Biomarkers of Parathyroid Carcinoma (original) (raw)

Abstract

The diagnosis of parathyroid carcinoma can be challenging, and adjuvant therapies such as radiotherapy and chemotherapy are not particularly beneficial in the management of this disease, creating a challenge when dealing with unresectable recurrent and metastatic malignancy. We investigated the expression profile of biomarkers that represent potential markers of malignancy or targets for novel therapies in this disease. We constructed a tissue microarray of parathyroid carcinomas from 10 patients as well as parathyroid adenomas from 25 patients and stained the slides for 34 proteins involved in angiogenesis (platelet-derived growth factor receptor (PDGFR)-α, PDGFR-β, vascular endothelial growth factor receptor-2 (VEGFR-2), and epidermal growth factor receptor (EGFR)), inflammation (cyclooxygenase (COX)-1 and COX-2), cell adhesion (matrix metalloproteinase (MMP)-1, CD9, and keratin 7), cell cycle (Cdc2p34, cyclin D1, retinoblastoma (Rb), p27, p21, parafibromin, Bmi-1, 14-3-3σ, and p53), and apoptosis (Bcl-2a, Mcl-1, Bcl-xL, and glutathione-_S_-transferase-isoenzyme π (Gst-π)) along with some markers of the sonic hedgehog (Smo, SHH, Gli-1, Gli-2, Gli-3, and patched), mTOR (AKT, mammalian target of rapamycin (mTOR), and Forkhead box O (FoxO)-1), and WNT (Wisp-1, Wisp-2, and β-catenin) signal transduction pathways. Protein expression was determined using computerized image analysis software (Spectrum Plus©, Aperio). Bcl-2a, parafibromin, Rb, and p27 were significantly decreased to variable degrees in all parathyroid carcinomas. COX-1/2, CD9, MMP-1, FoxO-1, VEGFR-2, PDGFR-α/β, Gst-π, Gli-1, Gli-2, Gli-3, and patched were expressed in the majority of benign and malignant tumor cells. These results indicate that the use of a panel that includes Bcl-2a, parafibromin, Rb, and p27 may be helpful in the assessment of atypical parathyroid neoplasms. Although the majority of other markers studied are also expressed in both benign and malignant parathyroid neoplasms, we have identified several potentially important target proteins related to angiogenesis and cell proliferation along with COX-1/2, Gst-π and members of sonic hedgehog pathway that may be therapeutic targets in parathyroid carcinoma. While these results are preliminary, a successful outcome of a clinical trial directed against these novel targets would provide much needed systemic adjuvant treatment for patients with metastatic parathyroid carcinoma.

