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αvβ3, αvβ5 and αvβ6 integrins in brain metastases of lung cancer

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Abstract

Integrins are transmembranous adhesion molecules postulated to be involved in the brain metastatic cascade. We investigated the correlation of alpha v beta 3 (αvβ3), alpha v beta 5 (αvβ5) and alpha v beta 6 (αvβ6) integrin isoform expression with clinical characteristics including survival times in lung cancer patients with brain metastases (BM). All BM from lung cancer operated at our institution between 1990 and 2011, were identified; where available, primary tumors were retrieved as well. Immunohistochemical analysis for αvβ3, αvβ5 and αvβ6 integrin subunits was performed and correlated with Ki67 and hypoxia-inducible factor (HIF)-1α indexes. Clinical data including survival data were obtained by chart review. 191 BM specimens of 191 patients with histologically confirmed lung cancer (172 non-small cell lung cancer and 19 small cell lung cancer) were included. In 18 patients matched primary tumor samples were available. αvβ6 expression was commonly found on BM tumor cells (103/191; 53.9 %) and showed a significant association with low Ki67 proliferation indices (46 vs. 36 %, p = 0.001, Mann–Whitney U test) and favorable survival times (p = 0.020; log rank test) in patients with non-squamous NSCLC BM. αvβ5 expression was highly expressed on vascular structures (167/191; 87.4 %) and tumor stroma in BM (151/191; 79.1 %) and associated with high HIF-1α indices (60 vs. 90, p = 0.007, Mann–Whitney U test). αvβ3 expression was more frequently found on vascular structures in BM than in primary tumors (68.1 vs. 5.6 %; p = 0.645; Chi square test) and its expression in BM tumor cells correlated with low Ki67 indices (41 vs. 28 %; p = 0.046, Mann–Whitney U test). Expression of αv integrin subunits seem to be of pathobiological and clinical relevance in patients with NSCLC BM. Further investigations of their involvement in the brain metastatic cascade and their role as biomarkers are warranted.

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Acknowledgments

We thank Orsolya Rajky, Manuel Magerle, Ayseguel Ilhan-Mutlu, Carina Dinhof, Irene Leisser and Gerda Ricken for excellent technical assistance with preparation of tissue specimens and data collection. This study was performed within the PhD thesis project of Anna Sophie Berghoff in the PhD program “Clinical Neuroscience (CLINS)” at the Medical University Vienna.

Conflict of interest

SLG has a patent application referring to the anti-integrin antibodies used here. MW has received research support and honoraria for lectures and advisory board from Merck-Serono. All other authors declare no conflict of interest.

Funding

The costs for this project were covered by the research budget of the Medical University of Vienna.

Author information

Authors and Affiliations

  1. Institute of Neurology, Medical University of Vienna, Vienna, Austria

    Anna Sophie Berghoff & Johannes A. Hainfellner

  2. Department of Medicine I and Comprehensive Cancer Center, Central Nervous System Tumours Unit (CCC-CNS), Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria

    Anna Sophie Berghoff, Astrid Kerstin Kovanda, Rupert Bartsch, Christoph C. Zielinski & Matthias Preusser

  3. Comprehensive Cancer Center – CNS Unit (CCC-CNS), Vienna, Austria

    Anna Sophie Berghoff, Astrid Kerstin Kovanda, Rupert Bartsch, Johannes A. Hainfellner, Christoph C. Zielinski, Georg Widhalm, Karin Dieckmann, Peter Birner & Matthias Preusser

  4. 3rd Medical Department, Paracelsus Medical University Hospital Salzburg, Salzburg, Austria

    Thomas Melchardt

  5. Department of Neuropathology, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, Germany

    Bence Sipos & Jens Schittenhelm

  6. Department of Neurosurgery, Medical University of Vienna, Vienna, Austria

    Georg Widhalm

  7. Department of Radiotherapy, Medical University of Vienna, Vienna, Austria

    Karin Dieckmann

  8. Department of Neurology, University Hospital Zurich, Zurich, Switzerland

    Michael Weller

  9. Therapeutic Innovation Platform, Oncology, Translational and Biomarkers Research, Merck KGaA, Darmstadt, Germany

    Simon L. Goodman

  10. Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria

    Peter Birner

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  1. Anna Sophie Berghoff
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Correspondence to Matthias Preusser.

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Berghoff, A.S., Kovanda, A.K., Melchardt, T. et al. αvβ3, αvβ5 and αvβ6 integrins in brain metastases of lung cancer. Clin Exp Metastasis 31, 841–851 (2014). https://doi.org/10.1007/s10585-014-9675-0

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