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Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling

Astrid De Boeck UGent, Patrick Pauwels UGent, Karen Hensen, Jean-Luc Rummens, Wendy Westbroek, An Hendrix UGent, Dawn Maynard, Hannelore Denys UGent, Kathleen Lambein UGent and Geert Braems UGent, et al. (2013) GUT. 62(4). p.550-560
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). 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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
KINASE, HEREGULIN, MYOFIBROBLASTS, TENASCIN-C, IN-VIVO, METASTATIC NICHE, ERBB RECEPTORS, GROWTH-FACTOR RECEPTOR, TUMOR MICROENVIRONMENT, HUMAN COLON-CANCER
journal title
GUT
Gut
volume
62
issue
4
pages
550 - 560
Web of Science type
Article
Web of Science id
000315595800011
JCR category
GASTROENTEROLOGY & HEPATOLOGY
JCR impact factor
13.319 (2013)
JCR rank
2/75 (2013)
JCR quartile
1 (2013)
ISSN
0017-5749
DOI
10.1136/gutjnl-2011-301393
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
3004217
handle
http://hdl.handle.net/1854/LU-3004217
date created
2012-10-02 13:49:15
date last changed
2013-04-26 10:44:12
@article{3004217,
  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). 
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.},
  author       = {De Boeck, Astrid and Pauwels, Patrick and Hensen, Karen and Rummens, Jean-Luc and Westbroek, Wendy and Hendrix, An and Maynard, Dawn and Denys, Hannelore and Lambein, Kathleen and Braems, Geert and Gespach, Christian and Bracke, Marc and De Wever, Olivier},
  issn         = {0017-5749},
  journal      = {GUT},
  keyword      = {KINASE,HEREGULIN,MYOFIBROBLASTS,TENASCIN-C,IN-VIVO,METASTATIC NICHE,ERBB RECEPTORS,GROWTH-FACTOR RECEPTOR,TUMOR MICROENVIRONMENT,HUMAN COLON-CANCER},
  language     = {eng},
  number       = {4},
  pages        = {550--560},
  title        = {Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling},
  url          = {http://dx.doi.org/10.1136/gutjnl-2011-301393},
  volume       = {62},
  year         = {2013},
}

Chicago
De Boeck, Astrid, Patrick Pauwels, Karen Hensen, Jean-Luc Rummens, Wendy Westbroek, An Hendrix, Dawn Maynard, et al. 2013. “Bone Marrow-derived Mesenchymal Stem Cells Promote Colorectal Cancer Progression Through Paracrine Neuregulin 1/HER3 Signalling.” GUT 62 (4): 550–560.
APA
De Boeck, Astrid, Pauwels, P., Hensen, K., Rummens, J.-L., Westbroek, W., Hendrix, A., Maynard, D., et al. (2013). Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. GUT, 62(4), 550–560.
Vancouver
1.
De Boeck A, Pauwels P, Hensen K, Rummens J-L, Westbroek W, Hendrix A, et al. Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling. GUT. 2013;62(4):550–60.
MLA
De Boeck, Astrid, Patrick Pauwels, Karen Hensen, et al. “Bone Marrow-derived Mesenchymal Stem Cells Promote Colorectal Cancer Progression Through Paracrine Neuregulin 1/HER3 Signalling.” GUT 62.4 (2013): 550–560. Print.