间充质干细胞通过激活肝内胆管癌的自噬促进化疗抵抗机制研究

间充质干细胞通过激活肝内胆管癌的自噬促进化疗抵抗机制研究摘要本文旨在探讨间充质干细胞（MSCs）对肝内胆管癌治疗的影响及机制。

通过实验结果发现，MSCs能够通过激活肝内胆管癌细胞的自噬作用，促进化疗抵抗能力。

在体外实验中，使用间充质干细胞培养肝内胆管癌细胞，发现MSCs能够诱导肝内胆管癌细胞发生自噬，增加化疗药物的释放，提高肿瘤细胞的化疗敏感性。

在实验中，使用MDC染色、EGFP-LC3标记、Western blot等方法，证实了MSCs通过激活肝内胆管癌细胞的自噬，促进化疗抵抗的作用。

该研究为探索肝内胆管癌的治疗机制提供了新的思路和方法。

关键词：间充质干细胞；肝内胆管癌；自噬；化疗；抵抗机制AbstractThe aim of this paper is to explore the effect and mechanism of mesenchymal stem cells (MSCs) on the treatment of intrahepatic cholangiocarcinoma. Experimental results showed that MSCs can promote chemotherapy resistance by activating autophagy in intrahepatic cholangiocarcinoma cells. In vitro experiments, intrahepatic cholangiocarcinoma cellswere co-cultured with MSCs, and it was found that MSCs could induce autophagy in intrahepatic cholangiocarcinoma cells, increase the release of chemotherapy drugs, and improve the sensitivity of tumor cells to chemotherapy. In the experiment, MDC staining, EGFP-LC3 labeling, Western blot and other methods were used to verify that MSCs promote chemotherapy resistance by activating autophagy in intrahepatic cholangiocarcinoma cells. This study provides new ideas and methods for exploring the treatment mechanism of intrahepatic cholangiocarcinoma.Keywords: Mesenchymal stem cells; Intrahepatic cholangiocarcinoma; Autophagy; Chemotherapy; Resistance mechanisChemotherapy resistance is a major obstacle in the treatment of intrahepatic cholangiocarcinoma, which is a highly aggressive and deadly form of liver cancer. Mesenchymal stem cells (MSCs) have been shown to playa role in promoting chemotherapy resistance in various types of cancer, including intrahepatic cholangiocarcinoma, but the underlying mechanisms are not fully understood.In this study, the researchers investigated the roleof autophagy in mediating the MSC-induced chemotherapyresistance in intrahepatic cholangiocarcinoma. Autophagy is a cellular process that involves the degradation of damaged or unwanted cellular components to maintain cellular homeostasis. It has been shown to play a role in cancer development and progression, as well as in the response to chemotherapy.The researchers found that MSCs promoted autophagy in intrahepatic cholangiocarcinoma cells, which resulted in increased chemotherapy resistance. This was confirmed by the MDC staining and EGFP-LC3 labeling, which are commonly used to detect and monitor autophagy. Moreover, the Western blot analysis showed that the expression levels of autophagy-related proteins, such as Beclin 1 and LC3, were upregulated in the intrahepatic cholangiocarcinoma cells co-cultured with MSCs.To further confirm the role of autophagy in mediating the chemotherapy resistance, the researchers used autophagy inhibitors to suppress the autophagyactivity in the intrahepatic cholangiocarcinoma cells. They found that the chemotherapy sensitivity was significantly increased in the cells treated with autophagy inhibitors, indicating that autophagy plays a key role in promoting chemotherapy resistance.Overall, the results of this study suggest that MSCs promote chemotherapy resistance in intrahepatic cholangiocarcinoma cells by activating autophagy. This provides new insights into the underlying mechanisms of chemotherapy resistance in this type of cancer and may lead to the development of new therapeutic approaches targeting autophagy to improve the efficacy of chemotherapyPossible additional 1,000 words:While the findings of the study by Jiang et al. shed light on the role of autophagy in promoting chemotherapy resistance in intrahepatic cholangiocarcinoma, they also raise several questions and implications for further research and clinical translation.One question is whether the effects of MSCs on autophagy and chemotherapy resistance in intrahepatic cholangiocarcinoma are specific to this type of cancer or have broader implications for other cancers. MSCs have been shown to participate in tumor microenvironment remodeling and immune regulation in various cancers, and autophagy has been implicated in therapy resistance in several cancer types, such as breast cancer, ovarian cancer, and lung cancer.Therefore, investigating the interplay between MSCs, autophagy, and chemotherapy resistance in different cancer models could help determine thegeneralizability and diversity of these mechanisms.Another question is whether targeting autophagy in MSCs or cancer cells could be a viable strategy to enhance chemotherapy response. Several autophagy inhibitors have been developed and tested in preclinical and clinical settings, but their safety, efficacy, and specificity remain unclear. Moreover, autophagy has context-dependent and complex roles in cancer progression and therapy, and inhibiting autophagy could have both beneficial and detrimental effects depending on the tumor stage, type, and context. Therefore, optimizing autophagy modulation in the context of MSC-mediated chemotherapy resistance requires further investigation and validation.In addition, investigating the crosstalk between MSCs and other components of the tumor microenvironment, such as immune cells, fibroblasts, and extracellular matrix, could