Top

Published in:

Open Access 01-12-2014 | Research article

Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors

Authors: Jose A Galván, Aurora Astudillo, Aitana Vallina, Guillermo Crespo, Maria Victoria Folgueras, Maria Victoria González

Published in: BMC Cancer | Issue 1/2014

Abstract

Background

Pulmonary neuroendocrine tumors (Pulmonary NETs) include a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and the intermediate-grade atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). Epithelial Mesenchymal Transition (EMT) is a process initially recognised during several critical stages of embryonic development, which has more recently been implicated in promoting carcinoma invasion and metastasis. The initial stage of the EMT process begins with the deregulation of adhesion molecules, such as E-cadherin, due to transcriptional repression carried out by factors such as Snail family members, Twist and Foxc2.

Methods

Immunohistochemistry for EMT markers and E-cadherin/ β-catenin complex in 134 patients with pulmonary NETs between 1990 – 2009. Analysis of potential associations with clinicopathological variables and survival.

Results

Pulmonary NETs of high malignant potential (LCNEC and SCLC) had reduced expression of the adhesion molecules and high level expression of transcriptional repressors (Snail1, Snail2, Twist and Foxc2). Snail high expression levels and the loss of E-cadherin/β-catenin complex integrity had the strongest negative effect on the five-year survival rates. E-cadherin/β-catenin complex integrity loss independently predicted lymph node involvement and helped in Atypical Carcinoid (AC) vs Typical Carcinoid (TC) differential diagnosis. Importantly, among the TC group, the loss of E-cadherin/β-catenin complex integrity identified patients with an adverse clinical course despite favourable clinicopathological features.

Conclusion

The immunohistochemical determination of E-cadherin/β-catenin complex integrity loss and EMT markers in the clinical setting might be a potential useful diagnostic and prognostic tool especially among the TC patients.

Available only for authorised users

Gustafsson BI, Kidd M, Chan A, Malfertheiner MV, Modlin IM: Bronchopulmonary neuroendocrine tumors. Cancer. 2008, 113 (1): 5-21. 10.1002/cncr.23542.CrossRefPubMed

Marchevsky AM: Neuroendocrine tumors of the lung. Pathology (Phila). 1996, 4 (1): 103-123.

Rekhtman N: Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med. 2010, 134 (11): 1628-1638.PubMed

Hage R, de la Riviere AB, Seldenrijk CA, van den Bosch JM: Update in pulmonary carcinoid tumors: a review article. Ann Surg Oncol. 2003, 10 (6): 697-704. 10.1245/ASO.2003.09.019.CrossRefPubMed

http://seer.cancer.gov/: The US National Cancer Institute. Surveillance Epidemiology and End Results (SEER) data base, 1973-2004. 2007

WHO. Classification of Tumors. Pathology and Genetics of Tumors of the Lung, Pleura, Thymus and Heart. Edited by: Travis WDBE, Muller-Hermelink HK, Harris CC. 2004, Lyon: IARC

Ozdamar B, Bose R, Barrios-Rodiles M, Wang HR, Zhang Y, Wrana JL: Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science. 2005, 307 (5715): 1603-1609. 10.1126/science.1105718.CrossRefPubMed

Ikenouchi J, Matsuda M, Furuse M, Tsukita S: Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail. J Cell Sci. 2003, 116 (Pt 10): 1959-1967.CrossRefPubMed

Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell. 2011, 144 (5): 646-674. 10.1016/j.cell.2011.02.013.CrossRefPubMed

10.

Thiery JP, Sleeman JP: Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006, 7 (2): 131-142. 10.1038/nrm1835.CrossRefPubMed

11.

Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED, Thompson EW: Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007, 213 (2): 374-383. 10.1002/jcp.21223.CrossRefPubMed

12.

Takeichi M: The cadherins: cell-cell adhesion molecules controlling animal morphogenesis. Development. 1988, 102 (4): 639-655.PubMed

13.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A: The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol. 2000, 2 (2): 84-89. 10.1038/35000034.CrossRefPubMed

14.

Bolos V, Peinado H, Perez-Moreno MA, Fraga MF, Esteller M, Cano A: The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors. J Cell Sci. 2003, 116 (Pt 3): 499-511.CrossRefPubMed

15.

