Zhao Di, Zhang Jing, Zhang Lingyuan, Wu Qingnan, Wang Yan, Zhang Weimin, Xiao Yuanfan, Chen Jie, Zhan Qimin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.
Research Unit of Molecular Cancer Research, Chinese Academy of Medical Sciences, Beijing 100021, China.
Acta Pharm Sin B. 2023 Feb;13(2):694-708. doi: 10.1016/j.apsb.2022.08.014. Epub 2022 Aug 24.
Stroma surrounding the tumor cells plays crucial roles for tumor progression. However, little is known about the factors that maintain the symbiosis between stroma and tumor cells. In this study, we found that the transcriptional regulator-signal transducer and activator of transcription 3 (Stat3) was frequently activated in cancer-associated fibroblasts (CAFs), which was a potent facilitator of tumor malignancy, and formed forward feedback loop with platelet-activating factor receptor (PAFR) both in CAFs and tumor cells. Importantly, PAFR/Stat3 axis connected intercellular signaling crosstalk between CAFs and cancer cells and drove mutual transcriptional programming of these two types of cells. Two central Stat3-related cytokine signaling molecules-interleukin 6 (IL-6) and IL-11 played the critical role in the process of PAFR/Stat3 axis-mediated communication between tumor and CAFs. Pharmacological inhibition of PAFR and Stat3 activities effectively reduced tumor progression using CAFs/tumor co-culture xenograft model. Our study reveals that PAFR/Stat3 axis enhances the interaction between tumor and its associated stroma and suggests that targeting this axis can be an effective therapeutic strategy against tumor malignancy.
肿瘤细胞周围的间质对肿瘤进展起着关键作用。然而，对于维持间质与肿瘤细胞共生关系的因素却知之甚少。在本研究中，我们发现转录调节因子——信号转导和转录激活因子3（Stat3）在癌症相关成纤维细胞（CAFs）中频繁激活，它是肿瘤恶性程度的有力促进因子，并且在CAFs和肿瘤细胞中均与血小板活化因子受体（PAFR）形成正向反馈环。重要的是，PAFR/Stat3轴连接了CAFs与癌细胞之间的细胞间信号串扰，并驱动这两种细胞的相互转录编程。两个与Stat3相关的核心细胞因子信号分子——白细胞介素6（IL-6）和IL-11在PAFR/Stat3轴介导的肿瘤与CAFs之间的通讯过程中起关键作用。使用CAFs/肿瘤共培养异种移植模型，对PAFR和Stat3活性进行药理学抑制可有效降低肿瘤进展。我们的研究表明，PAFR/Stat3轴增强了肿瘤与其相关间质之间的相互作用，并提示靶向该轴可能是对抗肿瘤恶性程度的有效治疗策略。
