal transition requiring concomitant MAP kinase and TGF[beta] signaling. Oncogene 30:3153–3162

    Article  PubMed  CAS  Google Scholar 

  30. Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S, Larin A, Savchenko V, Francis GL, La Chapelle A et al (2007) Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proceedings of the National Academy of Sciences 104:2803–2808

    Article  CAS  Google Scholar 

  31. Stathatos N, Bourdeau I, Espinosa AV, Saji M, Vasko VV, Burman KD, Stratakis CA, Ringel MD (2005) KiSS-1/G protein-coupled receptor 54 metastasis suppressor pathway increases myocyte-enriched calcineurin interacting protein 1 expression and chronically inhibits calcineurin activity. J Clin Endocrinol Metab 90:5432–5440

    Article  PubMed  CAS  Google Scholar 

  32. Wreesmann VB, Sieczka EM, Socci ND, Hezel M, Belbin TJ, Childs G, Patel SG, Patel KN, Tallini G, Prystowsky M et al (2004) Genome-Wide Profiling of Papillary Thyroid Cancer Identifies MUC1 as an Independent Prognostic Marker. Cancer Research 64:3780–3789

    Article  PubMed  CAS  Google Scholar 

  33. Cerutti JM, Oler G, Michaluart P, Delcelo R, Beaty RM, Shoemaker J, Riggins GJ (2007) Molecular profiling of matched samples identifies biomarkers of papillary thyroid carcinoma lymph node metastasis. Cancer Res 67:7885–7892

    Article  PubMed  CAS  Google Scholar 

  34. Kim JW, Kim JH, Yoon SY, Joo JH, Lee Y, Lee KS, Chung JH, Choe S (2002) S100A6 protein as a marker for differential diagnosis of cholangiocarcinoma from hepatocellular carcinoma. Hepatol Res 23:274–286

    Article  PubMed  Google Scholar 

  35. Maelandsmo GM, Florenes VA, Mellingsaeter T, Hovig E, Kerbel RS, Fodstad O (1997) Differential expression patterns of S100A2, S100A4 and S100A6 during progression of human malignant melanoma. Int J Cancer 74:464–469

    Article  PubMed  CAS  Google Scholar 

  36. Ito Y, Yoshida H, Tomoda C, Uruno T, Miya A, Kobayashi K, Matsuzuka F, Kakudo K, Kuma K, Miyauchi A (2005) Expression of S100A2 and S100A6 in thyroid carcinomas. Histopathology 46:569–575

    Article  PubMed  CAS  Google Scholar 

  37. Brown LM, Helmke SM, Hunsucker SW, Netea-Maier RT, Chiang SA, Heinz DE, Shroyer KR, Duncan MW, Haugen BR (2006) Quantitative and qualitative differences in protein expression between papillary thyroid carcinoma and normal thyroid tissue. Mol Carcinog 45:613–626

    Article  PubMed  CAS  Google Scholar 

  38. Komatsu K, Kobune-Fujiwara Y, Andoh A, Ishiguro S, Hunai H, Suzuki N, Kameyama M, Murata K, Miyoshi J, Akedo H et al (2000) Increased expression of S100A6 at the invading fronts of the primary lesion and liver metastasis in patients with colorectal adenocarcinoma. Br J Cancer 83:769–774

    Article  PubMed  CAS  Google Scholar 

  39. Ohuchida K, Mizumoto K, Ishikawa N, Fujii K, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M (2005) The Role of S100A6 in Pancreatic Cancer Development and Its Clinical Implication as a Diagnostic Marker and Therapeutic Target. Clin Cancer Res 11:7785–7793

    Article  PubMed  CAS  Google Scholar 

  40. Vimalachandran D, Greenhalf W, Thompson C, Lüttges J, Prime W, Campbell F, Dodson A, Watson R, Crnogorac-Jurcevic T, Lemoine N et al (2005) High Nuclear S100A6 (Calcyclin) Is Significantly Associated with Poor Survival in Pancreatic Cancer Patients. Cancer Research 65:3218–3225

    PubMed  CAS  Google Scholar 

  41. Breen EC, Tang K (2003) Calcyclin (S100A6) regulates pulmonary fibroblast proliferation, morphology, and cytoskeletal organization in vitro. J Cell Biochem 88:848–854

    Article  PubMed  CAS  Google Scholar 

  42. Sofiadis A, Dinets A, Orre LM, Branca RM, Juhlin CC, Foukakis T, Wallin G, Höög A, Hulchiy M, Zedenius J et al (2010) Proteomic Study of Thyroid Tumors Reveals Frequent Up-Regulation of the Ca2+−Binding Protein S100A6 in Papillary Thyroid Carcinoma. Thyroid 20:1067–1076

