Cancer Research on Prevention and Treatment    2022, Vol. 49 Issue (08) : 747-755     DOI: 10.3971/j.issn.1000-8578.2022.22.0377
Theoretical Update of Cancer Evo-Dev and Its Role in Targeted Immunotherapy for Hepatocellular Carcinoma
CAO Guangwen
Department of Epidemiology, Faculty of Naval Medicine, Second Military Medical University, Shanghai 200433, China
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Abstract Abstract: 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 activationinduced 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. Cancerpromoting 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 forenhanced 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.
Keywords Hepatitis B virus      Hepatocellular carcinoma      Tumor microenvironment      Mutation      Targeted therapy      Immunotherapy     
ZTFLH:  R735.7  
Fund:National Key Basic Research Program of China (973 Program) (No. 2015CB554000); National Natural Science Foundation of China (No. 81673250); Key Discipline from the “3-year Public Health Promotion” Program of Shanghai Municipal Health Commission (No. GWV-10.1-XK17)
Issue Date: 11 August 2022
 Cite this article:   
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(08): 747-755.
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