Tumor Biology

, Volume 37, Issue 6, pp 8197–8207 | Cite as

Expression of cancer-associated fibroblast-related proteins in thyroid papillary carcinoma

Original Article

Abstract

The purpose of this study was to evaluate the association between expression of cancer-associated fibroblast (CAF)-related proteins in papillary thyroid carcinoma (PTC) and clinicopathologic factors. Using tissue microarray (TMA) constructed from 339 cases of PTC (303 classic type, 36 follicular variant), we performed immunohistochemical staining for podoplanin, prolyl 4-hydroxylase, FAPα, S100A4, PDGFRα, PDGFRβ, NG2, 5-meC, and BRAF V600E and evaluated the association with clinicopathologic parameters. We classified the stroma of PTC as desmoplastic type, sclerotic type, pauci type, or inflammatory type. The expression of prolyl 4-hydroxylase (p = 0.042), FAPα (p = 0.044), PDGFRα (p < 0.001), and 5-meC (p = 0.030) in cancer cells differed according to the histologic subtype, higher in classic type than follicular type. The expression of FAPα (p = 0.034) and 5-meC (p = 0.021) in stromal cells was higher in the classic type than follicular type. PTC with BRAF mutation showed higher expression of podoplanin (p < 0.001), prolyl 4-hydroxylase (p = 0.013), FAPα (p < 0.001), S100A4 (p < 0.001), PDGFRα (p < 0.001), and 5-meC (p < 0.001) in the tumor cell compartment and of FAPα (p = 0.004), S100A4 (p < 0.001), PDGFRα (p = 0.002), PDGFRβ (p < 0.001), and 5-meC (p < 0.001) in the stromal cell compartment. There was also a difference in the expression of CAF-related proteins according to stromal phenotype; the expression of FAPα, S100A4, and PDGFRα was higher in desmoplastic type than in other subtypes, whereas NG2 expression was higher in inflammatory type (p < 0.001). Tumoral podoplanin negativity (p = 0.043) was associated with shorter DFS, and tumoral S100A4 positivity (p = 0.044) and stromal PDGFRβ positivity (p = 0.035) were associated with shorter OS. In conclusion, the expression of CAF-related proteins in cancer cells and stromal cells of PTC was different according to histologic subtype, BRAF V600E mutation, and subtype of stroma, and was related to prognosis.

Keywords

Cancer-associated fibroblast Papillary carcinoma Thyroid 

Notes

Acknowledgments

This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, and Republic of Korea (1420080). This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2015R1A1A1A05001209)

