| Citation: |
CAO Guangwen. Theoretical Update of Cancer Evo-Dev and Its Role in Targeted Immunotherapy for Hepatocellular Carcinoma[J]. Cancer Research on Prevention and Treatment, 2022, 49(8): 747-755. DOI: 10.3971/j.issn.1000-8578.2022.22.0377
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Primary liver cancer (PLC) is the first leading cause of immature cancer death in China. Hepatocellular carcinoma (HCC) in China accounts for 93.0% of PLC. Chronic infection with hepatitis B virus (HBV) HCC contributes to 84.4% of HCC. During HBV-induced hepatocarcinogenesis, non-resolving inflammation facilitates viral and host genome mutations via the up-regulated expression of activation-induced cytidine deaminase/APOBEC3s and decreases mutation repair via the down-regulated expression of uracil DNA glycosylase by proinflammatory cytokines such as interleukin-6. The proinflammatory tumor microenvironment (TME) provides necessary conditions for the "mutation-selection-adaptation" evolutionary process of HBV and human hepatocytes and facilitates the retrodifferentiation of mutated hepatic cells. This evolutionary process has two prerequisites: driving somatic mutations and immune-suppressive TME. Cancer-promoting chromosome instability and viral mutations inhibit type I interferon signaling via activating the cyclic GMP-AMP synthase stimulator of interferon genes, induce immune-suppressive inflammation, and recruit immune-suppressive immune cells, including tumor-associated macrophages, regulatory T cells, and myeloid-derived suppressor cells, to build immunosuppressive TME. In the TME, the rapid growth of tumor cell-caused hypoxia activates kynurenine metabolism in the HCC tissues by inducing the expression of immune-suppressive inflammatory factors to promote the expression of PD-1 on regulatory T cells for enhanced immunosuppression; it also inhibits the cytotoxicities of CD8+T and natural killer cells and facilitates angiogenesis. The theoretical update of "Cancer Evo-Dev" highlights the direction of cancer prophylaxis and treatment. The treatments targeting angiogenesis significantly inhibit the growth of HCC, increase anti-tumoral immunity, and enhance the efficacy of immunotherapy. The combination of targeted therapy and immunotherapy should be the major therapeutic option for the treatment of advanced liver cancer.
| [1] |
Jiang D, Zhang L, Liu W, et al. Trends in cancer mortality in China from 2004 to 2018: A nationwide longitudinal study[J]. Cancer Commun (Lond), 2021, 41(10): 1024-1036. doi: 10.1002/cac2.12195
|
| [2] |
Bray F, Laversanne M, Weiderpass E, et al. The ever-increasing importance of cancer as a leading cause of premature death worldwide[J]. Cancer, 2021, 127(16): 3029-3030. doi: 10.1002/cncr.33587
|
| [3] |
Lin J, Zhang H, Yu H, et al. Epidemiological Characteristics of Primary Liver Cancer in Mainland China From 2003 to 2020: A Representative Multicenter Study[J]. Front Oncol, 2022, 12: 906778. doi: 10.3389/fonc.2022.906778
|
| [4] |
陶常诚, 张凯, 荣维淇, 等. 肝细胞癌根治术后早期复发及其时间点的研究进展[J]. 肿瘤防治研究, 2022, 49(4): 359-363. doi: 10.3971/j.issn.1000-8578.2022.21.0828
Tao CC, Zhang K, Rong WQ, et al. Research Progress of Early Recurrence and Cut-off Time of Hepatocellular Carcinoma after Radical Hepatectomy[J]. Zhong Liu Fang Zhi Yan Jiu, 2022, 49(4): 359-363. doi: 10.3971/j.issn.1000-8578.2022.21.0828
|
| [5] |
Hu H, Qi S, Zeng S, et al. Importance of Microvascular Invasion Risk and Tumor Size on Recurrence and Survival of Hepatocellular Carcinoma After Anatomical Resection and Non-anatomical Resection[J]. Front Oncol, 2021, 11: 621622. doi: 10.3389/fonc.2021.621622
|
| [6] |
