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Open Access Highly Accessed Research article

Hypoxia increases membrane metallo-endopeptidase expression in a novel lung cancer ex vivo model – role of tumor stroma cells

Katharina Leithner1, Christoph Wohlkoenig1, Elvira Stacher2, Jörg Lindenmann3, Nicole A Hofmann45, Birgit Gallé6, Christian Guelly6, Franz Quehenberger7, Philipp Stiegler8, Freyja-Maria Smolle-Jüttner3, Sjaak Philipsen9, Helmut H Popper2, Andelko Hrzenjak111, Andrea Olschewski1011 and Horst Olschewski1*

Author Affiliations

1 Division of Pulmonology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 20, A-8036 Graz, Austria

2 Institute of Pathology, Medical University of Graz, Auenbruggerplatz 25, A-8036 Graz, Austria

3 Division of Thoracic and Hyperbaric Surgery, Department of Surgery, Medical University of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria

4 Stem Cell Research Unit, Medical University of Graz, Stiftingtalstraße 24, A-8010 Graz, Austria

5 Institute for Molecular Biology and Biochemistry, Medical University of Graz, Harrachgasse 21/III, A-8010 Graz, Austria

6 Core Facility Molecular Biology, Center for Medical Research, Medical University of Graz, Stiftingtalstraße 24, A-8010 Graz, Austria

7 Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, Auenbruggerplatz 2, A-8036 Graz, Austria

8 Division of Transplant Surgery, Department of Surgery, Medical University of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria

9 Department of Cell Biology, Erasmus University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands

10 Experimental Anesthesiology, University Clinic for Anesthesiology and Intensive Care Medicine, Medical University of Graz, Auenbruggerplatz 29, A-8036 Graz, Austria

11 Ludwig Boltzmann Institute for Lung Vascular Research, Stiftingtalstraße 24, A-8010 Graz, Austria

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BMC Cancer 2014, 14:40  doi:10.1186/1471-2407-14-40

Published: 25 January 2014



Hypoxia-induced genes are potential targets in cancer therapy. Responses to hypoxia have been extensively studied in vitro, however, they may differ in vivo due to the specific tumor microenvironment. In this study gene expression profiles were obtained from fresh human lung cancer tissue fragments cultured ex vivo under different oxygen concentrations in order to study responses to hypoxia in a model that mimics human lung cancer in vivo.


Non-small cell lung cancer (NSCLC) fragments from altogether 70 patients were maintained ex vivo in normoxia or hypoxia in short-term culture. Viability, apoptosis rates and tissue hypoxia were assessed. Gene expression profiles were studied using Affymetrix GeneChip 1.0 ST microarrays.


Apoptosis rates were comparable in normoxia and hypoxia despite different oxygenation levels, suggesting adaptation of tumor cells to hypoxia. Gene expression profiles in hypoxic compared to normoxic fragments largely overlapped with published hypoxia-signatures. While most of these genes were up-regulated by hypoxia also in NSCLC cell lines, membrane metallo-endopeptidase (MME, neprilysin, CD10) expression was not increased in hypoxia in NSCLC cell lines, but in carcinoma-associated fibroblasts isolated from non-small cell lung cancers. High MME expression was significantly associated with poor overall survival in 342 NSCLC patients in a meta-analysis of published microarray datasets.


The novel ex vivo model allowed for the first time to analyze hypoxia-regulated gene expression in preserved human lung cancer tissue. Gene expression profiles in human hypoxic lung cancer tissue overlapped with hypoxia-signatures from cancer cell lines, however, the elastase MME was identified as a novel hypoxia-induced gene in lung cancer. Due to the lack of hypoxia effects on MME expression in NSCLC cell lines in contrast to carcinoma-associated fibroblasts, a direct up-regulation of stroma fibroblast MME expression under hypoxia might contribute to enhanced aggressiveness of hypoxic cancers.

Hypoxia; Tumor; Expression array; Prognosis