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 ...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.展开更多
基金the corresponding author's laboratory was supported by grants from the National Basic Research Program of China(No.2017YFC1001403)the National Natural Science Foundation of China(No.31270969,81571512,and 81501334)。
文摘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.
