Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York.
Gastrointestinal Epithelium Modeling Program, Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Mol Cancer Res. 2023 Jul 5;21(7):741-752. doi: 10.1158/1541-7786.MCR-22-0872.
Cancer-associated fibroblasts (CAF) can promote tumor growth, metastasis, and therapeutic resistance in esophageal squamous cell carcinoma (ESCC), but the mechanisms of action remain elusive. Our objective was to identify secreted factor(s) that mediate the communication between CAFs and ESCC tumor cells with the aim of identifying potential druggable targets. Through unbiased cytokine arrays, we have identified CC motif chemokine ligand 5 (CCL5) as a secreted factor that is increased upon co-culture of ESCC cells and CAFs, which we replicated in esophageal adenocarcinoma (EAC) with CAFs. Loss of tumor-cell-derived CCL5 reduces ESCC cell proliferation in vitro and in vivo and we propose this is mediated, in part, by a reduction in ERK1/2 signaling. Loss of tumor-derived CCL5 reduces the percentage of CAFs recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists, namely Maraviroc. Maraviroc treatment reduced tumor volume, CAF recruitment, and ERK1/2 signaling in vivo, thus, mimicking the effects observed with genetic loss of CCL5. High CCL5 or CCR5 expression is associated with worse prognosis in low-grade esophageal carcinomas.
These data highlight the role of CCL5 in tumorigenesis and the therapeutic potential of targeting the CCL5-CCR5 axis in ESCC.
成纤维细胞（CAF）可以促进食管鳞状细胞癌（ESCC）的肿瘤生长、转移和治疗耐药，但作用机制仍不清楚。我们的目的是鉴定介导 CAF 和 ESCC 肿瘤细胞之间通讯的分泌因子，以期确定潜在的可药物治疗靶点。通过无偏性细胞因子阵列，我们已经鉴定出趋化因子配体 5（CCL5）是一种分泌因子，当 ESCC 细胞与 CAF 共培养时，其表达增加，我们在食管腺癌（EAC）中用 CAF 复制了这一现象。肿瘤细胞衍生的 CCL5 的缺失减少了 ESCC 细胞在体外和体内的增殖，我们提出这部分是通过减少 ERK1/2 信号传导介导的。肿瘤衍生的 CCL5 的缺失减少了体内异种移植肿瘤中招募的 CAF 的百分比。CCL5 是 CC 基序受体 5（CCR5）的配体，针对该受体存在一种临床批准的抑制剂，即马拉维若。马拉维若治疗减少了体内肿瘤体积、CAF 募集和 ERK1/2 信号传导，从而模拟了 CCL5 基因缺失观察到的效果。CCL5 或 CCR5 的高表达与低级别食管癌的预后较差相关。
这些数据强调了 CCL5 在肿瘤发生中的作用，以及靶向 ESCC 中 CCL5-CCR5 轴的治疗潜力。
