Der Pathologe

, Volume 33, Supplement 2, pp 311–317 | Cite as

Epithelial-mesenchymale Transition beim nichtkleinzelligen Bronchialkarzinom

Hauptreferate

Zusammenfassung

Das nichtkleinzellige Bronchialkarzinom (NSCLC) ist ein stark fibrosierender Tumor mit Ausbildung eines prominenten desmoplastischen Stromas. Die epithelial-mesenchymale Transition (EMT) ist eine der Hauptinvasionsarten. Mittels Massenspektrometrie identifizierten wir das stromale N-Glykoprotein Periostin in Pleuraergüssen von Lungenadenokarzinomen. Die immunhistochemische Validierung auf einem NSCLC-Tissue-Microarray sowie auf Großschnitten zeigte, dass Periostin an der Invasionsfront stark aufreguliert wird, sowohl in den Tumorepithelien als auch im umgebenden matrizellulären Stroma. Im Vergleich zu Kollagen, Elastin oder Vimentin war Periostin am engsten assoziiert mit Parametern der Progression, wie größerer Tumor oder höheres Stadium, mit dem Plattenepithelkarzinom und mit schlechterem Überleben. Eine Assoziation mit Letzterem wurde auch für das Zelladhäsionsmolekül L1CAM gefunden. Zusammenfassend kann gesagt werden, dass das NSCLC-Wachstum assoziiert ist mit vermehrter Stromabildung und Aufregulation von EMT-Markern an der Invasionsfront. Die Invasionsfront könnte eine topographisch wichtige Region für eine zielgerichtete Therapie gegen Stroma oder EMT sein.

Schlüsselwörter

Periostin Neoplasien  Maligner Pleuraerguss Bronchialkarzinom Desmoplastisches Stroma 

Epithelial−mesenchymal transition in non-small cell lung cancer

Abstract

Non-small cell lung carcinoma (NSCLC) is a highly fibrotic malignancy, which exhibits a prominent desmoplastic stroma. Epithelial–mesenchymal transition (EMT) is one of the main modes of carcinoma invasion. We identified the stromal N-glycoprotein periostin by mass spectrometry of lung adenocarcinoma pleural effusions. Validation on a NSCLC tissue microarray and on tumor whole sections by immunohistochemistry indicated that periostin is strongly upregulated at the invasive front in both tumor epithelia and the surrounding matricellular space. In comparison to collagen, elastin and vimentin, periostin was found to be most closely associated with parameters of tumor progression such as larger size and higher stage, with the squamous cell histotype, and with decreased survival. An association with decreased survival was also found for the cell adhesion molecule L1CAM. In conclusion, enlargement of NSCLC tumors is associated with an increase of desmoplastic stroma and concomitant upregulation of EMT markers at the invasive front. The tumor–stroma interface may be a candidate topographic region for stroma- or EMT-directed therapy.

Keywords

Periostin Neoplasms Pleural effusion, malignant Lung cancer Desmoplastic stroma 

Notes

Interessenkonflikt

Der korrespondierende Autor gibt an, dass kein Interessenkonflikt besteht.

The supplement this article is part of is not sponsored by the industry.

