【分　 类】 医药卫生
【关 键 词】 癌症，肝脏，微环境，肝细胞癌
【来 　源】 互联网
【收　 录】 中文学术期刊网

正文：

肿瘤细胞与ECM相互作用可促进肝细胞癌的进展和转移。已知通路包括钙黏蛋白下调、基质金属蛋白酶（MMP）上调和上皮间质转分化（EMT）[41]。细胞外基质金属蛋白酶诱导因子（EMMPRIN）的表达可调节这些通路。白细胞、肿瘤细胞和巨噬细胞分泌的EMMPRIN促使肝基质细胞、肝细胞相互作用促进MMP表达[42,43]。EMMPRIN的表达和MMP的激活与肝细胞癌的血管形成、侵袭、EMT、转移和复发相关[44]，也与癌细胞系凋亡减少相关[45]，使肝癌细胞在远离肝脏的部位生存避免术中被切除，导致早期肝癌的复发。
Hh（Hedgehog）通路是肝癌形成的常见信号通路，可改变肿瘤间质信号导致肝癌进展。肝癌Hh通路增加肌成纤维细胞的糖酵解产生大量游离乳酸，使肝癌细胞通过代谢脂肪酸途径产生能量[46]。Hh信号通路改变可活化肝基质细胞及祖细胞而促进肝纤维化[47]。另外，Wnt信号通路的激活也可驱使肝祖细胞向癌性细胞发展[48]。
HBV、HCV病毒通过DNA修复系统的修复作用和中心体的复制机制参与到肝癌的产生过程，通过病毒编码的癌基因蛋白转化能力裂解基因表达影响信号通路。由HCV、HBV编码的几种蛋白能改变细胞因子的表达，调节肿瘤微环境和肝脏免疫反应，促进肝癌的进展[49]。
基因（DNA）改变在肝癌发生中作用及机制
   接触或食入化学致癌物都可以直接改变DNA序列而导致DNA突变，黄曲霉素B1（AFB1）可造成氧化性DNA损伤导致DNA加合物形成和突变[5]。在体外接触AFB1的转基因小鼠成纤维细胞可发现p53的突变[50]。流行病学研究表明AFB1与肝癌病人p53突变有关[51]。AFB1可抑制p53对G1检查点阻滞，避开细胞DNA损伤应答，导致DNA突变率增加，促进肝癌的发生[52]。乙醇也是肝癌的一种危险因子，它能够增加肝细胞内ROS的浓度，导致DNA加合物形成增加[53]。乙肝病毒基因插入宿主细胞基因组，导致基因组不稳定，基因和染色体缺失和易位，使宿主细胞miRNA、癌基因和肿瘤抑制基因DNA发生突变及染色体拷贝数的改变，致使肝细胞癌基因得到表达[54]。启动子中CpG甲基化可激活JAK / STAT和其他肝细胞癌触发通路，导致肝细胞癌的发生[55,56]。
结语与展望
   肝癌发生不仅由于肝细胞的基因突变导致，也与肝脏微环境中介质刺激相关，研究肿瘤微环境与肿瘤的发生发展机制，对发现治疗肿瘤的新靶点至关重要。病毒相关分子机制和免疫介导是肝癌发生的主要因素，调节着肝癌微环境因子间关系，提示改变的信号通路可用于治疗肿瘤。肥胖和糖尿病、酒精、铁过载等辅助因子通过促进炎症和其它未知机制致癌。可通过多种方式协同治疗HCC，而减少肿瘤的发展和扩散。注射HBV疫苗可预防HCC，抗病毒治疗也可降低术后HCC复发率。生长因子、基质金属蛋白酶抑制剂和免疫调节剂药物，肿瘤 - 基质界面靶向治疗都可作为治疗肝癌的新方法。
 
