Kalamegam Gauthaman, Sait Khalid Hussein Wali, Anfinan Nisreen, Kadam Roaa, Ahmed Farid, Rasool Mahmood, Naseer Mohammad Imran, Pushparaj Peter Natesan, Al-Qahtani Mohammed
Center of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah 21589, Kingdom of Saudi Arabia.
Faculty of Medicine, AIMST University, Bedong, Kedah 08100, Malaysia.
Oncol Lett. 2019 May;17(5):4521-4531. doi: 10.3892/ol.2019.10094. Epub 2019 Mar 1.
Cytokines enhance tumour cell recognition via cytotoxic effector cells and are therefore effectively used in cancer immunotherapy. Mesenchymal stem cells have efficient homing potential and have been used to target and inhibit various types of cancer mediated by the release of soluble/bioactive factors. Initial evaluation of the human Wharton's jelly stem cell conditioned medium (hWJSC-CM) and cell lysate (hWJSC-CL) against an ovarian cancer cell line (OVCAR3) demonstrated their inhibitory effect . The secreted cytokine profile was then studied to understand whether the OVCAR3 inhibitory effect was mediated by the cytokines. Expression of cytokines in OVCAR3 following 48 h treatment with hWJSC extracts, namely the hWJSC-CM (50%) and hWJSC-CL (10 µg/ml), was evaluated using multiplex cytokine assay. Paclitaxel (5 nM) was used as a positive control. Cytokines tumour necrosis factor α, interleukin (IL)-4, IL-6, IL-8, IL-10, IL-13, IL-17, IL-1β and granulocyte colony-stimulating factor, reported to be involved in tumour growth, invasion and migration, were significantly decreased. Cytokines with antitumour effects, namely IL-1 receptor antagonist (IL-1RA), IL-2, IL-2 receptor, IL-5, IL-7, IL-12, IL-15, interferon (IFN)-α and IFN-γ, were mildly increased or decreased. Only the increases in IL-1RA (with paclitaxel, hWJSC-CM and hWJSC-CL) and granulocyte-macrophage colony-stimulating factor (with hWJSC-CL) were statistically significant. The chemokines monocyte chemoattractant protein 1, macrophage inflammatory protein (MIP)-1α, MIP-1β and Regulated Upon Activation, Normally T-Expressed, and Secreted were significantly decreased while monokine induced by IFN-γ, IFN-γ induced protein 10 and Eotaxin demonstrated mild decreases. The growth factors basic fibroblast growth factor, vascular endothelial growth factor and hepatocyte growth factor were significantly decreased. Heatmaps demonstrated differential fold changes in cytokines and hierarchical cluster analysis revealed 3 major and 7 minor sub-clusters of associated cytokines, chemokines and growth factors. In conclusion, the hWJSC extracts decreased the expression of oncogenic cytokines, chemokines and growth factors, which mediated the inhibition of OVCAR3 cells .
细胞因子可通过细胞毒性效应细胞增强肿瘤细胞识别，因此在癌症免疫治疗中得到有效应用。间充质干细胞具有高效的归巢潜能，已被用于靶向和抑制由可溶性/生物活性因子释放介导的各种类型癌症。对人脐带华通氏胶干细胞条件培养基（hWJSC-CM）和细胞裂解物（hWJSC-CL）针对卵巢癌细胞系（OVCAR3）进行的初步评估显示了它们的抑制作用。随后研究了分泌的细胞因子谱，以了解OVCAR3抑制作用是否由细胞因子介导。使用多重细胞因子检测法评估了用hWJSC提取物（即hWJSC-CM（50%）和hWJSC-CL（10µg/ml））处理48小时后OVCAR3中细胞因子的表达。紫杉醇（5 nM）用作阳性对照。据报道参与肿瘤生长、侵袭和迁移的细胞因子肿瘤坏死因子α、白细胞介素（IL）-4、IL-6、IL-8、IL-10、IL-13、IL-17、IL-1β和粒细胞集落刺激因子显著减少。具有抗肿瘤作用的细胞因子，即IL-1受体拮抗剂（IL-1RA）、IL-2、IL-2受体、IL-5、IL-7、IL-12、IL-15、干扰素（IFN）-α和IFN-γ，有轻度增加或减少。只有IL-1RA（与紫杉醇、hWJSC-CM和hWJSC-CL一起）和粒细胞-巨噬细胞集落刺激因子（与hWJSC-CL一起）的增加具有统计学意义。趋化因子单核细胞趋化蛋白1、巨噬细胞炎性蛋白（MIP）-1α、MIP-1β和活化后正常T细胞表达和分泌的调节因子显著减少，而IFN-γ诱导的单核因子、IFN-γ诱导蛋白10和嗜酸性粒细胞趋化因子有轻度减少。生长因子碱性成纤维细胞生长因子、血管内皮生长因子和肝细胞生长因子显著减少。热图显示了细胞因子的差异倍数变化，层次聚类分析揭示了相关细胞因子、趋化因子和生长因子的3个主要亚群和7个次要亚群。总之，hWJSC提取物降低了致癌细胞因子、趋化因子和生长因子 的表达，从而介导了对OVCAR3细胞的抑制作用。