Kang Y, Massague J: Epithelial-mesenchymal transitions: twist in development and metastasis. Cell. 2004, 118 (3): 277-279. 10.1016/j.cell.2004.07.011.CrossRefPubMed

16.

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004, 117 (7): 927-939. 10.1016/j.cell.2004.06.006.CrossRefPubMed

17.

Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA: Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A. 2007, 104 (24): 10069-10074. 10.1073/pnas.0703900104.CrossRefPubMedPubMedCentral

18.

Klymkowsky MW: beta-catenin and its regulatory network. Hum Pathol. 2005, 36 (3): 225-227. 10.1016/j.humpath.2005.02.002.CrossRefPubMed

19.

Maeda M, Johnson KR, Wheelock MJ: Cadherin switching: essential for behavioral but not morphological changes during an epithelium-to-mesenchyme transition. J Cell Sci. 2005, 118 (Pt 5): 873-887.CrossRefPubMed

20.

Wheelock MJ, Shintani Y, Maeda M, Fukumoto Y, Johnson KR: Cadherin switching. J Cell Sci. 2008, 121 (Pt 6): 727-735.CrossRefPubMed

21.

Galván JA, Gonzalez MV, Crespo G, Folgueras MV, Astudillo A: Snail nuclear expression parallels higher malignancy potential in neuroendocrine lung tumors. Lung Cancer. 2010, 69 (3): 289-295. 10.1016/j.lungcan.2009.12.010.CrossRefPubMed

22.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM: Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005, 97 (16): 1180-1184. 10.1093/jnci/dji237.CrossRefPubMed

23.

Trimboli AJ, Fukino K, de Bruin A, Wei G, Shen L, Tanner SM, Creasap N, Rosol TJ, Robinson ML, Eng C, Ostrowski MC, Leone G: Direct evidence for epithelial-mesenchymal transitions in breast cancer. Cancer Res. 2008, 68 (3): 937-945. 10.1158/0008-5472.CAN-07-2148.CrossRefPubMed

24.

Vergara D, Merlot B, Lucot JP, Collinet P, Vinatier D, Fournier I, Salzet M: Epithelial-mesenchymal transition in ovarian cancer. Cancer Lett. 2010, 291 (1): 59-66. 10.1016/j.canlet.2009.09.017.CrossRefPubMed

25.

Usami Y, Satake S, Nakayama F, Matsumoto M, Ohnuma K, Komori T, Semba S, Ito A, Yokozaki H: Snail-associated epithelial-mesenchymal transition promotes oesophageal squamous cell carcinoma motility and progression. J Pathol. 2008, 215 (3): 330-339. 10.1002/path.2365.CrossRefPubMed

26.

Meng W, Takeichi M: Adherens junction: molecular architecture and regulation. Cold Spring Harb Perspect Biol. 2009, 1 (6): a002899-CrossRefPubMedPubMedCentral

27.

Salon C, Moro D, Lantuejoul S, Brichon Py P, Drabkin H, Brambilla C, Brambilla E: E-cadherin-beta-catenin adhesion complex in neuroendocrine tumors of the lung: a suggested role upon local invasion and metastasis. Hum Pathol. 2004, 35 (9): 1148-1155. 10.1016/j.humpath.2004.04.015.CrossRefPubMed

28.

Pelosi G, Scarpa A, Puppa G, Veronesi G, Spaggiari L, Pasini F, Maisonneuve P, Iannucci A, Arrigoni G, Viale G: Alteration of the E-cadherin/beta-catenin cell adhesion system is common in pulmonary neuroendocrine tumors and is an independent predictor of lymph node metastasis in atypical carcinoids. Cancer. 2005, 103 (6): 1154-1164. 10.1002/cncr.20901.CrossRefPubMed

29.

Ilyas M, Tomlinson IP: The interactions of APC, E-cadherin and beta-catenin in tumour development and progression. J Pathol. 1997, 182 (2): 128-137. 10.1002/(SICI)1096-9896(199706)182:2<128::AID-PATH839>3.0.CO;2-Q.CrossRefPubMed

30.

van Es JH, Barker N, Clevers H: You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev. 2003, 13 (1): 28-33. 10.1016/S0959-437X(02)00012-6.CrossRefPubMed

31.

Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, Portillo F, Nieto MA: The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000, 2 (2): 76-83. 10.1038/35000025.CrossRefPubMed

32.

