nach oben

Medical Oncology

Erschienen in:

01.03.2017 | Original Paper

Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease

verfasst von: Malik Quasir Mahmood, Chris Ward, Hans Konrad Muller, Sukhwinder Singh Sohal, Eugene Haydn Walters

Erschienen in: Medical Oncology | Ausgabe 3/2017

Einloggen, um Zugang zu erhalten

Abstract

NSCLC is a leading cause of morbidity and mortality worldwide. It includes adeno- and squamous cell carcinoma. In the background, COPD and smoking play a vital role in development of NSCLC. Local progression and metastasis of NSCLC has been associated with various mechanisms, but in particular by a process called epithelial mesenchymal transition (EMT), which is implicated in COPD pathogenesis. In this study, we have investigated whether expression of EGFR (activation marker) and S100A4, vimentin and N-cadherin (as EMT) is different both in central and leading edge of NSCLC and to what extent related to EMT activity of both small and large airways, stage and differentiation of NSCLC. We have investigated EMT biomarkers (S100A4, vimentin, and N-cadherin), an epithelial activation marker (EGFR) and a vascularity marker (Type-IV collagen) in surgically resected tissue from patients with NSCLC (adeno- and squamous cell carcinoma), and compared them with expression in the corresponding non-tumorous airways. EGFR, S100A4, vimentin, N-cadherin expression was higher in tumor cells located at the peripheral leading edge of NSCLC when compared with centrally located tumor cells of same subjects (P < 0.01). Type-IV collagen-expressing blood vessels were also more at the leading edge in comparison with central parts of NSCLC. EGFR and S100A4 expression was related to differentiation status (P < 0.05) and TNM stage (P < 0.05) of NSCLC. Moreover, EMT markers in the leading edge were significantly related to airway EMT activity, while peripheral edge vascularity of squamous cell carcinoma only was significantly related to large airway Rbm vascularity (P < 0.05). EGFR- and EMT-related protein expression was markedly high in the peripheral leading edge of NSCLCs and related to tumor characteristics associated with poor prognosis. The relationships between EMT-related tumor biomarker expression and those in the airway epithelium and Rbm provide a background for utility of airway changes in clinical settings.

Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30.CrossRefPubMed

Williams BA, Sugimura H, Endo C, Nichols FC, Cassivi SD, Allen MS, et al. Predicting postrecurrence survival among completely resected nonsmall-cell lung cancer patients. Ann Thorac Surg. 2006;81(3):1021–7.CrossRefPubMed

D’Amico TA. Molecular biologic staging of lung cancer. Ann Thorac Surg. 2008;85(2):S737–42.CrossRefPubMed

Duffy MJ, McGowan PM, Gallagher WM. Cancer invasion and metastasis: changing views. J Pathol. 2008;214(3):283–93. doi:10.1002/path.2282.CrossRefPubMed

Liotta LA. Tumor invasion and metastases—role of the extracellular matrix: Rhoads Memorial Award lecture. Cancer Res. 1986;46(1):1–7.PubMed

Sakurai H, Maeshima A, Watanabe S, Suzuki K, Tsuchiya R, Maeshima AM, et al. Grade of stromal invasion in small adenocarcinoma of the lung: histopathological minimal invasion and prognosis. Am J Surg Pathol. 2004;28(2):198–206.CrossRefPubMed

Travis WD, Harris C. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon: IARC Press; 2004.

Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Investig. 2002;110(3):341–50.CrossRefPubMedPubMedCentral

Kang Y, Massagué J. Epithelial–mesenchymal transitions: twist in development and metastasis. Cell. 2004;118(3):277–9.CrossRefPubMed

10.

Yilmaz M, Christofori G, Lehembre F. Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med. 2007;13(12):535–41.CrossRefPubMed

11.

Chen N, Sato D, Saiki Y, Sunamura M, Fukushige S, Horii A. S100A4 is frequently overexpressed in lung cancer cells and promotes cell growth and cell motility. Biochem Biophys Res Commun. 2014;447(3):459–64. doi:10.1016/j.bbrc.2014.04.025.CrossRefPubMed

12.

Jechlinger M, Grunert S, Tamir IH, Janda E, Lüdemann S, Waerner T, et al. Expression profiling of epithelial plasticity in tumor progression. Oncogene. 2003;22(46):7155–69.CrossRefPubMed

13.

Gupta GP, Massagué J. Cancer metastasis: building a framework. Cell. 2006;127(4):679–95.CrossRefPubMed

14.

Gotzmann J, Mikula M, Eger A, Schulte-Hermann R, Foisner R, Beug H, et al. Molecular aspects of epithelial cell plasticity: implications for local tumor invasion and metastasis. Mutat Res Rev Mutat Res. 2004;566(1):9–20.CrossRef

15.

Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial–mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172(7):973–81.CrossRefPubMedPubMedCentral

16.

Klymkowsky MW, Savagner P. Epithelial-mesenchymal transition: a cancer researcher’s conceptual friend and foe. Am J Pathol. 2009;174(5):1588–93.CrossRefPubMedPubMedCentral

17.