Literatur

  1. 1.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674PubMedCrossRefGoogle Scholar
  2. 2.
    Yilmaz M, Christofori G, Lehembre F (2007) Distinct mechanisms of tumor invasion and metastasis. Trends Mol Med 13:535–541PubMedCrossRefGoogle Scholar
  3. 3.
    Mimeault M, Batra SK (2007) Interplay of distinct growth factors during epithelial mesenchymal transition of cancer progenitor cells and molecular targeting as novel cancer therapies. Ann Oncol 18:1605–1619PubMedCrossRefGoogle Scholar
  4. 4.
    Travis WD, Brambilla E, Noguchi M et al (2011) International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6:244–285PubMedCrossRefGoogle Scholar
  5. 5.
    Takahashi Y, Ishii G, Taira T et al (2011) Fibrous stroma is associated with poorer prognosis in lung squamous cell carcinoma patients. J Thorac Oncol 6:1460–1467PubMedCrossRefGoogle Scholar
  6. 6.
    Beck AH, Sangoi AR, Leung S et al (2011) Systematic analysis of breast cancer morphology uncovers stromal features associated with survival. Sci Transl Med 3:108ra113PubMedCrossRefGoogle Scholar
  7. 7.
    Matsui Y, Morimoto J, Uede T (2010) Role of matricellular proteins in cardiac tissue remodeling after myocardial infarction. World J Biol Chem 1:69–80PubMedCrossRefGoogle Scholar
  8. 8.
    Kudo Y, Siriwardena BS, Hatano H et al (2007) Periostin: novel diagnostic and therapeutic target for cancer. Histol Histopathol 22:1167–1174PubMedGoogle Scholar
  9. 9.
    Kii I, Nishiyama T, Li M et al (2010) Incorporation of tenascin-C into the extracellular matrix by periostin underlies an extracellular meshwork architecture. J Biol Chem 285:2028–2039PubMedCrossRefGoogle Scholar
  10. 10.
    Maruhashi T, Kii I, Saito M, Kudo A (2010) Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase. J Biol Chem 285:13294–13303PubMedCrossRefGoogle Scholar
  11. 11.
    Yan W, Shao R (2006) Transduction of a mesenchyme-specific gene periostin into 293 T cells induces cell invasive activity through epithelial-mesenchymal transformation. J Biol Chem 281:19700–19708PubMedCrossRefGoogle Scholar
  12. 12.
    Malanchi I, Santamaria-Martinez A, Susanto E et al (2012) Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481:85–89CrossRefGoogle Scholar
  13. 13.
    Soltermann A, Ossola R, Kilgus-Hawelski S et al (2008) N-glycoprotein profiling of lung adenocarcinoma pleural effusions by shotgun proteomics. Cancer 114:124–133PubMedCrossRefGoogle Scholar
  14. 14.
    Soltermann A, Tischler V, Arbogast S et al (2008) Prognostic significance of epithelial-mesenchymal and mesenchymal-epithelial transition protein expression in non-small cell lung cancer. Clin Cancer Res 14:7430–7437PubMedCrossRefGoogle Scholar
  15. 15.
    Schäfer MK, Altevogt P (2010) L1CAM malfunction in the nervous system and human carcinomas. Cell Mol Life Sci 67:2425–2437PubMedCrossRefGoogle Scholar
  16. 16.
    Tischler V, Pfeifer M, Hausladen S et al (2011) L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer. Mol Cancer 10:127PubMedCrossRefGoogle Scholar
  17. 17.
    Bonde AK, Tischler V, Kumar S et al (2012) Intratumoral macrophages contribute to epithelial-mesenchymal transition in solid tumors. BMC Cancer 12:35PubMedCrossRefGoogle Scholar
  18. 18.
    Morra L, Rechsteiner M, Casagrande S et al (2012) Characterization of periostin isoform pattern in non-small cell lung cancer. Lung Cancer 76:183–190PubMedCrossRefGoogle Scholar
  19. 19.
    Kim CJ, Isono T, Tambe Y et al (2008) Role of alternative splicing of periostin in human bladder carcinogenesis. Int J Oncol 32:161–169PubMedGoogle Scholar
  20. 20.
    Morra L, Rechsteiner M, Casagrande S et al (2011) Relevance of periostin splice variants in renal cell carcinoma. Am J Pathol 179:1513–1521PubMedCrossRefGoogle Scholar
  21. 21.
    Pedretti M, Soltermann A, Arni S et al (2009) Comparative immunohistochemistry of L19 and F16 in non-small cell lung cancer and mesothelioma: two human antibodies investigated in clinical trials in patients with cancer. Lung Cancer 64:28–33PubMedCrossRefGoogle Scholar
  22. 22.
    Palumbo A, Hauler F, Dziunycz P et al (2011) A chemically modified antibody mediates complete eradication of tumours by selective disruption of tumour blood vessels. Br J Cancer 104:1106–1115PubMedCrossRefGoogle Scholar
  23. 23.
    Castronovo V, Waltregny D, Kischel P et al (2006) A chemical proteomics approach for the identification of accessible antigens expressed in human kidney cancer. Mol Cell Proteomics 5:2083–2091PubMedCrossRefGoogle Scholar
  24. 24.
    Hoersch S, Andrade-Navarro MA (2010) Periostin shows increased evolutionary plasticity in its alternatively spliced region. BMC Evol Biol 10:30PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Institut für Klinische PathologieUniversitätsspital ZürichZürichSchweiz

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