title: Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling.
abstract: 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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology and Experimental Cancer Research, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium.
authors.forename: Astrid
authors.initials: A
authors.lastname: De Boeck
authors.forename: Patrick
authors.initials: P
authors.lastname: Pauwels
authors.forename: Karen
authors.initials: K
authors.lastname: Hensen
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Rummens
authors.forename: Wendy
authors.initials: W
authors.lastname: Westbroek
authors.forename: An
authors.initials: A
authors.lastname: Hendrix
authors.forename: Dawn
authors.initials: D
authors.lastname: Maynard
authors.forename: Hannelore
authors.initials: H
authors.lastname: Denys
authors.forename: Kathleen
authors.initials: K
authors.lastname: Lambein
authors.forename: Geert
authors.initials: G
authors.lastname: Braems
authors.forename: Christian
authors.initials: C
authors.lastname: Gespach
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.forename: Olivier
authors.initials: O
authors.lastname: De Wever
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology*; D000704:Analysis of Variance; D015153:Blotting, Western; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D016009:Chi-Square Distribution; D002853:Chromatography, Liquid; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D013058:Mass Spectrometry; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D020890:Neuregulin-1 / Q000378:metabolism*; D019899:Paracrine Communication; D010766:Phosphorylation; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction; D018709:Statistics, Nonparametric
chemical_list: D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3