Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Proc Natl Acad Sci U S A. 2019 Feb 5;116(6):2237-2242. doi: 10.1073/pnas.1820459116. Epub 2019 Jan 22.
Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6-producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.
食管腺癌 (EAC) 的预后较差，最近采用的多种治疗方法的生存获益仍然较小。已知癌症相关成纤维细胞 (CAF) 通过赋予各种癌症类型的治疗耐药性而导致不良预后，但这在 EAC 中尚未得到探索。重要的是，规避 CAF 诱导的耐药性的靶向策略尚未确定。通过使用 EAC 患者来源的 CAF、类器官培养物和异种移植模型，我们确定了 IL-6 是 EAC 中治疗耐药性的基质驱动因素。IL-6 在癌细胞中激活上皮间质转化，伴随着增强的治疗耐药性、迁移能力和克隆形成能力。IL-6 的抑制作用恢复了患者来源的类器官培养物和细胞系中的药物敏感性。对患者基因表达谱的分析确定了 ADAM12 是一种与炎症无关的血清源性标记物，用于产生 IL-6 的 CAF，并且该标记物的血清水平预测了 EAC 患者对新辅助放化疗的不利反应。这些结果表明 CAF 对 EAC 治疗耐药性有一定的贡献。这种信号可以被靶向以重新使 EAC 对治疗敏感，并且可以使用血清标志物来测量其活性。
