Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584CG Utrecht, The Netherlands.
Nutricia Research, 3584CT Utrecht, The Netherlands.
Int J Mol Sci. 2019 Apr 4;20(7):1689. doi: 10.3390/ijms20071689.
Mast cells (MCs) are one of the first immune cells recruited to a tumor. It is well recognized that MCs accumulate in colon cancer lesion and their density is associated with the clinical outcomes. However, the molecular mechanism of how colon cancer cells may modify MC function is still unclear. In this study, primary human MCs were generated from CD34⁺ progenitor cells and a 3D coculture model was developed to study the interplay between colon cancer cells and MCs. By comparing the transcriptomic profile of colon cancer-cocultured MCs versus control MCs, we identified a number of deregulated genes, such as MMP-2, VEGF-A, PDGF-A, COX2, NOTCH1 and ISG15, which contribute to the enrichment of cancer-related pathways. Intriguingly, pre-stimulation with a TLR2 agonist prior to colon cancer coculture induced upregulation of multiple interferon-inducible genes as well as MHC molecules in MCs. Our study provides an alternative approach to study the influence of colon cancer on MCs. The transcriptome signature of colon cancer-cocultured MCs may potentially reflect the mechanism of how colon cancer cells educate MCs to become pro-tumorigenic in the initial phase and how a subsequent inflammatory signal-e.g., TLR2 ligands-may modify their responses in the cancer milieu.
肥大细胞（MCs）是最先被招募到肿瘤中的免疫细胞之一。人们已经充分认识到，MCs 在结肠癌病变中聚集，其密度与临床结果相关。然而，结肠癌细胞可能改变 MC 功能的分子机制仍不清楚。在这项研究中，我们从 CD34⁺祖细胞中生成了原代人 MC，并建立了 3D 共培养模型来研究结肠癌细胞与 MC 之间的相互作用。通过比较与对照 MC 相比，结肠癌共培养 MC 的转录组图谱，我们鉴定出许多失调基因，如 MMP-2、VEGF-A、PDGF-A、COX2、NOTCH1 和 ISG15，这些基因有助于富集与癌症相关的途径。有趣的是，在与结肠癌共培养之前用 TLR2 激动剂预先刺激可诱导 MC 中多种干扰素诱导基因和 MHC 分子的上调。我们的研究提供了一种研究结肠癌对 MC 影响的替代方法。结肠癌共培养 MC 的转录组特征可能反映了结肠癌细胞在初始阶段如何教导 MC 成为促肿瘤的机制，以及随后的炎症信号（例如，TLR2 配体）如何在癌症环境中改变它们的反应。
