title: Inflammatory models drastically alter tumor growth and the immune microenvironment in hepatocellular carcinoma.
abstract: 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 microenvironment, we utilized two standard methods of fibrosis 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 controls, tumor growth was significantly enhanced under fibrotic conditions. The immune cells that infiltrated the tumors were also drastically different, with decreased numbers of natural killer cells but greatly increased numbers of immune-suppressive CD11b+Gr1himyeloid cells in both models of fibrosis. In addition, there were model-specific differences: Increased numbers of CD11b+myeloid cells and CD4+CD25+T cells were found in tumors in the bile duct ligation model but not in the carbon tetrachloride model. Induction of fibrosis altered the cytokine production of implanted tumor cells, which could have farreaching 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 microenvironment and tumor growth kinetics, emphasizing the necessity for more accurate modeling of HCC progression in mice, which takes into account the drastic changes in the tissue caused by chronic liver disease.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Markowitz
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michelotti
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
keywords: Bile duct ligation; Carbon tetrachloride; Cytokines; Fibrosis; Hepatocellular carcinoma; Tumor microenvironment