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References

  1. Hundahl SA, Fleming ID, Fremgen AM, Menck HR (1999) Two hundred eighty-six cases of parathyroid carcinoma treated in the U.S. between 1985 and 1995: a National Cancer Data Base Report. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 86:538–544.
    Article PubMed CAS Google Scholar
  2. Erovic BM, Goldstein DP, Kim D, Mete O, Brierly J, Tsang R, Freeman JL, Asa SL, Rotstein L, Irish JC (2012). Parathyroid cancer: outcome analysis of 16 patients treated at the Princess Margaret Hospital. Head Neck 2012, doi:10.1002/hed.22908.
  3. Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM (2007) Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer 109:1736–1741.
    Article PubMed Google Scholar
  4. Sandelin K, Auer G, Bondeson L, Grimelius L, Farnebo LO (1992) Prognostic factors in parathyroid cancer: a review of 95 cases. World J Surg 16:724–731.
    Article PubMed CAS Google Scholar
  5. Chow E, Tsang RW, Brierley JD, Filice S (1998) Parathyroid carcinoma—the Princess Margaret Hospital experience. Int J Radiat Oncol Biol Phys 41:569–572.
    Article PubMed CAS Google Scholar
  6. Munson ND, Foote RL, Northcutt RC, Tiegs RD, Fitzpatrick LA, Grant CS, van Heerden JA, Thompson GB, Lloyd RV (2003) Parathyroid carcinoma: is there a role for adjuvant radiation therapy? Cancer 98:2378–2384.
    Article PubMed Google Scholar
  7. Betea D, Bradwell AR, Harvey TC, Mead GP, Schmidt-Gayk H, Ghaye B, Daly AF, Beckers A. (2004) Hormonal and biochemical normalization and tumor shrinkage induced by anti-parathyroid hormone immunotherapy in a patient with metastatic parathyroid carcinoma. J Clin Endocrinol Metab 89:3413–3420.
    Article PubMed CAS Google Scholar
  8. Schott M, Feldkamp J, Schattenberg D, Krueger T, Dotzenrath C, Seissler J, Scherbaum WA (2000) Induction of cellular immunity in a parathyroid carcinoma treated with tumor lysate-pulsed dendritic cells. Eur J Endocrinol 142:300–306.
    Article PubMed CAS Google Scholar
  9. Schott M, Feldkamp J, Schattenberg D, Seissler J, Scherbaum WA (1999) Dendritic cell immuno-therapy in disseminated parathyroid carcinoma. Lancet 353:1188–1189.
    Article PubMed CAS Google Scholar
  10. Mete O, Asa SL (2011) Pathological definition and clinical significance of vascular invasion in thyroid carcinomas derived from follicular epithelium. Modern Pathology 24:1545–1552.
    Article PubMed Google Scholar
  11. Machiels JP, Schmitz S (2011) Molecular-targeted therapy of head and neck squamous cell carcinoma: beyond cetuximab-based therapy. Curr Opin Oncol 23:241–248.
    Article PubMed CAS Google Scholar
  12. Cataldo VD, Gibbons DL, Pérez-Soler R, Quintás-Cardama A (2011) Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N Engl J Med 364:947–955.
    Article PubMed CAS Google Scholar
  13. Chee CE, Sinicrope FA (2010) Targeted therapeutic agents for colorectal cancer. Gastroenterol Clin North Am 39:601–613.
    Article PubMed Google Scholar
  14. Hsu JY, Wakelee HA (2009) Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy. BioDrugs 23:289–304.
    Article PubMed CAS Google Scholar
  15. Chow LQ, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25:884–896.
    Article PubMed CAS Google Scholar
  16. Bukowski RM (2010) Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma. Expert Rev Anticancer Ther 10:635–645.
    Article PubMed CAS Google Scholar
  17. Perrone MG, Scilimati A, Simone L, Vitale P (2010) Selective COX-1 inhibition: a therapeutic target to be reconsidered. Curr Med Chem 17:3769–805.
    Article PubMed CAS Google Scholar
  18. Kao J, Sikora AT, Fu S (2009). Dual EGFR and COX-2 inhibition as a novel approach to targeting head and neck squamous cell carcinoma. Curr Cancer Drug Targets 9:931–937.
    Article PubMed CAS Google Scholar
  19. Moreira L, Castells A (2010). Cyclooxygenase as a target for colorectal cancer chemoprevention. Curr Drug Targets 12:1888–1894.
    Article Google Scholar
  20. Peukert S, Miller-Moslin K (2010) Small-molecule inhibitors of the hedgehog signaling pathway as cancer therapeutics. Chem Med Chem 5:500–512.
    PubMed CAS Google Scholar
  21. Narita S, So A, Ettinger S, Hayashi N, Muramaki M, Fazli L, Kim Y, Gleave ME (2008) GLI2 knockdown using an antisense oligonucleotide induces apoptosis and chemosensitizes cells to paclitaxel in androgen-independent prostate cancer. Clin Cancer Res 14:5769–5777.
    Article PubMed CAS Google Scholar
  22. Hegde GV, Munger CM, Emanuel K, Joshi AD, Greiner TC, Weisenburger DD, Vose JM, Joshi SS (2008) Targeting of sonic hedgehog-GLI signaling: a potential strategy to improve therapy for mantle cell lymphoma. Mol Cancer Ther 7:1450–1460.
    Article PubMed CAS Google Scholar
  23. Fu Z, Tindall DJ. FOXOs, cancer and regulation of apoptosis (2008) Oncogene 27:2312–2319.
    Article PubMed CAS Google Scholar
  24. Reagan-Shaw S, Ahmad N. The role of Forkhead-box Class O (FoxO) transcription factors in cancer: a target for the management of cancer (2007) Toxicol Appl Pharmacol 224:360–368.
    Article PubMed CAS Google Scholar
  25. Erovic BM, Pammer J, Hollemann D, Woegerbauer M, Geleff S, Fischer MB, Burian M, Frommlet F, Neuchrist C (2003) Motility-related protein-1/CD9 expression in head and neck squamous cell carcinoma. Head Neck 25:848–857.
    Article PubMed Google Scholar
  26. Kohmo S, Kijima T, Otani Y, Mori M, Minami T, Takahashi R, Nagatomo I, Takeda Y, Kida H, Goya S, Yoshida M, Kumagai T, Tachibana I, Yokota S, Kawase I (2010) Cell surface tetraspanin CD9 mediates chemoresistance in small cell lung cancer. Cancer Res 70:8025–8035.
    Article PubMed CAS Google Scholar
  27. Takino T, Saeki H, Miyamori H, Kudo T, Sato H (2007) Inhibition of membrane-type 1 matrix metalloproteinase at cell-matrix adhesions. Cancer Res 67:11621–11629.
    Article PubMed CAS Google Scholar
  28. Thévenin AF, Zony CL, Bahnson BJ, Colman RF (2011) GST pi modulates JNK activity through a direct interaction with JNK substrate, ATF2. Protein Sci 20:834–848.
    Article PubMed Google Scholar
  29. Edelman MJ (2006) Novel cytotoxic agents for non-small cell lung cancer. J Thorac Oncol 1:752–755.
    Article PubMed Google Scholar
  30. Singh S, Okamura T, Ali-Osman F (2010) Serine phosphorylation of glutathione _S_-transferase P1 (GSTP1) by PKCα enhances GSTP1-dependent cisplatin metabolism and resistance in human glioma cells. Biochem Pharmacol 80:1343–1355.
    Article PubMed CAS Google Scholar
  31. Shattuck TM, Välimäki S, Obara T, Gaz RD, Clark OH, Shoback D, Wierman ME, Tojo K, Robbins CM, Carpten JD, Farnebo LO, Larsson C, Arnold A (2003) Somatic and germ-line mutations of the HRPT2 gene in sporadic parathyroid carcinoma. N Engl J Med 349:1722–1729.
    Article PubMed CAS Google Scholar
  32. Cryns VL, Rubio MP, Thor AD, Louis DN, Arnold A (1994) p53 abnormalities in human parathyroid carcinoma. J Clin Endocrinol Metab 78:1320–1324.
    Article PubMed CAS Google Scholar
  33. Cryns VL, Thor A, Xu HJ, Hu SX, Wierman ME, Vickery AL Jr, Benedict WF, Arnold A (1994) Loss of the retinoblastoma tumor-suppressor gene in parathyroid carcinoma. N Engl J Med 330:757–761.
    Article PubMed CAS Google Scholar
  34. Gill AJ, Clarkson A, Gimm O, et al. (2006) Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias. Am J Surg Pathol 30:1140–1149.
    Article PubMed Google Scholar
  35. Krebs LJ, Shattuck TM, Arnold A (2005) HRPT2 mutational analysis of typical sporadic parathyroid adenomas. J Clin Endocrinol Metab 90:5015–5017.
    Article PubMed CAS Google Scholar
  36. Erickson LA, Jin L, Wollan P, Thompson GB, van Heerden JA, Lloyd RV (1999). Parathyroid hyperplasia, adenomas, and carcinomas: differential expression of p27Kip1 protein. Am J Surg Pathol 23:288–295.
    Article PubMed CAS Google Scholar
  37. DeLellis RA, Lloyd RV, Heitz PU, editors (2004) World Health Organization Classification of Tumours. Pathology and genetics of tumours of endocrine organs. IARC Press, Lyon.
    Google Scholar

