靶向抑制骨髓源性肌成纤维细胞来源的TGF-β和STAT3信号抑制结直肠肿瘤生长的作用及其机制研究
| 作 者：程鑫, 何丽娜, 成小姣, 涂水平 |
| 单 位：上海交通大学医学院附属仁济医院 |
| 基金项目：上海市2022年度“科技创新行动计划”自然科学基金项目 |
| 摘 要： |
| 背景：骨髓源性肌成纤维细胞（BMFs）在结直肠癌发生、发展和肿瘤耐药中起重要作用，但目前尚缺乏特异性抑制BMFs的药物。目的：探索靶向抑制BMFs来源的转化生长因子-β（TGF-β）和信号转导及转录活化因子3（STAT3）信号对结直肠癌生长的影响。方法：将结肠癌细胞株MC38与BMFs共培养，体外观察BMFs对MC38细胞生长的影响。构建MC38细胞与BMFs混合细胞小鼠皮下移植瘤模型，研究BMFs对MC38细胞体内皮下移植瘤生长的影响。以转录组测序和免疫组化技术分析BMFs来源的TGF-β、STAT3信号通路在结直肠癌生长中的作用。应用TGF-β和STAT3特异性抑制剂治疗BMF+MC38混合细胞皮下移植瘤，探索靶向BMFs来源的TGF-β和STAT3信号以抑制BMFs对结直肠癌促生长作用的疗效和安全性。结果：体外共培养实验显示BMFs能显著促进MC38细胞增殖和生长（P<0.01）。小鼠皮下移植瘤实验结果显示，BMFs能显著促进体内MC38细胞移植瘤生长（P<0.001）。免疫组化结果证实，BMF+MC38混合细胞移植瘤中的TGF-β1和p-STAT3表达显著高于MC38细胞移植瘤（P均<0.01）；转录组测序进一步显示，混合移植瘤中组织发育、细胞外基质组成以及趋化因子/白细胞介素（IL）-17信号通路相关基因表达发生显著改变，提示BMFs来源的TGF-β和STAT3可促进结直肠癌生长。联合TGF-β和STAT3信号特异性小分子抑制剂治疗BMF+MC38混合移植瘤，可显著抑制混合细胞皮下移植瘤生长（P<0.000 1），未见明显毒性反应。结论：BMFs能显著促进MC38细胞的体内外生长，靶向抑制TGF-β和STAT3信号能显著抑制BMFs介导的促结直肠癌生长作用。 |
| 关键词：结直肠肿瘤；骨髓源性肌成纤维细胞；转化生长因子β；信号转导及转录活化因子3 |
Role and Mechanism of Targeted Inhibition of TGF-β and STAT3 Signaling Derived From Bone Marrow-derived Myofibroblasts in Suppressing Colorectal Tumor Growth
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| Abstract: |
| Background: Bone marrow-derived myofibroblasts (BMFs) play a significant role in colorectal tumorigenesis, progression, and drug resistance. However, specific drugs to inhibit BMFs are currently lacking. Aims: To investigate the impact of targeted inhibition of transforming growth factor-β (TGF-β) and signal transducer and activator of transcription 3 (STAT3) signaling derived from BMFs on colorectal cancer growth. Methods: The effect of BMFs on the growth of colon cancer cell line MC38 was observed in vitro using a co-culture system of MC38 cells and BMFs. A mouse subcutaneous xenograft model with mixed MC38 cells and BMFs was established to study the effect of BMFs on in vivo subcutaneous xenografts growth of MC38 cells. Transcriptome sequencing and immunohistochemistry were employed to analyze the role of signaling pathways such as TGF-β and STAT3 derived from BMFs in colorectal cancer growth. Specific inhibitors of TGF-β and STAT3 were used to treat subcutaneous xenografts formed from BMF+MC38 mixed cells, to explore the efficacy and safety of targeting BMF-derived TGF-β and STAT3 signaling in inhibiting the tumor-promoting effect of BMFs on colorectal cancer. Results: In vitro co-culture experiments showed that BMFs significantly promoted the proliferation and growth of MC38 cells (P<0.01). Mouse subcutaneous xenograft experiments indicated that BMFs significantly promoted the growth of MC38 cell xenografts in vivo (P<0.001). Immunohistochemical results confirmed that the levels of TGF-β1 and p-STAT3 were significantly higher in BMF+MC38 mixed cell xenografts compared to MC38 cell xenografts (all P<0.01); transcriptome sequencing further revealed significant alterations in the expression of genes associated with tissue development, extracellular matrix composition, as well as chemokine and interleukin (IL)-17 signaling pathways in the mixed xenografts, suggesting that BMF-derived TGF-β and STAT3 promoted colorectal cancer growth. Treatment of BMF+MC38 mixed subcutaneous xenografts with specific small molecule inhibitors of TGF-β and STAT3 signaling significantly inhibited the growth of the mixed-cell subcutaneous xenografts (P<0.000 1) with no apparent toxic reactions observed. Conclusions: BMFs significantly enhance the growth of MC38 cells both in vitro and in vivo. Targeted inhibition of TGF-β and STAT3 signaling significantly suppresses the BMF-mediated promoting effect of colorectal cancer growth. |
| Keywords: Colorectal Neoplasms; Bone Marrow-Derived Myofibroblasts; Transforming Growth Factor-beta; Signal Transducer and Activator of Transcription 3 |
| 投稿时间：2026-02-09 |
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