Centre for Cancer and Inflammation, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Cancer Research UK, Bioinformatics and Biostatistics Service, London, United Kingdom.
Cancer Res. 2012 Jan 1;72(1):66-75. doi: 10.1158/0008-5472.CAN-11-2178. Epub 2011 Nov 7.
Constitutive production of inflammatory cytokines is a characteristic of many human malignant cell lines; however, the in vitro and in vivo interdependence of these cytokines, and their significance to the human cancer microenvironment, are both poorly understood. Here, we describe for the first time how three key cytokine/chemokine mediators of cancer-related inflammation, TNF, CXCL12, and interleukin 6, are involved in an autocrine cytokine network, the "TNF network," in human ovarian cancer. We show that this network has paracrine actions on angiogenesis, infiltration of myeloid cells, and NOTCH signaling in both murine xenografts and human ovarian tumor biopsies. Neutralizing antibodies or siRNA to individual members of this TNF network reduced angiogenesis, myeloid cell infiltration, and experimental peritoneal ovarian tumor growth. The dependency of network genes on TNF was shown by their downregulation in tumor cells from patients with advanced ovarian cancer following the infusion of anti-TNF antibodies. Together, the findings define a network of inflammatory cytokine interactions that are crucial to tumor growth and validate this network as a key therapeutic target in ovarian cancer.
炎症细胞因子的组成性产生是许多人类恶性细胞系的特征；然而，这些细胞因子在体外和体内的相互依赖性及其对人类癌症微环境的意义都知之甚少。在这里，我们首次描述了三种关键的癌症相关炎症细胞因子/趋化因子介质 TNF、CXCL12 和白细胞介素 6 如何参与人类卵巢癌中的自分泌细胞因子网络“TNF 网络”。我们表明，该网络在小鼠异种移植物和人类卵巢肿瘤活检中具有旁分泌作用，可影响血管生成、髓样细胞浸润和 NOTCH 信号传导。针对该 TNF 网络中单个成员的中和抗体或 siRNA 可减少血管生成、髓样细胞浸润和实验性腹膜卵巢肿瘤生长。通过输注抗 TNF 抗体后，晚期卵巢癌患者肿瘤细胞中网络基因的下调，显示出它们对 TNF 的依赖性。总之，这些发现定义了一个炎症细胞因子相互作用网络，这对肿瘤生长至关重要，并将该网络验证为卵巢癌的一个关键治疗靶点。
