Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling
Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling
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DOI：
10.1136/gutjnl-2011-301393
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发表时间：
2013-04-01
期刊：
影响因子：
24.5
通讯作者：
De Wever, Olivier
中科院分区：
文献类型：
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作者：
De Boeck, Astrid;Pauwels, Patrick;De Wever, Olivier
目的骨髓间充质干细胞（BM-MSC）迁移至原发肿瘤并驱动肿瘤进展。本研究旨在确定与这些异型细胞相互作用相关的分子机制，并分析其在结直肠癌（CRC）中的相关性。设计使用胶原侵袭测定、细胞计数、流式细胞术细胞周期分析和肿瘤异种移植模型研究BM-MSC与CRC细胞的旁分泌相互作用。神经调节蛋白1（NRG 1）和人表皮生长因子受体（HER）家族途径的作用进行了研究，使用酪氨酸激酶测定，质谱，药理学抑制，抗体介导的中和和RNA干扰。采用免疫组化方法检测54例原发性结直肠癌、4例癌旁正常结直肠组织、3例肝转移癌和3例癌旁正常肝组织中跨膜神经调节蛋白1（Transmembrane neuregulin 1，tNRG 1）、HER 2和HER 3的表达。激活CRC细胞中的HER 2/HER 3依赖性PI 3 K/AKT信号级联。类似地，CRC中的肿瘤相关间充质细胞（T-MC）表现出高tNRG 1表达，这与国际癌症控制联盟的晚期分期（p = 0.005）和浸润深度（p = 0.04）以及5年无进展生存率降低（p = 0.01）显著相关。结论BM-MSC和T-MC启动的旁分泌NRG 1/HER 3信号促进结直肠癌细胞的生长，tNRG 1高表达与结直肠癌预后不良有关。
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.