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

作者：De Boeck Astrid; Pauwels Patrick; Hensen Karen; Rummens Jean Luc; Westbroek Wendy; Hendrix An; Maynard Dawn; Denys Hannelore; Lambein Kathleen; Braems Geert; Gespach Christian; Bracke Marc; De Wever Olivier^*

来源：Gut, 2013, 62(4): 550-560.

DOI：10.1136/gutjnl-2011-301393

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). %26lt;br%26gt;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. %26lt;br%26gt;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. %26lt;br%26gt;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.

• 出版日期2013-4