Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
Institute of Clinical Molecular Biology, UKSH Campus Kiel, 24105 Kiel, Germany.
Int J Mol Sci. 2018 Jun 4;19(6):1661. doi: 10.3390/ijms19061661.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance.
胰腺导管腺癌 (PDAC) 是最致命的恶性肿瘤之一，在西方国家的死亡率不断上升。由于其在晚期才被发现，具有极强的侵袭性，以及目前可用疗法的效果有限，PDAC 是临床领域的一个挑战。PDAC 的一个特征是明显的纤维组织增生，由成纤维细胞、内皮细胞和免疫细胞以及非细胞成分组成，导致对治疗的耐药性。已经证实 NF-κB 信号通路控制着 PDAC 中的炎症、癌症进展和细胞凋亡抵抗。本研究试图鉴定 NF-κB 靶基因，这些基因介导人类 PDAC 细胞系对死亡配体诱导的细胞凋亡的治疗耐药性。通过使用全基因组无偏方法，鉴定趋化因子 CX3CL1 作为介导治疗耐药性的中央 NF-κB 靶基因。虽然在共培养实验中没有发现 CX3CL1 表达对癌细胞凋亡有直接影响，但显然 CX3CL1 以旁分泌的方式起作用，导致炎症细胞的募集增加。这些炎症细胞反过来介导 PDAC 细胞的凋亡抵抗。因此，我们的数据揭示了 PDAC 中肿瘤细胞和免疫细胞之间的一种双功能交叉信号通路，导致治疗耐药性的产生。
