Skip to main content

Advertisement

SpringerLink
Log in

Expression of the Transcription Factor Snail and Its Target Gene Twist Are Associated with Malignancy in Pheochromocytomas

  • Endocrine Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

One of the best known functions of the zinc-finger transcription factor Snail is to induce epithelial-mesenchymal transition (EMT). Twist, a target genes of Snail, is known to promote the development of distant metastases in mice. Increasing evidence suggests that EMT plays a pivotal role in tumor progression and metastatic spread.

Methods

Snail, Twist, and E-cadherin expression were assessed by immunohistochemistry and real-time quantitative reverse transcriptase–polymerase chain reaction in 12 malignant and 35 benign pheochromocytomas (PCC). Data were correlated with clinical characteristics and genetics.

Results

We found Snail expression in 13 (28%) of 47 primary PCC samples. Twist was expressed in 31 (66%) of 47 cases. Only one of 47 PCC showed E-cadherin expression. We observed Snail expression in 7 (58%) of 12 malignant PCC, whereas only 6 (17%) of 35 apparently benign PCC revealed Snail expression (P = 0.01). Furthermore, 11 (92%) of 12 malignant PCC, but only 20 (57%) of 35 benign PCC, revealed Twist expression (P = 0.03). Interestingly, all five metastases showed Snail and Twist expression. In normal adrenal medulla, Snail, Twist, and E-cadherin expression could not be detected.

Conclusions

We describe for the first time that EMT markers Snail and Twist are expressed in PCC and that their expression is associated with malignancy. Our study supports a role for EMT in the malignant transformation of PCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Stenstrom G, Svardsudd K. Pheochromocytoma in Sweden, 1958–1981. An analysis of the National Cancer Registry Data. Acta Med Scand. 1986;220:225–32.

    PubMed  CAS  Google Scholar 

  2. Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58:802–4.

    PubMed  CAS  Google Scholar 

  3. Sinclair A, Isles CG, Brown I, Cameron H, Murray GD. Secondary hypertension in a blood pressure clinic. Arch Intern Med. 1987;147:1289–93.

    Article  PubMed  CAS  Google Scholar 

  4. Lo CY, Lam KY, Wat MS, Lam KS. Adrenal pheochromocytoma remains a frequently overlooked diagnosis. Am J Surg. 2000;179:212–5.

    Article  PubMed  CAS  Google Scholar 

  5. Neumann HP, Bausch B, McWhinney SR, et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346:1459–66.

    Article  PubMed  CAS  Google Scholar 

  6. Lehnert H, Mundschenk J, Hahn K. Malignant pheochromocytoma. Front Horm Res. 2004;31:155–62.

    Article  PubMed  Google Scholar 

  7. Eisenhofer G, Bornstein SR, Brouwers FM, et al. Malignant pheochromocytoma: current status and initiatives for future progress. Endocr Relat Cancer. 2004;11:423–36.

    Article  PubMed  CAS  Google Scholar 

  8. Zhou BP, Hung MC. Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis. Cell Cycle. 2005;4:772–6.

    PubMed  CAS  Google Scholar 

  9. Cano A, Perez-Moreno MA, Rodrigo I, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76–83.

    Article  PubMed  CAS  Google Scholar 

  10. Christofori G. New signals from the invasive front. Nature. 2006;441(7092):444–50.

    Article  PubMed  CAS  Google Scholar 

  11. Moody SE, Perez D, Pan TC, et al. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell. 2005;8:197–209.

    Article  PubMed  CAS  Google Scholar 

  12. O’Rourke MP, Tam PP. Twist functions in mouse development. Int J Dev Biol. 2002;46:401–13.

    PubMed  Google Scholar 

  13. Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927–39.

    Article  PubMed  CAS  Google Scholar 

  14. Yang J, Mani SA, Weinberg RA. Exploring a new twist on tumor metastasis. Cancer Res. 2006;66:4549–52.

    Article  PubMed  CAS  Google Scholar 

  15. Fendrich VW, Farzad J, Ramaswamy E, et al. Snail and sonic hedgehog activation in neuroendocrine tumors of the ileum. Endocr Relat Cancer. 2007;14:865–74.

    Article  PubMed  CAS  Google Scholar 

  16. Waldmann J FG, Slater EP, Langer P, et al. Expression of the zinc-finger transcription factor Snail in adrenocortical carcinoma is associated with decreased survival. Br J Cancer. 2008;99:1900–7.

    Article  PubMed  CAS  Google Scholar 

  17. Esni F, Ghosh B, Biankin AV, et al. Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas. Development. 2004;131:4213–24.

    Article  PubMed  CAS  Google Scholar 

  18. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402–8.

    Article  PubMed  CAS  Google Scholar 

  19. Hammer GD, Parker KL, Schimmer BP. Minireview: transcriptional regulation of adrenocortical development. Endocrinology. 2005;146:1018–24.