Compliance with ethical standards

Conflicts of interest

None

References

  1. 1.
    Sherman SI. Thyroid carcinoma. Lancet. 2003;361(9356):501–11.CrossRefPubMedGoogle Scholar
  2. 2.
    Franco OE, Shaw AK, Strand DW, Hayward SW. Cancer associated fibroblasts in cancer pathogenesis. Semin Cell Dev Biol. 2010;21(1):33–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Ostman A. Cancer-associated fibroblasts: recent developments and emerging challenges. Semin Cancer Biol. 2014;25:1–2.CrossRefPubMedGoogle Scholar
  4. 4.
    Desmouliere A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol. 2004;48(5–6):509–17.CrossRefPubMedGoogle Scholar
  5. 5.
    De Wever O, Nguyen QD, Van Hoorde L, Bracke M, Bruyneel E, Gespach C, et al. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 2004;18(9):1016–8.PubMedGoogle Scholar
  6. 6.
    Sugimoto H, Mundel TM, Kieran MW, Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 2006;5(12):1640–6.CrossRefPubMedGoogle Scholar
  7. 7.
    Pietras K, Sjoblom T, Rubin K, Heldin CH, Ostman A. PDGF receptors as cancer drug targets. Cancer Cell. 2003;3(5):439–43.CrossRefPubMedGoogle Scholar
  8. 8.
    Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010;330(6005):827–30.CrossRefPubMedGoogle Scholar
  9. 9.
    Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, et al. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008;123(5):1053–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010;107(46):20009–14.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cortez E, Roswall P, Pietras K. Functional subsets of mesenchymal cell types in the tumor microenvironment. Semin Cancer Biol. 2014;25:3–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhang J, Wang Y, Li D, Jing S. Notch and TGF-beta/Smad3 pathways are involved in the interaction between cancer cells and cancer-associated fibroblasts in papillary thyroid carcinoma. Tumour Biol. 2014;35(1):379–85.CrossRefPubMedGoogle Scholar
  13. 13.
    Henry LR, Lee HO, Lee JS, Klein-Szanto A, Watts P, Ross EA, et al. Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res. 2007;13(6):1736–41.CrossRefPubMedGoogle Scholar
  14. 14.
    Bullock M, O'Neill C, Chou A, Clarkson A, Dodds T, Toon C, et al. Utilization of a MAB for BRAF(V600E) detection in papillary thyroid carcinoma. Endocr Relat Cancer. 2012;19(6):779–84.CrossRefPubMedGoogle Scholar
  15. 15.
    Baird SK, Allan L, Renner C, Scott FE, Scott AM. Fibroblast activation protein increases metastatic potential of fibrosarcoma line HT1080 through upregulation of integrin-mediated signaling pathways. Clin Exp Metastasis. 2015;32(5):507–16.CrossRefPubMedGoogle Scholar
  16. 16.
    Hayashi Y, Bardsley MR, Toyomasu Y, Milosavljevic S, Gajdos GB, Choi KM, et al. Platelet-derived growth factor receptor-alpha regulates proliferation of gastrointestinal stromal tumor cells with mutations in KIT by stabilizing ETV1. Gastroenterology. 2015;149(2):420–32.e16.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Scanlan MJ, Raj BK, Calvo B, Garin-Chesa P, Sanz-Moncasi MP, Healey JH, et al. Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc Natl Acad Sci U S A. 1994;91(12):5657–61.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Lee HO, Mullins SR, Franco-Barraza J, Valianou M, Cukierman E, Cheng JD. FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells. BMC Cancer. 2011;11:245.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Saadi A, Shannon NB, Lao-Sirieix P, O'Donovan M, Walker E, Clemons NJ, et al. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers. Proc Natl Acad Sci U S A. 2010;107(5):2177–82.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Cunha GR, Hayward SW, Wang YZ. Role of stroma in carcinogenesis of the prostate. Differentiation. 2002;70(9–10):473–85.CrossRefPubMedGoogle Scholar
  21. 21.
    Rodriguez-Canales J, Hanson JC, Tangrea MA, Erickson HS, Albert PS, Wallis BS, et al. Identification of a unique epigenetic sub-microenvironment in prostate cancer. J Pathol. 2007;211(4):410–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Hanson JA, Gillespie JW, Grover A, Tangrea MA, Chuaqui RF, Emmert-Buck MR, et al. Gene promoter methylation in prostate tumor-associated stromal cells. J Natl Cancer Inst. 2006;98(4):255–61.CrossRefPubMedGoogle Scholar
  23. 23.
    Couillard J, Demers M, Lavoie G, St-Pierre Y. The role of DNA hypomethylation in the control of stromelysin gene expression. Biochem Biophys Res Commun. 2006;342(4):1233–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Shahrzad S, Bertrand K, Minhas K, Coomber BL. Induction of DNA hypomethylation by tumor hypoxia. Epigenetics. 2007;2(2):119–25.CrossRefPubMedGoogle Scholar
  25. 25.
    Lim SO, Gu JM, Kim MS, Kim HS, Park YN, Park CK, et al. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology. 2008;135(6):2128–40. 40.e1-8.CrossRefPubMedGoogle Scholar
  26. 26.
    Liu X, Yan K, Lin X, Zhao L, An W, Wang C, et al. The association between BRAF (V600E) mutation and pathological features in PTC. Eur Arch Otorhinolaryngol. 2014;271(11):3041–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Whipple CA, Brinckerhoff CE. BRAF(V600E) melanoma cells secrete factors that activate stromal fibroblasts and enhance tumourigenicity. Br J Cancer. 2014;111(8):1625–33.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Khalili JS, Liu S, Rodriguez-Cruz TG, Whittington M, Wardell S, Liu C, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res. 2012;18(19):5329–40.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 2014;4(4):423–33.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Koperek O, Akin E, Asari R, Niederle B, Neuhold N. Expression of hypoxia-inducible factor 1 alpha in papillary thyroid carcinoma is associated with desmoplastic stromal reaction and lymph node metastasis. Virchows Arch. 2013;463(6):795–802.CrossRefPubMedGoogle Scholar
  31. 31.
    Tanaka M, Kijima H, Shimada H, Makuuchi H, Ozawa S, Inokuchi S. Expression of podoplanin and vimentin is correlated with prognosis in esophageal squamous cell carcinoma. Mol Med Rep. 2015;12(3):4029–36.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Kim HY, Rha KS, Shim GA, Kim JH, Kim JM, Huang SM, et al. Podoplanin is involved in the prognosis of head and neck squamous cell carcinoma through interaction with VEGF-C. Oncol Rep. 2015;34(2):833–42.PubMedGoogle Scholar
  33. 33.
    Seki S, Fujiwara M, Matsuura M, Fujita S, Ikeda H, Umeda M, et al. Prognostic value of podoplanin expression in oral squamous cell carcinoma—a regression model auxiliary to UICC classification. Pathol Oncol Res. 2014;20(3):521–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Renart J, Carrasco-Ramirez P, Fernandez-Munoz B, Martin-Villar E, Montero L, Yurrita MM, et al. New insights into the role of podoplanin in epithelial-mesenchymal transition. Int Rev Cell Mol Biol. 2015;317:185–239.CrossRefPubMedGoogle Scholar
  35. 35.
    Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med. 2014;211(8):1503–23.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Haubeiss S, Schmid JO, Murdter TE, Sonnenberg M, Friedel G, van der Kuip H, et al. Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010;9:168.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther. 2012;11(2):257–66.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Santos AM, Jung J, Aziz N, Kissil JL, Pure E. Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice. J Clin Invest. 2009;119(12):3613–25.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Scott AM, Wiseman G, Welt S, Adjei A, Lee FT, Hopkins W, et al. A phase I dose-escalation study of sibrotuzumab in patients with advanced or metastatic fibroblast activation protein-positive cancer. Clin Cancer Res. 2003;9(5):1639–47.PubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  1. 1.Department of SurgeryDaejeon St. Mary’s Hospital, The Cathololic University of Korea College of MedicineDaejeonSouth Korea
  2. 2.Department of PathologyYonsei University College of MedicineSeodaemun-guSouth Korea

Personalised recommendations