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Acknowledgments

The preliminary results of this paper were presented in part at the 101st United States and Canadian Academy of Pathology Annual Meeting, 17–23 March 2012, Vancouver, BC, Canada.

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Authors and Affiliations

  1. Department of Otolaryngology-Head and Neck Surgery/Surgical Oncology, Wharton Head and Neck Program, Toronto, Ontario, Canada
    Boban M. Erovic, Luke Harris, David P. Goldstein & Jonathan C. Irish
  2. Department of Pathology, University Health Network, Toronto, Ontario, Canada
    Mina Jamali, Sylvia L. Asa & Ozgur Mete
  3. Department of Pathology, University Health Network, 200 Elizabeth Street, 11th Floor, Toronto, ON, M5G 2C4, Canada
    Ozgur Mete

Authors

  1. Boban M. Erovic
  2. Luke Harris
  3. Mina Jamali
  4. David P. Goldstein
  5. Jonathan C. Irish
  6. Sylvia L. Asa
  7. Ozgur Mete

Corresponding author

Correspondence toOzgur Mete.

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Erovic, B.M., Harris, L., Jamali, M. et al. Biomarkers of Parathyroid Carcinoma.Endocr Pathol 23, 221–231 (2012). https://doi.org/10.1007/s12022-012-9222-y

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