1. Su CH, Lin Y, Cai L (2013) Genetic factors, viral infection, other factors and liver cancer: an update on current progress. Asian Pac J Cancer Prev 14: 4953-4960.
2. Fares N, Peron JM (2013) [Epidemiology, natural history, and risk factors of hepatocellular carcinoma]. Rev Prat 63: 216-217, 220-212.
3. Zucman-Rossi J, Nault JC, Zender L (2013) Primary liver carcinomas can originate from different cell types: a new level of complexity in hepatocarcinogenesis. Gastroenterology 145: 53-55.
4. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM (2013) Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144: 512-527.
5. Guindon-Kezis KA, Mulder JE, Massey TE (2014) In vivo treatment with aflatoxin B1 increases DNA oxidation, base excision repair activity and 8-oxoguanine DNA glycosylase 1 levels in mouse lung. Toxicology 321: 21-26.
6. Kew MC (2014) Hepatic iron overload and hepatocellular carcinoma. Liver Cancer 3: 31-40.
7. Duan XY, Zhang L, Fan JG, Qiao L (2014) NAFLD leads to liver cancer: do we have sufficient evidence? Cancer Lett 345: 230-234.
8. Valenti R, Huber V, Filipazzi P, Pilla L, Sovena G, et al. (2006) Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytes. Cancer Res 66: 9290-9298.
9. Yu S, Liu C, Su K, Wang J, Liu Y, et al. (2007) Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol 178: 6867-6875.
10. Taylor DD, Gercel-Taylor C (2011) Exosomes/microvesicles: mediators of cancer-associated immunosuppressive microenvironments. Semin Immunopathol 33: 441-454.
11. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S, et al. (2013) Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499: 97-101.
12. Bouchard MJ, Navas-Martin S (2011) Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges. Cancer Lett 305: 123-143.
13. Aebischer T, Meyer TF, Andersen LP (2010) Inflammation, immunity, and vaccines for Helicobacter. Helicobacter 15 Suppl 1: 21-28.
14. Freeman AJ, Marinos G, Ffrench RA, Lloyd AR (2001) Immunopathogenesis of hepatitis C virus infection. Immunol Cell Biol 79: 515-536.
15. Krawczynski K, Alter MJ, Tankersley DL, Beach M, Robertson BH, et al. (1996) Effect of immune globulin on the prevention of experimental hepatitis C virus infection. J Infect Dis 173: 822-828.
16. Rehermann B (2000) Intrahepatic T cells in hepatitis B: viral control versus liver cell injury. J Exp Med 191: 1263-1268.
17. Rapicetta M, Ferrari C, Levrero M (2002) Viral determinants and host immune responses in the pathogenesis of HBV infection. J Med Virol 67: 454-457.
18. Kaulmann A, Bohn T (2014) Carotenoids, inflammation, and oxidative stress-implications of cellular signaling pathways and relation to chronic disease prevention. Nutr Res.
19. Li HC, Ma HC, Yang CH, Lo SY (2014) Production and pathogenicity of hepatitis C virus core gene products. World J Gastroenterol 20: 7104-7122.
20. Cardin R, Piciocchi M, Sinigaglia A, Lavezzo E, Bortolami M, et al. (2012) Oxidative DNA damage correlates with cell immortalization and mir-92 expression in hepatocellular carcinoma. BMC Cancer 12: 177.
21. Burhans WC, Weinberger M (2007) DNA replication stress, genome instability and aging. Nucleic Acids Res 35: 7545-7556.
22. Saini N, Srinivasan R, Chawla Y, Sharma S, Chakraborti A, et al. (2009) Telomerase activity, telomere length and human telomerase reverse transcriptase expression in hepatocellular carcinoma is independent of hepatitis virus status. Liver Int 29: 1162-1170.
23. Lin J, Wu JF, Zhang Q, Zhang HW, Cao GW (2014) Virus-related liver cirrhosis: molecular basis and therapeutic options. World J Gastroenterol 20: 6457-6469.
24. Michalopoulos GK (2013) Principles of liver regeneration and growth homeostasis. Compr Physiol 3: 485-513.
25. Luan X, Liao W, Lai X, He Y, Liu Y, et al. (2012) Dynamic changes of indoleamine 2,3-dioxygenase of Kupffer cells in rat liver transplant rejection and tolerance. Transplant Proc 44: 1045-1047.
26. You Q, Cheng L, Kedl RM, Ju C (2008) Mechanism of T cell tolerance induction by murine hepatic Kupffer cells. Hepatology 48: 978-990.
27. Knolle PA, Thimme R (2014) Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology 146: 1193-1207.
28. Thomson AW, Knolle PA (2010) Antigen-presenting cell function in the tolerogenic liver environment. Nat Rev Immunol 10: 753-766.
29. Ha SJ, West EE, Araki K, Smith KA, Ahmed R (2008) Manipulating both the inhibitory and stimulatory immune system towards the success of therapeutic vaccination against chronic viral infections. Immunol Rev 223: 317-333.

 2/3   首页 上一页 1 2 3 下一页 尾页