Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of University of Science and Technology of China, Hefei, People's Republic of China.
Cell Commun Signal. 2024 Mar 8;22(1):170. doi: 10.1186/s12964-024-01550-9.
Heterogeneous cancer-associated fibroblasts (CAFs) play important roles in cancer progression. However, the specific biological functions and regulatory mechanisms involved in endometrial cancer have yet to be elucidated. We aimed to explore the potential mechanisms of heterogeneous CAFs in promoting endometrial cancer progression. The presence of melanoma cell adhesion molecule (MCAM; CD146) positive CAFs was confirmed by tissue multi-immunofluorescence (mIF), and fluorescence activated cell sorting (FACS). The biological functions were determined by wound healing assays, tuber formation assays and cord formation assays. The effects of CD146CAFs on endometrial cancer cells were studied in vitro and in vivo. The expression level of interleukin 10 (IL-10) was measured by quantitative real time polymerase chain reaction (qRT-PCR), western boltting and enzyme linked immunosorbent assays (ELISAs). In addition, the transcription factor STAT3 was identified by bioinformatics methods and chromatin immunoprecipitation (ChIP). A subtype of CAFs marked with CD146 was found in endometrial cancer and correlated with poor prognosis. CD146CAFs promoted angiogenesis and vasculogenic mimicry (VM) in vitro. A xenograft tumour model also showed that CD146CAFs can facilitate tumour progression. The expression of IL-10 was elevated in CD146CAFs. IL-10 promoted epithelial-endothelial transformation (EET) and further VM formation in endometrial cancer cells via the janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) signalling pathway. This process could be blocked by the JAK1/STAT3 inhibitor niclosamide. Mechanically, STAT3 can bind to the promoter of cadherin5 (CDH5) to promote its transcription which may be stimulated by IL-10. We concluded that CD146CAFs could promote angiogenesis and VM formation via the IL-10/JAK1/STAT3 signalling pathway. These findings may lead to the identification of potential targets for antiangiogenic therapeutic strategies for endometrial cancers.
异质性癌症相关成纤维细胞（CAFs）在癌症进展中发挥重要作用。然而，子宫内膜癌中涉及的具体生物学功能和调控机制尚不清楚。我们旨在探讨促进子宫内膜癌进展的异质性 CAFs 的潜在机制。通过组织多免疫荧光（mIF）和荧光激活细胞分选（FACS）证实了黑色素瘤细胞黏附分子（MCAM；CD146）阳性 CAFs 的存在。通过划痕愈合实验、结节形成实验和索状形成实验确定了 CAFs 的生物学功能。在体外和体内研究了 CD146CAFs 对子宫内膜癌细胞的影响。通过定量实时聚合酶链反应（qRT-PCR）、western blot 和酶联免疫吸附测定（ELISA）测量白细胞介素 10（IL-10）的表达水平。此外，通过生物信息学方法和染色质免疫沉淀（ChIP）鉴定了转录因子 STAT3。在子宫内膜癌中发现了一种标记有 CD146 的 CAF 亚群，与预后不良相关。CD146CAFs 促进了体外血管生成和血管生成拟态（VM）。异种移植肿瘤模型也表明 CD146CAFs 可促进肿瘤进展。CD146CAFs 中的 IL-10 表达升高。IL-10 通过 Janus 激酶 1/信号转导和转录激活因子 3（JAK1/STAT3）信号通路促进子宫内膜癌细胞的上皮-内皮转化（EET）和进一步的 VM 形成。该过程可被 JAK1/STAT3 抑制剂尼洛替尼阻断。机制上，STAT3 可以与钙粘蛋白 5（CDH5）的启动子结合，促进其转录，而 IL-10 可能会刺激这种转录。我们得出结论，CD146CAFs 可以通过 IL-10/JAK1/STAT3 信号通路促进血管生成和 VM 形成。这些发现可能为子宫内膜癌的抗血管生成治疗策略确定潜在靶点。