    Article  PubMed  CAS  Google Scholar 

  20. Clouthier DE, Williams SC, Yanagisawa H, et al. Signaling pathways crucial for craniofacial development revealed by endothelin-A receptor–deficient mice. Dev Biol. 2000;217:10–24.

    Article  PubMed  CAS  Google Scholar 

  21. Murray SA, Carver EA, Gridley T. Generation of a Snail1 (Snai1) conditional null allele. Genesis. 2006;44:7–11.

    Article  PubMed  CAS  Google Scholar 

  22. Amar L, Servais A, Gimenez-Roqueplo AP, et al. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab. 2005;90:2110–6.

    Article  PubMed  CAS  Google Scholar 

  23. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS. Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med. 2001;134:315–29.

    PubMed  CAS  Google Scholar 

  24. Barallo-Gimeno A, Nieto MA. The snail genes as inducers of cell movement and survival. Implications in development and cancer. Development. 2005;132:3151–61.

    Article  Google Scholar 

  25. Selleck MA, Bronner-Fraser M. Origins of the avian neural crest: the role of neural plate-epidermal interactions. Development. 1995;121:525–38.

    PubMed  CAS  Google Scholar 

  26. Liem KF Jr, Tremml G, Jessell TM. A role for the roof plate and its resident TGFbeta-related proteins in neuronal patterning in the dorsal spinal cord. Cell. 1997;91:127–38.

    Article  PubMed  CAS  Google Scholar 

  27. Newgreen DF, Erickson CA. The migration of neural crest cells. Int Rev Cytol. 1986;103:89–145.

    Article  PubMed  CAS  Google Scholar 

  28. Schlumberger M, Gicquel C, Lumbroso J, et al. Malignant pheochromocytoma: clinical, biological, histologic and therapeutic data in a series of 20 patients with distant metastases. J Endocrinol Invest. 1992;15:631–42.

    PubMed  CAS  Google Scholar 

  29. Timmers HJ, Brouwers FM, Hermus AR, et al. Metastases but not cardiovascular mortality reduce life expectancy following surgical resection of apparently benign pheochromocytoma. Endocr Relat Cancer. 2008;15(4):1127–33.

    Article  PubMed  CAS  Google Scholar 

  30. Khorram-Manesh A, Ahlman H, Jansson S, Nilsson O. N-cadherin expression in adrenal tumors: upregulation in malignant pheochromocytoma and downregulation in adrenocortical carcinoma. Endocr Pathol. 2002;13:99–110.

    Article  PubMed  CAS  Google Scholar 

  31. Gupta D, Shidham V, Holden J, Layfield L. Prognostic value of immunohistochemical expression of topoisomerase alpha II, MIB-1, p53, E-cadherin, retinoblastoma gene protein product, and HER-2/neu in adrenal and extra-adrenal pheochromocytomas. Appl Immunohistochem Mol Morphol. 2000;8:267–74.

    Article  PubMed  CAS  Google Scholar 

  32. Ohta S, Lai EW, Pang AL, et al. Downregulation of metastasis suppressor genes in malignant pheochromocytoma. Int J Cancer. 2005;114:139–43.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

G.F. was supported by a fellowship grant within the Postdoc-Programm of the German Academic Exchange Service (DAAD). V.F. was supported by a research grant of the University Medical Center Giessen and Marburg.

Author information

Authors and Affiliations

  1. Department of Surgery, Philipps-University Marburg, Marburg, Germany

    Jens Waldmann MD, Emily P. Slater PhD, Peter Langer MD, Detlef K. Bartsch MD & Volker Fendrich MD

  2. Department of Internal Medicine, Division of Gastroenterology and Endocrinology, Philipps-University Marburg, Marburg, Germany

    Malte Buchholz PhD

  3. Department of Pathology, Philipps-University Marburg, Marburg, Germany

    Annette Ramaswamy MD

  4. Department of Surgery and Centre of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany

    Martin K. Walz MD

  5. Institute of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    Kurt W. Schmid MD

  6. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Georg Feldmann MD

  7. The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Georg Feldmann MD

Authors
  1. Jens Waldmann MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Emily P. Slater PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Langer MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Malte Buchholz PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annette Ramaswamy MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Martin K. Walz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kurt W. Schmid MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georg Feldmann MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Detlef K. Bartsch MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Volker Fendrich MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jens Waldmann MD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Waldmann, J., Slater, E.P., Langer, P. et al. Expression of the Transcription Factor Snail and Its Target Gene Twist Are Associated with Malignancy in Pheochromocytomas. Ann Surg Oncol 16, 1997–2005 (2009). https://doi.org/10.1245/s10434-009-0480-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1245/s10434-009-0480-y

Keywords

Search

Navigation