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Inflammatory models drastically alter tumor grow.h and the immune microenvironment in hepatocellular carcinoma

Science Bulletin 2015年第8期60卷 762-772,M0003页

作者： Geoffrey J. Markow.tz gregory A. Michelotti Anna Mae Diehl Xiao-Fan w.ng Department of Pharmacology and Cancer Biology Duke University Medical Center Division of Gastroenterology Department of Medicine Duke University Medical Center

Initiation and progression of hepatocellular carcinoma （HCC） is intimately associated w.th a chronically diseased liver tissue. This diseased liver tissue background is a drastically different microenvironment from the healthy liver, especially w.th regard to immune cell prevalence and presence of mediators of immune function. To better understand the consequences of liver disease on tumor grow.h and the interplay w.th its mi- croenvironment, w. utilized tw. 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 grow.h w.s significantly enhanced under fi- brotic conditions. The immune cells that infiltrated the tumors w.re also drastically different, w.th 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 w.re model- specific differences： Increased numbers of CD11b^＋ mye- loid cells and CD4^＋ CD25^＋ T cells w.re 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, w.ich could have far- reaching consequences on the immune infiltrate and its functionality. Taken together, this w.rk demonstrates that the combination of fibrosis induction w.th orthotopic tumor implantation results in a markedly different tumor mi- croenvironment and tumor grow.h kinetics, emphasizing the necessity for more accurate modeling of HCC pro- gression in mice, w.ich takes into account the drastic changes in the tissue caused by chronic liver disease.

关键词： Hepatocellular carcinoma Fibrosis Tumor microenvironment Carbon tetrachloride Bile duct ligation Cytokines

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