Yin J, Chen X, Li N, et al. Compartmentalized evolution of hepatitis B virus contributes differently to the prognosis of hepatocellular carcinoma[J]. Carcinogenesis, 2021, 42(3): 461-470. doi: 10.1093/carcin/bgaa127
|
| [7] |
Yin J, Li N, Han Y, et al. Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study[J]. J Clin Oncol, 2013, 31(29): 3647-3655. doi: 10.1200/JCO.2012.48.5896
|
| [8] |
Wang S, Shi H, Liu T, et al. Mutation profile and its correlation with clinicopathology in Chinese hepatocellular carcinoma patients[J]. Hepatobiliary Surg Nutr, 2021, 10(2): 172-179. doi: 10.21037/hbsn.2019.09.17
|
| [9] |
Chaudhary K, Poirion OB, Lu L, et al. Multimodal Meta-Analysis of 1, 494 Hepatocellular Carcinoma Samples Reveals Significant Impact of Consensus Driver Genes on Phenotypes[J]. Clin Cancer Res, 2019, 25(2): 463-472. doi: 10.1158/1078-0432.CCR-18-0088
|
| [10] |
Zhang S, Zhou YF, Cao J, et al. mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma[J]. Cancer Res, 2021, 81(22): 5652-5665. doi: 10.1158/0008-5472.CAN-21-0206
|
| [11] |
Péneau C, Imbeaud S, La Bella T, et al. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma[J]. Gut, 2022, 71(3): 616-626. doi: 10.1136/gutjnl-2020-323153
|
| [12] |
An J, Kim D, Oh B, et al. Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas[J]. Hepatology, 2022, 75(4): 997-1011. doi: 10.1002/hep.32135
|
| [13] |
孙秋月, 孙力超, 张稚淳, 等. 基于CiteSpace的肿瘤干细胞研究态势的文献计量学分析[J]. 肿瘤防治研究, 2021, 48(9): 839-845. doi: 10.3971/j.issn.1000-8578.2021.21.0416
Sun QY, Sun LC, Zhang ZC, et al. Trends in Research of Cancer Stem Cells: A Bibliometric Analysis Based on CiteSpace[J]. Zhong Liu Fang Zhi Yan Jiu, 2021, 48(9): 839-845. doi: 10.3971/j.issn.1000-8578.2021.21.0416
|
| [14] |
Sangro B, Sarobe P, Hervás-Stubbs S, et al. Advances in immunotherapy for hepatocellular carcinoma[J]. Nat Rev Gastroenterol Hepatol, 2021, 18(8): 525-543. doi: 10.1038/s41575-021-00438-0
|
| [15] |
Wu S, Turner KM, Nguyen N, et al. Circular ecDNA promotes accessible chromatin and high oncogene expression[J]. Nature, 2019, 575(7784): 699-703. doi: 10.1038/s41586-019-1763-5
|
| [16] |
Hsu CW, Chu YD, Lai MW, et al. Hepatitis B Virus Covalently Closed Circular DNA Predicts Postoperative Liver Cancer Metastasis Independent of Virological Suppression[J]. Cancers (Basel), 2021, 13(3): 538. doi: 10.3390/cancers13030538
|
| [17] |
Bakhoum SF, Cantley LC. The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment[J]. Cell, 2018, 174(6): 1347-1360. doi: 10.1016/j.cell.2018.08.027
|
| [18] |
Hanahan D. Hallmarks of Cancer: New Dimensions[J]. Cancer Discov, 2022, 12(1): 31-46. doi: 10.1158/2159-8290.CD-21-1059
|
| [19] |
Liu W, Deng Y, Li Z, et al. Cancer Evo-Dev: A Theory of Inflammation-Induced Oncogenesis[J]. Front Immunol, 2021, 12: 768098. doi: 10.3389/fimmu.2021.768098
|
| [20] |
Chen L, Zhang Q, Chang W, et al. Viral and host inflammation-related factors that can predict the prognosis of hepatocellular carcinoma[J]. Eur J Cancer, 2012, 48(13): 1977-1987. doi: 10.1016/j.ejca.2012.01.015
|
| [21] |
Zheng X, Wang P, Li L, et al. Cancer-Associated Fibroblasts Promote Vascular Invasion of Hepatocellular Carcinoma via Downregulating Decorin-integrin β1 Signaling[J]. Front Cell Dev Biol, 2021, 9: 678670. doi: 10.3389/fcell.2021.678670
|
| [22] |
Song M, He J, Pan QZ, et al. Cancer-Associated Fibroblast-Mediated Cellular Crosstalk Supports Hepatocellular Carcinoma Progression[J]. Hepatology, 2021, 73(5): 1717-1735. doi: 10.1002/hep.31792
|
| [23] |
Zhang Q, He Y, Luo N, et al. Landscape and Dynamics of Single Immune Cells in Hepatocellular Carcinoma[J]. Cell, 2019, 179: 829-845. doi: 10.1016/j.cell.2019.10.003
|
| [24] |
Lin CA, Chang LL, Zhu H, et al. Hypoxic microenvironment and hepatocellular carcinoma treatment[J]. Hepatoma Res, 2018, (6): 104-111.
