摘要
Initiation and progression of hepatocellular carcinoma （HCC） is intimately associated with a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially with regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor growth and the interplay with its mi- croenvironment, we utilized two standard methods of fi- brosis induction and orthotopic implantation of tumors into the inflamed and fibrotic liver to mimic the liver condition in human HCC patients. Compared to non-diseased con- trols, tumor growth was significantly enhanced under fi- brotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased num- bers of immune-suppressive CDllb^＋ Gr1^hi myeloid cells in both models of fibrosis. In addition, there were model- specific differences： Increased numbers of CD11b^＋ mye- loid cells and CD4^＋ CD25^＋ T cells were found in tumors in the bile duct ligation model but not in the carbon te- trachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have far- reaching consequences on the immune infiltrate and its functionality. Taken together, this work demonstrates that the combination of fibrosis induction with orthotopic tumor implantation results in a markedly different tumor mi- croenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC pro- gression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.
原发性肝细胞癌(HCC)的起始和发展与肝脏慢性疾病密切相关.与正常肝脏相比,肝脏慢性疾病引起微环境的剧烈变化,尤其影响免疫细胞的功能.为了研究肝脏疾病对于肿瘤生长的影响以及与肿瘤微环境的互相作用,我们采用两种标准化方法诱导肝脏纤维化,并将肿瘤原位移植到发炎并纤维化的肝脏上模拟人类HCC患者的肝脏状态.与健康对照组相比,肝脏的纤维化显著促进肿瘤生长.在两种诱导纤维化的模型中,浸润肿瘤的免疫细胞也发生显著变化:自然杀伤细胞减少,而免疫抑制的骨髓细胞CD11b+Gr1hi显著增加.此外,存在模型特异的区别:在胆管结扎模型的肿瘤中,CD11b+骨髓细胞和CD4+CD25+T细胞数量增加,但在四氯甲烷模型中没有变化.纤维化能改变移植的肿瘤细胞中的细胞因子产生,可能对免疫功能产生深远的影响.综上所述,本研究揭示了肝脏纤维化诱导结合肿瘤原位移植能显著改变肿瘤微环境以及肿瘤生长动态,提示在动物模型中模拟HCC时需要考虑慢性肝脏疾病对肝脏的重要影响.
基金
supported by Grant CA154151
