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+ Gr1hi myeloid 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.

C‑reactive protein/albumin and neutrophil/lymphocyte ratios and their combination predict overall survival in patients with gastric cancer

“…of transcription 3 and nuclear factor κB, and recruit an increased number of inflammatory cells, including neutrophilic granulocytes and mononuclear macrophages, to the lesion site and thereby assist in forming an inflammatory microenvironment (13,30,31). The interaction between tumor cells and inflammatory factors may suppress the immunosurveillance of T and natural killer cells (32), enhance the permeability of blood and lymphatic vessels and degrade the extracellular matrix, thereby potentiating tumor development and metastasis (12,33). Furthermore, tumor cells may secrete inflammatory mediators and thereby assist in forming an inflammatory microenvironment (34).…”

“…Previous studies have indicated that inflammation is associated with the formation of the tumor microenvironment by inflammatory mediators, including vasoactive amines and cytokines (11)(12)(13). The C-reactive protein (CRP)/albumin (Alb) ratio is used as a novel inflammation-based prognostic indicator in multiple types of tumor.…”

Inflammation-Dependent IL18 Signaling Restricts Hepatocellular Carcinoma Growth by Enhancing the Accumulation and Activity of Tumor-Infiltrating Lymphocytes

“…To do this, we first established a mouse model combining carbon tetrachloride (CCl 4 )-induced liver fibrosis with orthotopic implantation of tumor cells (Fig. 2A and (34)). This model induced robust fibrosis in wild-type (WT) mice, as demonstrated by increases in circulating aminotransferases, hepatic stellate cell activation, and collagen deposition (Supplementary Fig.…”

“…S2). Induction of inflammatory liver fibrosis enhanced tumor growth, with increased infiltration and altered immune composition in non-tumor liver and tumor compared with tumor engraftment without fibrosis induction (34). IL-18 is produced by many constituents of the tumor microenvironment (25).…”

“…This diseased microenvironment is drastically different from the healthy liver, including different cytokines, growth factors, activated stromal cells, extracellular matrix, and infiltrating immune cells. This altered microenvironment has been well-known to be integral to liver carcinogenesis, however studies examining the interplay between this altered environment, the tumor, and effects on the progression of the disease post-transformation have been less abundant (34). Numerous molecules have been shown to modulate this disease, but many more remain to be discovered and evaluated using more rigorous and relevant models with intact immune systems and functional microenvironments necessary for these experiments.…”