    Article  PubMed  CAS  Google Scholar 

  43. Kwon M, MacLeod TJ, Zhang Y, Waisman DM (2005) S100A10, annexin A2, and annexin a2 heterotetramer as candidate plasminogen. Front Biosci 10:300–325

    Article  PubMed  CAS  Google Scholar 

  44. Dano K, Behrendt N, Hoyer-Hansen G, Johnsen M, Lund LR, Ploug M, Romer J (2005) Plasminogen activation and cancer. Thromb Haemost 93:676–681

    PubMed  CAS  Google Scholar 

  45. Nozaki S, Endo Y, Nakahara H, Yoshizawa K, Ohara T, Yamamoto E (2006) Targeting urokinase-type plasminogen activator and its receptor for cancer. Anticancer Drugs 17:1109–1117

    Article  PubMed  CAS  Google Scholar 

  46. Mochizuki M, Kwon Y-W, Yodoi J, Masutani H (2009) Thioredoxin regulates cell cycle via the ERK1/2-cyclin D1 pathway. Antioxid Redox Signal 11:2957–2971

    Article  PubMed  CAS  Google Scholar 

  47. Powis G, Kirkpatrick DL (2007) Thioredoxin signaling as a target for cancer therapy. Curr Opin Pharmacol 7:392–397

    Article  PubMed  CAS  Google Scholar 

  48. Akhurst RJ, Derynck R (2001) TGF-beta signaling in cancer—a double-edged sword. Trends Cell Biol 11:44–51

    Google Scholar 

  49. Massagué J, Blain SW, Lo RS (2000) TGF[beta] signaling in growth control, cancer, and heritable disorders. Cell 103:295–309

    Article  PubMed  Google Scholar 

  50. Elliott RL, Blobe GC (2005) Role of transforming growth factor beta in human cancer. J Clin Oncol 23:2078–2093

    Article  PubMed  CAS  Google Scholar 

  51. Bierie B, Moses HL (2006) Tumour microenvironment: TGF[beta]: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer 6:506–520

    Article  PubMed  CAS  Google Scholar 

  52. Laverty HG, Wakefield LM, Occleston NL, O’Kane S, Ferguson MWJ (2009) TGF-[beta]3 and cancer: A review. Cytokine Growth Factor Rev 20:305–317

    Article  PubMed  CAS  Google Scholar 

  53. Feighery R, Maguire P, Ryan MP, McMorrow T (2008) A proteomic approach to immune-mediated epithelial-mesenchymal transition. Proteomics Clin Appl 2:1110–1117

    Article  PubMed  CAS  Google Scholar 

  54. Grande M, Franzen A, Karlsson J-O, Ericson LE, Heldin N-E, Nilsson M (2002) Transforming growth factor-{beta} and epidermal growth factor synergistically stimulate epithelial to mesenchymal transition (EMT) through a MEK-dependent mechanism in primary cultured pig thyrocytes. J Cell Sci 115:4227–4236

    Article  PubMed  CAS  Google Scholar 

  55. Rr I, Db R (1983) Plasminogen is present in the basal layer of the epidermis. J Investig Dermatol 80:297–299

    Article  Google Scholar 

  56. Andreasen PA, Egelund R, Petersen HH (2000) The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 57:25–40

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors gratefully acknowledge the financial support of the Federal Ministry of Education and Research (BMBF) Germany. The authors thank Ulrike Buchholz, Claudia-Mareike Pflueger, Andreas Voss, and Nina Weber for providing excellent technical assistance.

Conflict of Interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Radiation Sciences, Research Unit of Radiation Cytogenetics, Helmholtz Zentrum München-German Research Center for Environmental Health GmbH, Ingolstaedter Landstraße 1, 85764, Neuherberg, Germany

    Martin Nipp & Horst Zitzelsberger

  2. Institute of Pathology, Helmholtz Zentrum München-German Research Center for Environmental Health GmbH, Neuherberg, Germany

    Mareike Elsner, Benjamin Balluff, Stephan Meding, Sandra Rauser, Heinz Höfler & Axel Walch

  3. Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Benjamin Balluff

  4. Research Unit of Protein Science, Helmholtz Zentrum München-German Research Center for Environmental Health GmbH, Neuherberg, Germany

    Hakan Sarioglu & Marius Ueffing

  5. Human Cancer Studies Group, Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, London, UK

    Kristian Unger

  6. Institute of Pathology, Technische Universität München, Munich, Germany

    Heinz Höfler

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  1. Martin Nipp
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Nipp, M., Elsner, M., Balluff, B. et al. S100-A10, thioredoxin, and S100-A6 as biomarkers of papillary thyroid carcinoma with lymph node metastasis identified by MALDI Imaging. J Mol Med 90, 163–174 (2012). https://doi.org/10.1007/s00109-011-0815-6

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