BMP2 response pattern in human lung fibroblasts predicts outcome in lung adenocarcinomas.
BACKGROUND
Bone morphogenetic proteins play important roles in development, morphogenesis and cancer. With this study we aimed to characterize the response of lung stromal fibroblasts to BMPs and their antagonists on a genome wide level and investigate its potential role in human lung adenocarcinomas.


METHODS
We used an ex vivo culture model and measured gene expression changes in human lung fibroblasts after stimulation with BMPs and their antagonists using HEEBO microarrays. The in vitro data were correlated with in vivo observations in published expression datasets of human lung adenocarcinomas.


RESULTS
We have systematically analyzed the response to BMP2, BMP4, BMP7 and their antagonists, Gremlin and Noggin, to define common and specific gene expression patterns. A BMP2 induced gene expression signature was defined, which is specific for stromal fibroblasts. Gene expression profiles from lung adenocarcinoma biopsies were analyzed to determine the prognostic significance of the "Fibroblast specific BMP2 induced gene list". This gene list successfully segregated patients with different prognostic outcome in 3 datasets. In a small dataset (Garber et al.) there was a strong trend for a worse prognosis of patients with adenocarcinomas of all stages over-expressing the "Fibroblast specific BMP2 induced gene list". In two larger datasets with stage I adenocarcinomas we observed a significantly worse disease-free (p = 0.002, Lee et al. and p = 0.002, Bhattacharjee et al.) and overall survival (p = 0.0002).


CONCLUSIONS
The effects of BMPs and their antagonists are heterogeneous in different cell types. The gene expression pattern induced by BMP2 in primary lung fibroblasts may predict outcomes of patients with lung adenocarcinomas.
Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland. michal.rajski@access.uzh.ch.|Institute of Physiology, University of Zürich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland. michal.rajski@access.uzh.ch.
Michal
M
Rajski
Department of Biochemistry and Molecular Biology, The University of Chicago, 900 East 57th Street, Chicago, IL, 60637, USA. asaaf@uchicago.edu.
Annika
A
Saaf
Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland. Martin.Buess@claraspital.ch.|Division of Medical Oncology, Department of Internal Medicine, St. Claraspital, Kleinriehenstrasse 20, CH-4016, Basel, Switzerland. Martin.Buess@claraspital.ch.
Martin
M
Buess
D000230:Adenocarcinoma / Q000378:metabolism*; D000077192:Adenocarcinoma of Lung; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D019295:Computational Biology; D030541:Databases, Genetic; D005347:Fibroblasts / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008168:Lung / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525809:BMP4 protein, human; C525819:BMP7 protein, human; C486399:GREM1 protein, human