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黄酮类化合物通过调节肿瘤微环境抑制胶质母细胞瘤相关研究进展
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Abstract:
胶质母细胞瘤(Glioblastoma, GBM)是脑部原发性恶性肿瘤中最常见、也是恶性程度最高的类型之一。GBM患者的预后极差,即使在标准治疗下,中位生存时间也往往不足18个月。因此,长期以来GBM一直是中枢神经系统肿瘤领域研究的热点。免疫抑制是GBM发生发展的关键环节之一,肿瘤微环境(Tumor Microenvironment, TME)异常在其中发挥了重要的作用。通过逆转TME中异常表达的细胞因子和生长受体等,可以抑制GBM的增殖和侵袭能力,并降低其恶性程度。近年来,黄酮类化合物对GBM细胞的抑制作用及其分子机制得到了深入研究,其中黄酮类化合物通过改变GBM细胞的TME发挥重要作用。研究表明,黄酮类化合物可以在遗传物质水平上降低异常细胞因子及生长受体的表达改变TME,转化免疫抑制环境,并将肿瘤相关巨噬细胞(Tumor-Associated Macrophages, TAMs)转化为具有肿瘤抑制功能的正常巨噬细胞。本文旨在探讨黄酮类化合物通过调控TME对GBM的抑制作用,为GBM的研究提供新的思路。
Glioblastoma (GBM) is one of the most common and highly malignant types of primary brain tumors. Patients with glioblastoma have a very poor prognosis, with a median survival time often less than 18 months even with standard treatment. Therefore, glioblastoma has long been a research focus in the field of central nervous system tumors. Immunosuppression is one of the key aspects in the development and progression of glioblastoma, with abnormalities in the tumor microenvironment playing a significant role. By reversing the abnormal expression of cytokines and growth receptors within the tumor microenvironment (TME), the proliferation and invasive capabilities of glioblastoma can be suppressed, reducing its malignancy. In recent years, the inhibitory effects and molecular mechanisms of flavonoids on glioblastoma cells have been extensively researched. Flavonoids play a significant role in modifying the TME of glioblastoma cells. Studies have demonstrated that flavonoids can reduce the expression of abnormal cytokines and growth receptors at the genetic level, altering the TME, transforming the immunosuppressive environment, and transforming tumor-associated macrophages (TAMs) into normal macrophages with tumor-suppressing capabilities. This article aims to explore the inhibitory effects of flavonoids on glioblastoma through the modulation of the TME, offering new perspectives for glioblastoma research.
[1] | Gimple, R.C., Bhargava, S., Dixit, D. and Rich, J.N. (2019) Glioblastoma Stem Cells: Lessons from the Tumor Hierarchy in a Lethal Cancer. Genes & Development, 33, 591-609. https://doi.org/10.1101/gad.324301.119 |
[2] | Ostrom, Q.T., Price, M., Neff, C., Cioffi, G., Waite, K.A., Kruchko, C., et al. (2023) CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2016-2020. Neuro-Oncology, 25, iv1-iv99. https://doi.org/10.1093/neuonc/noad149 |
[3] | Rautajoki, K.J., Jaatinen, S., Hartewig, A., Tiihonen, A.M., Annala, M., Salonen, I., et al. (2023) Genomic Characterization of IDH-Mutant Astrocytoma Progression to Grade 4 in the Treatment Setting. Acta Neuropathologica Communications, 11, Article No. 176. https://doi.org/10.1186/s40478-023-01669-9 |
[4] | Vaz-Salgado, M.A., Villamayor, M., Albarrán, V., Alía, V., Sotoca, P., Chamorro, J., et al. (2023) Recurrent Glioblastoma: A Review of the Treatment Options. Cancers, 15, Article 4279. https://doi.org/10.3390/cancers15174279 |
[5] | Iturrioz-Rodríguez, N., Sampron, N. and Matheu, A. (2023) Current Advances in Temozolomide Encapsulation for the Enhancement of Glioblastoma Treatment. Theranostics, 13, 2734-2756. https://doi.org/10.7150/thno.82005 |
[6] | Wen, P.Y. and Kesari, S. (2008) Malignant Gliomas in Adults. New England Journal of Medicine, 359, 492-507. https://doi.org/10.1056/nejmra0708126 |
[7] | Wolbers, J.G. (2014) Novel Strategies in Glioblastoma Surgery Aim at Safe, Supra-Maximum Resection in Conjunction with Local Therapies. Chinese Journal of Cancer, 33, 8-15. https://doi.org/10.5732/cjc.013.10219 |