Nishioka R, Itoh S, Gui T, Gai Z, Oikawa K, Kawai M, et al. SNAIL induces epithelial-to-mesenchymal transition in a human pancreatic cancer cell line (BxPC3) and promotes distant metastasis and invasiveness in vivo. Exp Mol Pathol. 2010;89(2):149–57.CrossRefPubMed

18.

Alves CC, Rosivatz E, Schott C, Hollweck R, Becker I, Sarbia M, et al. Slug is overexpressed in gastric carcinomas and may act synergistically with SIP1 and Snail in the down-regulation of E-cadherin. J Pathol. 2007;211(5):507–15.CrossRef

19.

Bukholm IK, Nesland JM, Borresen-Dale AL. Re-expression of E-cadherin, alpha-catenin and beta-catenin, but not of gamma-catenin, in metastatic tissue from breast cancer patients (see comments). J Pathol. 2000;190(1):15–9. doi:10.1002/(sici)1096-9896(200001)190:1<15:aid-path489>3.0.co;2-l.CrossRefPubMed

20.

Kang H, Min BS, Lee KY, Kim NK, Kim SN, Choi J, et al. Loss of E-cadherin and MUC2 expressions correlated with poor survival in patients with stages II and III colorectal carcinoma. Ann Surg Oncol. 2011;18(3):711–9. doi:10.1245/s10434-010-1338-z.CrossRefPubMed

21.

Thiery JP. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442–54. doi:10.1038/nrc822.CrossRefPubMed

22.

Soltani A, Wood-Baker R, Sohal SS, Muller HK, Reid D, Walters EH. Reticular basement membrane vessels are increased in COPD bronchial mucosa by both factor VIII and collagen IV immunostaining and are hyperpermeable. J Allergy. 2012;2012:958383. doi:10.1155/2012/958383.CrossRef

23.

GOLD. Global initiative for chronic obstructive pulmonary lung disease. 2015. http://www.goldcopdorg.

24.

Sohal SS, Reid D, Soltani A, Ward C, Weston S, Muller HK. Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Respirology. 2010. doi:10.1111/j.1440-1843.2010.01808.x.

25.

Shukla SD, Sohal SS, Mahmood MQ, Reid D, Muller HK, Walters EH. Airway epithelial platelet-activating factor receptor expression is markedly upregulated in chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2014;9:853–61. doi:10.2147/copd.s67044.CrossRefPubMedPubMedCentral

26.

Mahmood MQ, Sohal SS, Shukla SD, Ward C, Hardikar A, Noor WD, et al. Epithelial mesenchymal transition in smokers: large versus small airways and relation to airflow obstruction. Int J Chron Obstruct Pulmon Dis. 2015;10:1515–24. doi:10.2147/copd.s81032.CrossRefPubMedPubMedCentral

27.

Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Der Pathol. 1987;8(3):138–40.

28.

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300. doi:10.3322/caac.20073.CrossRefPubMed

29.

Uruga H, Kishi K, Fujii T, Beika Y, Enomoto T, Takaya H, et al. Efficacy of gefitinib for elderly patients with advanced non-small cell lung cancer harboring epidermal growth factor receptor gene mutations: a retrospective analysis. Intern Med (Tokyo, Jpn). 2010;49(2):103–7.CrossRef

30.

Otto C, Csanadi A, Fisch P, Werner M, Kayser G. Molecular modeling and description of a newly characterized activating mutation of the EGFR gene in non-small cell lung cancer. Diagn Pathol. 2012;7:146. doi:10.1186/1746-1596-7-146.CrossRefPubMedPubMedCentral

31.

Beljan Perak R, Durdov MG, Capkun V, Ivcevic V, Pavlovic A, Soljic V, et al. IMP3 can predict aggressive behaviour of lung adenocarcinoma. Diagn Pathol. 2012;7:165. doi:10.1186/1746-1596-7-165.CrossRefPubMedPubMedCentral

32.

Ji M, Zhang Y, Shi B, Hou P. Association of promoter methylation with histologic type and pleural indentation in non-small cell lung cancer (NSCLC). Diagn Pathol. 2011;6:48. doi:10.1186/1746-1596-6-48.CrossRefPubMedPubMedCentral

33.

Hung JJ, Yang MH, Hsu HS, Hsu WH, Liu JS, Wu KJ. Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax. 2009;64(12):1082–9. doi:10.1136/thx.2009.115691.CrossRefPubMed

34.

Tischler V, Pfeifer M, Hausladen S, Schirmer U, Bonde AK, Kristiansen G, et al. L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer. Mol Cancer. 2011;10:127. doi:10.1186/1476-4598-10-127.CrossRefPubMedPubMedCentral

35.

Chiou SH, Wang ML, Chou YT, Chen CJ, Hong CF, Hsieh WJ, et al. Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res. 2010;70(24):10433–44. doi:10.1158/0008-5472.can-10-2638.CrossRefPubMed

36.

