Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling
- Astrid De Boeck1,
- Patrick Pauwels2,
- Karen Hensen3,
- Jean-Luc Rummens3,
- Wendy Westbroek4,
- An Hendrix1,5,
- Dawn Maynard4,
- Hannelore Denys5,
- Kathleen Lambein6,
- Geert Braems7,
- Christian Gespach8,
- Marc Bracke1,
- Olivier De Wever1
- 1Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, Ghent, Belgium
- 2Department of Pathology, University of Antwerp, Wilrijk, Belgium
- 3Laboratory of Experimental Hematology, Jesse Hospital, Hasselt, Belgium
- 4Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA
- 5Department of Medical Oncology, Ghent University Hospital, Ghent, Belgium
- 6Department of Pathology, Ghent University Hospital, Ghent, Belgium
- 7Department of Gynaecology, Ghent University Hospital, Ghent, Belgium
- 8INSERM UMR_S938, Molecular and Clinical Oncology, Université Paris VI Pierre et Marie Curie, Centre de Recherche Saint-Antoine, Paris, France
- Correspondence to Dr Olivier De Wever, Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium;
Contributors ADB: concept and design, acquisition of data, analysis and interpretation of data, drafting of the manuscript, statistical analysis, obtaining funding, approval of the final version. PP, GB and CG: concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, statistical analysis, approval of the final version. KH, JLR, WW, AH, DM, HD and KL: acquisition of data, analysis and interpretation of data, revision of the manuscript, material and technical support, approval of the final version. MB and ODW: concept and design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, study supervision, obtaining funding, approval of the final version.
- Revised 10 February 2012
- Accepted 11 February 2012
- Published Online First 25 April 2012
Objective Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumours and drive tumour progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC).
Design Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumour xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane neuregulin 1 (tNRG1), HER2 and HER3 expression was analysed in primary CRC (n=54), adjacent normal colorectal tissues (n=4), liver metastases (n=3) and adjacent normal liver tissues (n=3) by immunohistochemistry.
Results BM-MSC stimulate invasion, survival and tumorigenesis of CRC through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in CRC cells. Similarly, tumour-associated mesenchymal cells (T-MC) in CRC demonstrate high tNRG1 expression, which is significantly associated with advanced Union for International Cancer Control stage (p=0.005) and invasion depth (p=0.04) and decreased 5-year progression-free survival (p=0.01). HER2 and HER3 show membrane localisation in cancer cells of CRC tissue.
Conclusion Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis in CRC.
- Colorectal cancer
- mesenchymal stem cells
- molecular oncology
- neuregulin 1
Funding This work was supported by the Intramural Research Program of the National Human Genome Research Institute, Centrum voor Gezwelziekten, the Scientific Exchange Program between the Flemish community and France (I.2007.03, T.2009.14, T.2010.14), Vlaamse Liga tegen Kanker, Stichting tegen Kanker, Bijzonder Onderzoeksfonds UGent, travel grant (AH and ODW), a doctoral grant (ADB; 1148408N) and a postdoctoral researcher (ODW) from the Fund for Scientific Research-Flanders.
Competing interests None.
Patient consent Obtained.
Ethics approval Ethics approval was granted by the local ethics committees of the University Hospital Antwerp, Ghent University Hospital and Virga Jesse Hospital Hasselt.
Provenance and peer review Not commissioned; externally peer reviewed.