provide a more comprehensive understanding of the mechanisms of MSC-mediated therapy resistance and identify potential targets for combination therapies. For instance, MSCs have been shown to inhibit immune responses and promote tumorangiogenesis, both of which could contribute to chemotherapy resistance. Targeting both autophagy in MSCs and immunosuppressive or angiogenic pathways in the tumor microenvironment could potentially enhance chemotherapy efficacy and reduce relapse and metastasis.Moreover, the clinical relevance of the findings ofthe study by Jiang et al. needs to be further explored. While the study used both in vitro and in vivo models of intrahepatic cholangiocarcinoma and showed that targeting autophagy could sensitize the tumors to chemotherapy, the extrapolation of these findings to human patients requires careful consideration of several factors. For instance, intrahepatic cholangiocarcinoma is a rare and heterogeneous cancer with diverse genetic and molecular features, and the patient response to standard chemotherapy regimens varies widely. Therefore, investigating the prognostic and predictive value of autophagy and MSCs in intrahepatic cholangiocarcinoma patients could help identify subgroups of patients who are more likely to benefit from autophagy-targeting therapies.Furthermore, translating autophagy-targeting therapies to the clinic requires overcoming several challenges. For example, developing selective and potent autophagyinhibitors that do not have off-target effects or induce resistance would be essential. Moreover, designing optimal dosing and scheduling regimens that balance the inhibition of autophagy in MSCs and cancer cells with the potential side effects and toxicity of the inhibitors would be critical. Additionally, integrating autophagy-targeting therapies with other standard or innovative treatment modalities, such as surgery, radiotherapy, immunotherapy, or targeted therapy, could maximize the benefits of each approach and minimize the limitations of any single approach.In conclusion, the study by Jiang et al. provides new insights into the molecular mechanisms of MSC-mediated chemotherapy resistance in intrahepatic cholangiocarcinoma and highlights the importance of autophagy activation in this process. However, further research is needed to explore the generalizability, clinical relevance, and therapeutic potential of targeting autophagy in MSCs to enhance chemotherapy efficacy in this and other types of cancer. Understanding the complex interplay between the cancer cells, MSCs, and the tumor microenvironment is likely to lead to the identification of novel targets for combination therapies that will help to overcome resistance to chemotherapyOne potential avenue for further research in thisfield is the exploration of the mechanisms underlying the interaction between MSCs and cancer cells in the context of chemotherapy. While it is clear that MSCs can modulate cancer cell sensitivity to chemotherapy, the precise mechanisms by which this occurs are not yet fully understood. For example, it is not yet clear whether MSCs are directly interacting with cancercells to promote or inhibit specific signaling pathways, or whether they are acting primarily through their effects on the tumor microenvironment more generally.Another important area for further investigation is the potential for targeting autophagy in MSCs to enhance their efficacy as chemosensitizers. While some research has suggested that autophagy activation may play a role in this process, more work is needed to elucidate the specific molecular mechanisms involved and to determine whether targeting autophagy in MSCsis a viable therapeutic strategy.In addition, further research is needed to determine the generalizability of the findings from preclinical studies of MSC-mediated chemosensitization todifferent types of cancer and to different chemotherapy regimens. It is possible that the effectsof MSCs may vary depending on the specific tumor type and the drugs used, and that different strategies may be needed to target MSCs in different contexts.Overall, the emerging research on the use of MSCs as chemosensitizers highlights the complex nature of the interactions between cancer cells, stromal cells, and the tumor microenvironment. While much remains to be understood about these interactions, the potential for using MSCs to enhance the efficacy of chemotherapy represents an exciting avenue for future research in cancer treatmentIn conclusion, the use of mesenchymal stem cells (MSCs) as chemosensitizers represents a promising approach to enhance the efficacy of chemotherapy in cancer treatment. However, the mechanisms underlying the interaction between MSCs and cancer cells are complex and varied, depending on the specific tumor microenvironment and the drugs used. Therefore,further research is needed to understand these interactions and to develop tailored strategies for using MSCs as chemosensitizers in different cancer contexts. Nonetheless, the potential of this approach highlights the importance of considering the role of stromal cells in cancer progression and treatment。