Bartis D, Mise N, Mahida RY, Eickelberg O, Thickett DR. Epithelial-mesenchymal transition in lung development and disease: does it exist and is it important? Thorax. 2014;69(8):760–5. doi:10.1136/thoraxjnl-2013-204608.CrossRefPubMed

37.

Chen Z, Fillmore CM, Hammerman PS, Kim CF, Wong K-K. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer. 2014;14(8):535–46. doi:10.1038/nrc3775.CrossRefPubMed

38.

Funai K, Yokose T, Ishii G, Araki K, Yoshida J, Nishimura M, et al. Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung. Am J Surg Pathol. 2003;27(7):978–84.CrossRefPubMed

39.

Watanabe Y, Yokose T, Sakuma Y, Hasegawa C, Saito H, Yamada K, et al. Alveolar space filling ratio as a favorable prognostic factor in small peripheral squamous cell carcinoma of the lung. Lung Cancer (Amst, Neth). 2011;73(2):217–21. doi:10.1016/j.lungcan.2010.12.001.CrossRef

40.

Udagawa H, Ishii G, Morise M, Umemura S, Matsumoto S, Yoh K, et al. Comparison of the expression levels of molecular markers among the peripheral area and central area of primary tumor and metastatic lymph node tumor in patients with squamous cell carcinoma of the lung. J Cancer Res Clin Oncol. 2015;141(8):1417–25. doi:10.1007/s00432-015-1912-7.CrossRefPubMed

41.

Lee S-J, Choi SY, Kim W-J, Ji M, Lee T-G, Son B-R, et al. Combined aberrant expression of E-cadherin and S100A4, but not β-catenin is associated with disease-free survival and overall survival in colorectal cancer patients. Diagn Pathol. 2013;8(1):1.CrossRef

42.

Wang X, Zhang J, Fan M, Zhou Q, Deng H, Aisharif MJ, et al. The expression of E-cadherin at the invasive tumor front of oral squamous cell carcinoma: immunohistochemical and RT-PCR analysis with clinicopathological correlation. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol. 2009;107(4):547–54.CrossRef

43.

Gravdal K, Halvorsen OJ, Haukaas SA, Akslen LA. A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2007;13(23):7003–11. doi:10.1158/1078-0432.ccr-07-1263.CrossRef

44.

Andersson J, Linderholm B, Bergh J, Elmberger G. HER-2/neu (c-erbB-2) evaluation in primary breast carcinoma by fluorescent in situ hybridization and immunohistochemistry with special focus on intratumor heterogeneity and comparison of invasive and in situ components. Appl Immunohistochem Mol Morphol AIMM Off Publ Soc Appl Immunohistochem. 2004;12(1):14–20.CrossRef

45.

Grob TJ, Hoenig T, Clauditz TS, Atanackovic D, Koenig AM, Vashist YK, et al. Frequent intratumoral heterogeneity of EGFR gene copy gain in non-small cell lung cancer. Lung Cancer (Amst, Neth). 2013;79(3):221–7. doi:10.1016/j.lungcan.2012.11.009.CrossRef

46.

Italiano A, Vandenbos FB, Otto J, Mouroux J, Fontaine D, Marcy P-Y, et al. Comparison of the epidermal growth factor receptor gene and protein in primary non-small-cell-lung cancer and metastatic sites: implications for treatment with EGFR-inhibitors. Ann Oncol. 2006;17(6):981–5.CrossRefPubMed

47.

Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, et al. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012;13(1):33–42. doi:10.1016/s1470-2045(11)70318-7.CrossRefPubMed

Titel: Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease
verfasst von: Malik Quasir Mahmood
Chris Ward
Hans Konrad Muller
Sukhwinder Singh Sohal
Eugene Haydn Walters
Publikationsdatum: 01.03.2017
Verlag: Springer US
Erschienen in: Medical Oncology / Ausgabe 3/2017
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-017-0900-y

Neu im Fachgebiet Onkologie

24.04.2024 | DGIM 2024 | Nachrichten

Springer Medizin

Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease

Abstract

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie

Springer Medizin

Abstract

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 3/2017

Resolution of thrombocytopenia, but not polycythemia after ruxolitinib for polycythemia vera with detectable mutation in the exon 12 of the JAK2 gene

Combination treatment using DDX3 and PARP inhibitors induces synthetic lethality in BRCA1-proficient breast cancer

Use of an alpha lipoic, methylsulfonylmethane and bromelain dietary supplement (Opera®) for chemotherapy-induced peripheral neuropathy management, a prospective study

Third-line treatment of colorectal liver metastases using DEBIRI chemoembolization

Irradiation enhances dendritic cell potential antitumor activity by inducing tumor cell expressing TNF-α

Concurrent chemotherapy alone versus irreversible electroporation followed by chemotherapy on survival in patients with locally advanced pancreatic cancer

Neu im Fachgebiet Onkologie

Bei Senioren mit Prostatakarzinom auf Anämie achten!

ICI-Therapie in der Schwangerschaft wird gut toleriert

Krebspatienten impfen: Was? Wen? Und wann nicht?

Müde im Alter? Auch an die Nebenniere denken

Update Onkologie