[8] | Youngblood, M.W., Stupp, R. and Sonabend, A.M. (2021) Role of Resection in Glioblastoma Management. Neurosurgery Clinics of North America, 32, 9-22. https://doi.org/10.1016/j.nec.2020.08.002 |
[9] | Muir, M., Gopakumar, S., Traylor, J., Lee, S. and Rao, G. (2020) Glioblastoma Multiforme: Novel Therapeutic Targets. Expert Opinion on Therapeutic Targets, 24, 605-614. https://doi.org/10.1080/14728222.2020.1762568 |
[10] | Rice-Evans, C.A., Miller, N.J. and Paganga, G. (1996) Structure-Antioxidant Activity Relationships of Flavonoids and Phenolic Acids. Free Radical Biology and Medicine, 20, 933-956. https://doi.org/10.1016/0891-5849(95)02227-9 |
[11] | Sun, Q., Liu, Q., Zhou, X., Wang, X., Li, H., Zhang, W., et al. (2022) Flavonoids Regulate Tumor-Associated Macrophages—From Structure-Activity Relationship to Clinical Potential (Review). Pharmacological Research, 184, Article 106419. https://doi.org/10.1016/j.phrs.2022.106419 |
[12] | Ross, J.A. and Kasum, C.M. (2002) Dietary Flavonoids: Bioavailability, Metabolic Effects, and Safety. Annual Review of Nutrition, 22, 19-34. https://doi.org/10.1146/annurev.nutr.22.111401.144957 |
[13] | Yassin, N.Y.S., AbouZid, S.F., El-Kalaawy, A.M., Ali, T.M., Almehmadi, M.M. and Ahmed, O.M. (2022) Silybum marianum Total Extract, Silymarin and Silibinin Abate Hepatocarcinogenesis and Hepatocellular Carcinoma Growth via Modulation of the HGF/c-Met, Wnt/β-Catenin, and PI3K/Akt/mTOR Signaling Pathways. Biomedicine & Pharmacotherapy, 145, Article 112409. https://doi.org/10.1016/j.biopha.2021.112409 |
[14] | Kim, S., Choo, G., Yoo, E., Woo, J., Han, S., Lee, J., et al. (2019) Silymarin Induces Inhibition of Growth and Apoptosis through Modulation of the MAPK Signaling Pathway in AGS Human Gastric Cancer Cells. Oncology Reports, 42, 1904-1914. https://doi.org/10.3892/or.2019.7295 |
[15] | Yu, H., Chen, L., Cheng, K., Li, Y., Yeh, C. and Cheng, J. (2011) Silymarin Inhibits Cervical Cancer Cell through an Increase of Phosphatase and Tensin Homolog. Phytotherapy Research, 26, 709-715. https://doi.org/10.1002/ptr.3618 |
[16] | Chen, B., Li, X., Wu, L., Zhou, D., Song, Y., Zhang, L., et al. (2022) Quercetin Suppresses Human Glioblastoma Migration and Invasion via GSK3β/β-Catenin/Zeb1 Signaling Pathway. Frontiers in Pharmacology, 13, Article 963614. https://doi.org/10.3389/fphar.2022.963614 |
[17] | Zhai, K., Mazurakova, A., Koklesova, L., Kubatka, P. and Büsselberg, D. (2021) Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs. Biomolecules, 11, Article 1841. https://doi.org/10.3390/biom11121841 |
[18] | Ravi, V.M., Will, P., Kueckelhaus, J., Sun, N., Joseph, K., Salié, H., et al. (2022) Spatially Resolved Multi-Omics Deciphers Bidirectional Tumor-Host Interdependence in Glioblastoma. Cancer Cell, 40, 639-655.e13. https://doi.org/10.1016/j.ccell.2022.05.009 |
[19] | Wu, L., Wu, W., Zhang, J., Zhao, Z., Li, L., Zhu, M., et al. (2022) Natural Coevolution of Tumor and Immunoenvironment in Glioblastoma. Cancer Discovery, 12, 2820-2837. https://doi.org/10.1158/2159-8290.cd-22-0196 |
[20] | Bikfalvi, A., da Costa, C.A., Avril, T., Barnier, J., Bauchet, L., Brisson, L., et al. (2023) Challenges in Glioblastoma Research: Focus on the Tumor Microenvironment. Trends in Cancer, 9, 9-27. https://doi.org/10.1016/j.trecan.2022.09.005 |
