Radioresistance observed in patients with colorectal cancer (CRC) may be related to the presence of cancer stem cells (CSCs), but the underlying mechanism(s) remain unclear. Cancer-associated fibroblasts (CAFs) can regulate the stemness of cancer cells and tumor radiosensitivity. In addition, exosomes have been reported to modify treatment response by mediating cell-cell communication. In this study, we aimed to investigate whether exosomes derived from CAFs (CAF-exosomes) are involved in mediating resistance to radiotherapy in colorectal cancer and to explore the underlying mechanism. We found that CSCs were inherently resistant to cell death induced by radiotherapy. CAF-derived CM promoted clonogenicity and radioresistance of CRC cells. Further investigations revealed that exosomes isolated from CM induced the above effects whereas exosome-depleted CM (solution) was not able to induce clonogenicity and radioresistance. Finally, exosomes could activate transforming growth factor-β (TGF-β) signaling pathway and TGFβ1-neutralizing antibody inhibit this effect and decrease clonogenicity and expression levels of stemness genes. In conclusion,our findings suggest CAFs promote stemness of CRC cells and thus increase radiation resistance. Exosomes derived from CAFs play a crucial role through activating TGF-β signaling pathway in this process.

中文翻译：

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癌症相关成纤维细胞衍生的外泌体通过促进结直肠癌干细胞表型而有助于放射抗性。

在结直肠癌 (CRC) 患者中观察到的放射抗性可能与癌症干细胞 (CSC) 的存在有关，但其潜在机制仍不清楚。癌症相关成纤维细胞（CAF）可以调节癌细胞的干性和肿瘤放射敏感性。此外，据报道外泌体可以通过介导细胞间通讯来改变治疗反应。在本研究中，我们旨在研究源自CAF的外泌体（CAF-exosomes）是否参与介导结直肠癌的放疗耐药性并探讨其潜在机制。我们发现CSC本质上对放射治疗引起的细胞死亡具有抵抗力。CAF 衍生的 CM 促进 CRC 细胞的克隆形成和放射抗性。进一步的研究表明，从 CM 中分离的外泌体诱导了上述效应，而外泌体耗尽的 CM（溶液）无法诱导克隆形成和放射抗性。最后，外泌体可以激活转化生长因子-β (TGF-β) 信号通路，而 TGFβ1 中和抗体可抑制这种作用，并降低干性基因的克隆形成性和表达水平。总之，我们的研究结果表明 CAF 可以促进 CRC 细胞的干性，从而提高抗辐射能力。CAF 衍生的外泌体通过激活 TGF-β 信号通路在此过程中发挥着至关重要的作用。