|
| [25] |
Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments[J]. Cancer Cell, 2022, 40(2): 201-218. doi: 10.1016/j.ccell.2022.01.001
|
| [26] |
Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid[J]. Nature, 2021, 591: 645-651. doi: 10.1038/s41586-020-03045-2
|
| [27] |
Wu S, Xing X, Wang Y, et al. The pathological significance of LOXL2 in pre-metastatic niche formation of HCC and its related molecular mechanism[J]. Eur J Cancer, 2021, 147: 63-73. doi: 10.1016/j.ejca.2021.01.011
|
| [28] |
Krishnan MS, Rajan Kd A, Park J, et al. Genomic Analysis of Vascular Invasion in HCC Reveals Molecular Drivers and Predictive Biomarkers[J]. Hepatology, 2021, 73(6): 2342-2360. doi: 10.1002/hep.31614
|
| [29] |
Krishnamurthy S, Gilot D, Ahn SB, et al. Involvement of Kynurenine Pathway in Hepatocellular Carcinoma[J]. Cancers (Basel), 2021, 13(20): 5180. doi: 10.3390/cancers13205180
|
| [30] |
Liu W, Wu J, Yang F, et al. Genetic Polymorphisms Predisposing the Interleukin 6-Induced APOBEC3B-UNG Imbalance Increase HCC Risk via Promoting the Generation of APOBEC-Signature HBV Mutations[J]. Clin Cancer Res, 2019, 25(18): 5525-5536. doi: 10.1158/1078-0432.CCR-18-3083
|
| [31] |
Liu W, Ji H, Zhao J, et al. Transcriptional repression and apoptosis influence the effect of APOBEC3A/3B functional polymorphisms on biliary tract cancer risk[J]. Int J Cancer, 2022, 150(11): 1825-1837. doi: 10.1002/ijc.33930
|
| [32] |
Tan X, Zheng S, Liu W, et al. Effect of APOBEC3A functional polymorphism on renal cell carcinoma is influenced by tumor necrosis factor-α and transcriptional repressor ETS1[J]. Am J Cancer Res, 2021, 11(9): 4347-4363.
|
| [33] |
Chen X, Zhang M, Li N, et al. Nucleotide variants in hepatitis B virus preS region predict the recurrence of hepatocellular carcinoma[J]. Aging (Albany NY), 2021, 13(18): 22256-22275.
|
| [34] |
Pu R, Liu W, Zhou X, et al. The Effects and Underlying Mechanisms of Hepatitis B Virus X Gene Mutants on the Development of Hepatocellular Carcinoma[J]. Front Oncol, 2022, 12: 836517. doi: 10.3389/fonc.2022.836517
|
| [35] |
Chen S, Morine Y, Tokuda K, et al. Cancer-associated fibroblast-induced M2-polarized macrophages promote hepatocellular carcinoma progression via the plasminogen activator inhibitor-1 pathway[J]. Int J Oncol, 2021, 59(2): 59. doi: 10.3892/ijo.2021.5239
|
| [36] |
丁一波, 陈一凡, 曹广文. 癌症进化发育学的新证据: 结直肠癌和肝细胞癌的研究发现[J]. 中国癌症防治杂志, 2020, 12(1): 1-5. https://www.cnki.com.cn/Article/CJFDTOTAL-ZAZF202001001.htm
Ding YB, Chen YF, Cao GW. Novel Evidence of Cancer Rev-Dev: the Discovery in Colorectal Carcinoma and Hepatocellular Carcinoma[J]. Zhongguo Ai Zeng Fang Zhi Za Zhi, 2020, 12(1): 1-5. https://www.cnki.com.cn/Article/CJFDTOTAL-ZAZF202001001.htm
|
| [37] |
Wang SZ, Lee SD, Sarkar D, et al. Immunological characterization of hepatocellular carcinoma[J]. Hepatoma Res, 2021, 7(1): 65-88.
|
| [38] |
Feng ZY, Xu FG, Liu Y, et al. The immune microenvironment and progression of immunotherapy and combination therapeutic strategies for hepatocellular carcinoma[J]. Hepatoma Res, 2021, 7(1): 23-37.
|
| [39] |
Jin H, Shi Y, Lv Y, et al. EGFR activation limits the response of liver cancer to lenvatinib[J]. Nature, 2021, 595(7869): 730-734. doi: 10.1038/s41586-021-03741-7
|
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