[21] | Skog, J., Würdinger, T., van Rijn, S., Meijer, D.H., Gainche, L., Curry, W.T., et al. (2008) Glioblastoma Microvesicles Transport RNA and Proteins That Promote Tumour Growth and Provide Diagnostic Biomarkers. Nature Cell Biology, 10, 1470-1476. https://doi.org/10.1038/ncb1800 |
[22] | Parat, M.-O. and Riggins, G.J. (2012) Caveolin-1, Caveolae, and Glioblastoma. Neuro-Oncology, 14, 679-688. https://doi.org/10.1093/neuonc/nos079 |
[23] | Lambrechts, D., Wauters, E., Boeckx, B., Aibar, S., Nittner, D., Burton, O., et al. (2018) Phenotype Molding of Stromal Cells in the Lung Tumor Microenvironment. Nature Medicine, 24, 1277-1289. https://doi.org/10.1038/s41591-018-0096-5 |
[24] | Tao, W., Chu, C., Zhou, W., Huang, Z., Zhai, K., Fang, X., et al. (2020) Dual Role of WISP1 in Maintaining Glioma Stem Cells and Tumor-Supportive Macrophages in Glioblastoma. Nature Communications, 11, Article No. 3015. https://doi.org/10.1038/s41467-020-16827-z |
[25] | Zhai, K., Huang, Z., Huang, Q., Tao, W., Fang, X., Zhang, A., et al. (2021) Pharmacological Inhibition of BACE1 Suppresses Glioblastoma Growth by Stimulating Macrophage Phagocytosis of Tumor Cells. Nature Cancer, 2, 1136-1151. https://doi.org/10.1038/s43018-021-00267-9 |
[26] | Yang, F., He, Z., Duan, H., Zhang, D., Li, J., Yang, H., et al. (2021) Synergistic Immunotherapy of Glioblastoma by Dual Targeting of IL-6 and CD40. Nature Communications, 12, Article No. 3424. https://doi.org/10.1038/s41467-021-23832-3 |
[27] | Kenig, S., Alonso, M.B.D., Mueller, M.M. and Lah, T.T. (2010) Glioblastoma and Endothelial Cells Cross-Talk, Mediated by SDF-1, Enhances Tumour Invasion and Endothelial Proliferation by Increasing Expression of Cathepsins B, S, and MMP-9. Cancer Letters, 289, 53-61. https://doi.org/10.1016/j.canlet.2009.07.014 |
[28] | Joseph, J.V., Magaut, C.R., Storevik, S., Geraldo, L.H., Mathivet, T., Latif, M.A., et al. (2021) TGF-β Promotes Microtube Formation in Glioblastoma through Thrombospondin 1. Neuro-Oncology, 24, 541-553. https://doi.org/10.1093/neuonc/noab212 |
[29] | Pepper, M.S., Vassalli, J.-D., Orci, L. and Montesano, R. (1993) Biphasic Effect of Transforming Growth Factor-β1 on in Vitro Angiogenesis. Experimental Cell Research, 204, 356-363. https://doi.org/10.1006/excr.1993.1043 |
[30] | Seoane, J. and Gomis, R.R. (2017) TGF-β Family Signaling in Tumor Suppression and Cancer Progression. Cold Spring Harbor Perspectives in Biology, 9, a022277. https://doi.org/10.1101/cshperspect.a022277 |
[31] | Su, X., Yang, Y., Guo, C., Zhang, R., Sun, S., Wang, Y., et al. (2021) NOX4-Derived ROS Mediates TGF-β1-Induced Metabolic Reprogramming during Epithelial-Mesenchymal Transition through the PI3K/AKT/HIF-1α Pathway in Glioblastoma. Oxidative Medicine and Cellular Longevity, 2021, Article 5549047. https://doi.org/10.1155/2021/5549047 |
[32] | Seystahl, K., Papachristodoulou, A., Burghardt, I., Schneider, H., Hasenbach, K., Janicot, M., et al. (2017) Biological Role and Therapeutic Targeting of TGF-β3 in Glioblastoma. Molecular Cancer Therapeutics, 16, 1177-1186. https://doi.org/10.1158/1535-7163.mct-16-0465 |
[33] | Peleli, M., Moustakas, A. and Papapetropoulos, A. (2020) Endothelial-Tumor Cell Interaction in Brain and CNS Malignancies. International Journal of Molecular Sciences, 21, Article 7371. https://doi.org/10.3390/ijms21197371 |
[34] | Seystahl, K., Tritschler, I., Szabo, E., Tabatabai, G. and Weller, M. (2014) Differential Regulation of TGF-β-Induced, ALK-5-Mediated VEGF Release by SMAD2/3 versus SMAD1/5/8 Signaling in Glioblastoma. Neuro-Oncology, 17, 254-265. https://doi.org/10.1093/neuonc/nou218 |