Kokkinos MI, Wafai R, Wong MK, Newgreen DF, Thompson EW, Waltham M: Vimentin and epithelial-mesenchymal transition in human breast cancer–observations in vitro and in vivo. Cells Tissues Organs. 2007, 185 (1–3): 191-203.CrossRefPubMed

33.

Travis WD, Gal AA, Colby TV, Klimstra DS, Falk R, Koss MN: Reproducibility of neuroendocrine lung tumor classification. Hum Pathol. 1998, 29 (3): 272-279. 10.1016/S0046-8177(98)90047-8.CrossRefPubMed

34.

Gheldof A, Berx G: Cadherins and Epithelial-to-Mesenchymal Transition. Prog Mol Biol Transl Sci. 2013, 116: 317-336.CrossRefPubMed

35.

Kaarteenaho R, Lappi-Blanco E, Lehtonen S: Epithelial N-cadherin and nuclear beta-catenin are up-regulated during early development of human lung. BMC Dev Biol. 2010, 10: 113-10.1186/1471-213X-10-113.CrossRefPubMedPubMedCentral

36.

Satomi K, Morishita Y, Sakashita S, Kondou Y, Furuya S, Minami Y, Noguchi M: Specific expression of ZO-1 and N-cadherin in rosette structures of various tumors: possible recapitulation of neural tube formation in embryogenesis and utility as a potentially novel immunohistochemical marker of rosette formation in pulmonary neuroendocrine tumors. Virchows Arch. 2011, 459 (4): 399-407. 10.1007/s00428-011-1120-z.CrossRefPubMed

37.

Zynger DL, Dimov ND, Ho LC, Laskin WB, Yeldandi AV: Differential expression of neural-cadherin in pulmonary epithelial tumours. Histopathology. 2008, 52 (3): 348-354. 10.1111/j.1365-2559.2007.02952.x.CrossRefPubMed

38.

Utsuki S, Sato Y, Oka H, Tsuchiya B, Suzuki S, Fujii K: Relationship between the expression of E-, N-cadherins and beta-catenin and tumor grade in astrocytomas. J Neurooncol. 2002, 57 (3): 187-192. 10.1023/A:1015720220602.CrossRefPubMed

39.

Vlahova L, Doerflinger Y, Houben R, Becker JC, Schrama D, Weiss C, Goebeler M, Helmbold P, Goerdt S, Peitsch WK: P-cadherin expression in Merkel cell carcinomas is associated with prolonged recurrence-free survival. Br J Dermatol. 2012, 166 (5): 1043-1052. 10.1111/j.1365-2133.2012.10853.x.CrossRefPubMed

40.

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 (2): 99-110. 10.1385/EP:13:2:099.CrossRefPubMed

41.

Galvan JA, Astudillo A, Vallina A, Fonseca PJ, Gomez-Izquierdo L, Garcia-Carbonero R, Gonzalez MV: Epithelial-mesenchymal transition markers in the differential diagnosis of gastroenteropancreatic neuroendocrine tumors. Am J Clin Pathol. 2013, 140 (1): 61-72. 10.1309/AJCPIV40ISTBXRAX.CrossRefPubMed

42.

Travis WD: Lung tumours with neuroendocrine differentiation. Eur J Cancer. 2009, 45 (Suppl 1): 251-266.CrossRefPubMed

43.

Travis WD: Advances in neuroendocrine lung tumors. Ann Oncol. 2010, 21 (Suppl 7): vii65-vii71.PubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/855/prepub

Title: Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors
Authors: Jose A Galván
Aurora Astudillo
Aitana Vallina
Guillermo Crespo
Maria Victoria Folgueras
Maria Victoria González
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-14-855

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

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

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2014

Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia

Solitary breast metastasis from myxoid liposarcoma

Suppression of the epithelial-mesenchymal transition by SHARP1 is linked to the NOTCH1 signaling pathway in metastasis of endometrial cancer

Primary small cell carcinoma of the esophagus: clinicopathological study of 44 cases

Risk of breast cancer and family history of other cancers in first-degree relatives in Chinese women: a case control study

The inflammatory cytokine TNFα cooperates with Ras in elevating metastasis and turns WT-Ras to a tumor-promoting entity in MCF-7 cells

Keynote webinar | Spotlight on antibody–drug conjugates in cancer