Division of Molecular Virology, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Neoplasia. 2011 Aug;13(8):664-75. doi: 10.1593/neo.11332.
The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) is dynamic, with an extensive interaction between the stroma and tumor cells. The aim of this study was to delineate the cross talk between PDAC and cancer-associated fibroblasts (CAFs), with a focus on the mechanism creating the chronic inflammatory tumor milieu. We assessed the effects of the cross talk between PDAC and CAF cell lines on the creation and sustenance of the inflammatory tumor microenvironment in pancreatic cancer. The coculture of PDAC and CAF cell lines enhanced the levels of inflammatory factors including IL-1α, IL-6, CXCL8, VEGF-A, CCL20, and COX-2. CAFs were superior to tumor cells regarding the production of most inflammatory factors, and tumor cell-associated IL-1α was established as the initiator of the enhanced production of inflammatory factors through the binding of IL-1α to IL-1 receptor 1 (IL-1R1) expressed predominantly by CAFs. Furthermore, we found a correlation between IL-1α and CXCL8 expression levels in PDAC tissues and correlation between IL-1α expression and the clinical outcome of the patients. This confirmed an important role for the IL-1 signaling cascade in the creation and sustenance of a tumor favorable microenvironment. Neutralization of the IL-1α signaling efficiently diminished the cross talk-induced production of inflammatory factors. These data suggest that the cross talk between PDAC cells and the main stroma cell type, i.e. CAFs, is one essential factor in the formation of the inflammatory tumor environment, and we propose that neutralization of the IL-1α signaling might be a potential therapy for this cancer.
胰腺导管腺癌 (PDAC) 的肿瘤微环境是动态的，基质细胞和肿瘤细胞之间存在广泛的相互作用。本研究旨在描绘 PDAC 与癌相关成纤维细胞 (CAF) 之间的串扰，重点研究产生慢性炎症肿瘤微环境的机制。我们评估了 PDAC 和 CAF 细胞系之间串扰对胰腺癌中炎症肿瘤微环境的形成和维持的影响。PDAC 和 CAF 细胞系的共培养增强了包括 IL-1α、IL-6、CXCL8、VEGF-A、CCL20 和 COX-2 在内的炎症因子的水平。CAF 在产生大多数炎症因子方面优于肿瘤细胞，并且肿瘤细胞相关的 IL-1α 被确定为通过与主要由 CAF 表达的 IL-1 受体 1 (IL-1R1) 结合而增强炎症因子产生的起始子。此外，我们发现 PDAC 组织中 IL-1α 和 CXCL8 表达水平之间存在相关性，以及 IL-1α 表达与患者临床结果之间存在相关性。这证实了 IL-1 信号级联在创建和维持有利于肿瘤的微环境方面的重要作用。IL-1α 信号的中和有效地减少了串扰诱导的炎症因子产生。这些数据表明，PDAC 细胞与主要基质细胞类型（即 CAF）之间的串扰是炎症肿瘤环境形成的一个重要因素，我们提出中和 IL-1α 信号可能是这种癌症的一种潜在治疗方法。