[35] | Freitas, S., Costa, S., Azevedo, C., Carvalho, G., Freire, S., Barbosa, P., et al. (2010) Flavonoids Inhibit Angiogenic Cytokine Production by Human Glioma Cells. Phytotherapy Research, 25, 916-921. https://doi.org/10.1002/ptr.3338 |
[36] | Ouanouki, A., Lamy, S. and Annabi, B. (2016) Anthocyanidins Inhibit Epithelial-Mesenchymal Transition through a TGFβ/Smad2 Signaling Pathway in Glioblastoma Cells. Molecular Carcinogenesis, 56, 1088-1099. https://doi.org/10.1002/mc.22575 |
[37] | Gao, X., Xia, X., Li, F., Zhang, M., Zhou, H., Wu, X., et al. (2021) Circular RNA-Encoded Oncogenic E-Cadherin Variant Promotes Glioblastoma Tumorigenicity through Activation of EGFR-STAT3 Signalling. Nature Cell Biology, 23, 278-291. https://doi.org/10.1038/s41556-021-00639-4 |
[38] | Fang, R., Chen, X., Zhang, S., Shi, H., Ye, Y., Shi, H., et al. (2021) EGFR/SRC/ERK-Stabilized YTHDF2 Promotes Cholesterol Dysregulation and Invasive Growth of Glioblastoma. Nature Communications, 12, Article No. 177. https://doi.org/10.1038/s41467-020-20379-7 |
[39] | Weller, M., Butowski, N., Tran, D., Recht, L., Lim, M., Hirte, H., et al. (2016) ATIM-03. Act IV: An International, Double-Blind, Phase 3 Trial of Rindopepimut in Newly Diagnosed, EGFRvIII-Expressing Glioblastoma. Neuro-Oncology, 18, vi17-vi18. https://doi.org/10.1093/neuonc/now212.068 |
[40] | An, Z., Aksoy, O., Zheng, T., Fan, Q. and Weiss, W.A. (2018) Epidermal Growth Factor Receptor and Egfrviii in Glioblastoma: Signaling Pathways and Targeted Therapies. Oncogene, 37, 1561-1575. https://doi.org/10.1038/s41388-017-0045-7 |
[41] | Gao, M., Fu, Y., Zhou, W., Gui, G., Lal, B., Li, Y., et al. (2021) EGFR Activates a Taz-Driven Oncogenic Program in Glioblastoma. Cancer Research, 81, 3580-3592. https://doi.org/10.1158/0008-5472.can-20-2773 |
[42] | Thorburn, A. (2007) Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) Pathway Signaling. Journal of Thoracic Oncology, 2, 461-465. https://doi.org/10.1097/jto.0b013e31805fea64 |
[43] | Park, D., Ha, I.J., Park, S., Choi, M., Lim, S., Kim, S., et al. (2016) Morusin Induces TRAIL Sensitization by Regulating EGFR and DR5 in Human Glioblastoma Cells. Journal of Natural Products, 79, 317-323. https://doi.org/10.1021/acs.jnatprod.5b00919 |
[44] | Penar, P.L., Khoshyomn, S., Bhushan, A. and Tritton, T.R. (1997) Inhibition of Epidermal Growth Factor Receptor-Associated Tyrosine Kinase Blocks Glioblastoma Invasion of the Brain. Neurosurgery, 40, 141-151. https://doi.org/10.1227/00006123-199701000-00032 |
[45] | Gu, R., Zhang, X., Zhang, G., Tao, T., Yu, H., Liu, L., et al. (2017) Probing the Bi-Directional Interaction between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice. Neurochemical Research, 42, 1478-1487. https://doi.org/10.1007/s11064-017-2204-1 |
[46] | da Silva, A.B., Cerqueira Coelho, P.L., das Neves Oliveira, M., Oliveira, J.L., Oliveira Amparo, J.A., da Silva, K.C., et al. (2020) The Flavonoid Rutin and Its Aglycone Quercetin Modulate the Microglia Inflammatory Profile Improving Antiglioma Activity. Brain, Behavior, and Immunity, 85, 170-185. https://doi.org/10.1016/j.bbi.2019.05.003 |
[47] | Chen, L., Ackerman, R. and Guo, A.M. (2012) 20-HETE in neovascularization. Prostaglandins & Other Lipid Mediators, 98, 63-68. https://doi.org/10.1016/j.prostaglandins.2011.12.005 |
[48] | Wang, C., Li, Y., Chen, H., Zhang, J., Zhang, J., Qin, T., et al. (2017) Inhibition of CYP4A by a Novel Flavonoid FLA-16 Prolongs Survival and Normalizes Tumor Vasculature in Glioma. Cancer Letters, 402, 131-141. https://doi.org/10.1016/j.canlet.2017.05.030 |