Modulation of the tumor promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma. Modulation of the tumor promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

The chemotherapy resistance of esophageal adenocarcinomas (EAC) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that by targeting the tumor-promoting functions of the predominant TME cell type, cancer associated fibroblasts (CAF) with phosphodiesterase type 5 inhibitors (PDE5i) we can enhance the efficacy of standard-of-care chemotherapy. These findings demonstrate that CAF drive chemotherapy resistance in EAC and can be targeted by repurposing PDE5i, a safe and well tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction. Overall design: RNA sequencing was used to compare the transcriptomes of esophageal cancer specimens, and esophageal cancer specimen derived cells established and expanded on fibroblast feeder layer cells and subsequently grown in 3D-tumour growth assays with and without mesenchymal stem cells (as described in detailed in PMID:27736801).

食管腺癌（EAC）的化疗耐药由肿瘤微环境（TME）的癌细胞外在机制所介导。本研究证实，通过5型磷酸二酯酶抑制剂（PDE5i）靶向肿瘤微环境中占主导的细胞类型——癌相关成纤维细胞（CAF）的促肿瘤功能，可增强标准治疗化疗的疗效。上述研究结果表明，癌相关成纤维细胞可驱动食管腺癌的化疗耐药，且可通过重新利用5型磷酸二酯酶抑制剂进行靶向干预；该类药物安全性良好、耐受性佳，全球已有数百万患者使用其治疗勃起功能障碍。实验整体设计：本研究采用RNA测序技术，对比了食管癌标本、在成纤维细胞饲养层细胞上建立并扩增的食管癌来源细胞的转录组；随后将这些细胞置于添加或未添加间充质干细胞的三维肿瘤生长实验中培养（详细实验方法参见文献PMID:27736801）。