巨噬细胞在肝癌发生、发展中的作用机制及其靶向治疗研究进展

摘要/Abstract

摘要： 动物及临床的研究结果提示,巨噬细胞是肝癌肿瘤组织含量最多的免疫细胞,其功能表型与肿瘤微环境密切相关。在肝癌微环境中,巨噬细胞经趋化聚集和表型转化发挥建立免疫耐受、促进肝癌血管形成及恶性转归、增加肝癌化疗耐药性的作用。抑制单核细胞的募集,清除已有的TAMs,诱导TAMs再分化等与巨噬细胞相关的肿瘤免疫治疗具有可行性。总之,巨噬细胞在肝癌的发生、发展中发挥重要的免疫调节作用,靶向巨噬细胞的免疫治疗为肝癌治疗提供潜在抗癌方法。

关键词: 肝癌, 巨噬细胞, 作用机制, 靶向治疗

黄鑫昱, 苏盛元, 王开琛, 王甘露. 巨噬细胞在肝癌发生、发展中的作用机制及其靶向治疗研究进展[J]. 肝脏, 2022, 27(6): 708-711.

参考文献

[1] El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology, 2007,132(7):2557-2576.
[2] 肖向苑. 探讨乙肝患者不同的病毒感染模式与原发性肝癌之间的关系. 特别健康, 2020, (26) : 68-69.
[3] Sanchez LR, Borriello L, Entenberg D, et al. The emerging roles of macrophages in cancer metastasis and response to chemotherapy. J Leukoc Biol, 2019, 106(2):259-274.
[4] 王咪咪, 王艳红. 胚胎来源巨噬细胞的起源及其在肝脏中功能的研究进展. 中国临床医学, 2018,25(1) : 123-128.
[5] Elchaninov AV, Fatkhudinov TK, Vishnyakova PA, et al. Phenotypical and Functional Polymorphism of Liver Resident Macrophages. Cells, 2019, 8(9): 1032.
[6] Tian Z, Hou X, Liu W, et al. Macrophages and hepatocellular carcinoma. Cell Biosci, 2019, 9:79.
[7] 兰达治, 张磊, 韦尚谋, 等. M2型肿瘤相关巨噬细胞对肝癌细胞侵袭转移和上皮间质转化的影响. 医学检验与临床, 2020, 31(7): 1-6.
[8] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell, 2010, 141(1):39-51.
[9] Li X, Yao W, Yuan Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut, 2017, 66(1):157-167.
[10] Zhu XD, Zhang JB, Zhuang PY, et al. High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol, 2008, 26(16):2707-2716.
[11] Kuang DM, Zhao Q, Peng C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med, 2009, 206(6):1327-1337.
[12] 李跃, 王长利. 巨噬细胞与PD-1/PD-L1轴在肿瘤进展和治疗中的作用. 癌症, 2020, 39(10) : 437-444.
[13] Wu Q, Zhou W, Yin S, et al. Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer. Hepatology, 2019, 70(1):198-214.
[14] Li H, Wu K, Tao K, et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology, 2012, 56(4):1342-1351.
[15] 陈景森, 欧希, 赵洋, 等. LAP+CD4+T细胞在肝癌微环境中的分布特点及意义. 岭南现代临床外科, 2019, 19(5): 528-532.
[16] 姚本来, 李晓明, 李芳飘, 等. Treg和IL-10在肝癌组织的表达及评估预后的价值. 肝脏, 2019, 24(8): 921-922.
[17] Zhou J, Ding T, Pan W, et al. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer, 2009, 125(7):1640-1648.
[18] 韩晨阳, 杨毅, 王瑾, 等. M2型巨噬细胞促进肝癌肿瘤血管生成的作用. 中华微生物学和免疫学杂志, 2020, 40(4) : 283-289.
[19] Bartneck M, Schrammen PL, Möckel D, et al. The CCR2+ Macrophage Subset Promotes Pathogenic Angiogenesis for Tumor Vascularization in Fibrotic Livers. Cell Mol Gastroenterol Hepatol, 2019, 7(2):371-390.
[20] Zang M, Li Y, He H, et al. IL-23 production of liver inflammatory macrophages to damaged hepatocytes promotes hepatocellular carcinoma development after chronic hepatitis B virus infection. Biochim Biophys Acta Mol Basis Dis, 2018, 1864(12):3759-3770.
[21] Liang S, Ma HY, Zhong Z, et al. NADPH Oxidase 1 in Liver Macrophages Promotes Inflammation and Tumor Development in Mice. Gastroenterology, 2019, 156(4):1156-1172.e6.
[22] Fu XT, Dai Z, Song K, et al. Macrophage-secreted IL-8 induces epithelial-mesenchymal transition in hepatocellular carcinoma cells by activating the JAK2/STAT3/Snail pathway. Int J Oncol, 2015, 46(2):587-596.
[23] Yan L, Xu F, Dai CL, Relationship between epithelial-to-mesenchymal transition and the inflammatory microenvironment of hepatocellular carcinoma. J Exp Clin Cancer Res, 2018, 37(1):203.
[24] Capece D, Fischietti M, Verzella D, et al. The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages. Biomed Res Int, 2013, 2013:187204.
[25] Jiang J, Wang GZ, Wang Y, et al. Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res, 2018, 367(1):81-88.
[26] Zhang W, Zhu XD, Sun HC, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res, 2010, 16(13):3420-3430.
[27] Dong N, Shi X, Wang S, et al. M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br J Cancer, 2019, 121(1):22-33.
[28] Fu XT, Song K, Zhou J, et al. Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma. Cancer Cell Int, 2019, 19:71.
[29] Iwamoto H, Izumi K, Mizokami A. Is the C-C Motif Ligand 2-C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis?. Int J Mol Sci, 2020, 21(23) : 9328.
[30] Li X, Yao W, Yuan Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut, 2017, 66(1):157-167.
[31] Yao W, Ba Q, Li X, et al. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine, 2017, 22:58-67.
[32] Teng KY, Han J, Zhang X, et al. Blocking the CCL2-CCR2 Axis Using CCL2-Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model. Mol Cancer Ther, 2017, 16(2):312-322.
[33] Zhou DY, Qin J, Huang J, et al. Zoledronic acid inhibits infiltration of tumor-associated macrophages and angiogenesis following transcatheter arterial chemoembolization in rat hepatocellular carcinoma models. Oncol Lett, 2017, 14(4):4078-4084.
[34] Sprinzl MF, Puschnik A, Schlitter MA, et al. Sorafenib inhibits macrophage-induced growth of hepatoma cells by interference with insulin-like growth factor-1 secretion. J Hepatol, 2015, 62(4):863-870.
[35] Tan HY, Wang N, Man K, et al. Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. Cell Death Dis, 2015, 6(10):e1942.