Tumor regulation of the tissue environment in the liver

Abstract

The tumor microenvironment (TME) in the liver plays an important role in primary and metastatic liver tumor formation and tumor growth promotion. Cellular and non-cellular components of the TME significantly influence tumor development, growth, metastatic spread, anti-tumor immunity and response to tumor therapy. The cellular components of the TME in the liver not only consist of infiltrating immune cells, but also of liver-resident cells such as liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC), which promote tumor growth by negatively regulating tumor-associated immune responses. In this review, we characterize cells of the TME with pro- and anti-tumor function in primary and metastatic liver tumors. Furthermore, we summarize mechanisms that permit growth of hepatic tumors despite the occurrence of spontaneous anti-tumor immune responses and how novel therapeutic approaches targeting the TME could unleash tumor-specific immune responses to improve survival of liver cancer patients.

Allogenic Natural Killer Cell Immunotherapy Combined with Irreversible Electroporation for Stage IV Hepatocellular Carcinoma: Survival Outcome

“…Furthermore, the patients tolerated the treatment well. Numerous analyses in recent years have shown that tumor immune responses influence cancer formation and progression in advanced hepatic cancer [32], indicating the possible effectiveness of immune-based therapy as a cancer treatment option.…”

Immunotherapy of Hepatocellular Carcinoma

“…Premalignant hepatocytes secrete cytokines, which attract macrophages to clear affected cells. However, if a tumor-preventive senescence program is bypassed, senescence-recruited myeloid cells promote HCC development [17,18]. Furthermore, APCs change their profile by secreting less immune-stimulatory antitumorigenic cytokines like interleukin-12 (IL-12) or IFN-γ [19].…”

Characterization of Pattern Recognition Receptor Expression and Functionality in Liver Primary Cells and Derived Cell Lines

“…LSEC are also well known to participate in liver immune response by secreting cytokines upon pathogenic stimuli [8]. These cells also play a key role upon danger signal leading to fibrosis since, upon shear stress, they will undergo cytoskeletal remodeling, leading to a loss of fenestration [8,9]. Hepatic stellate cell (HSC), the liver fibroblasts, and producers of extracellular matrix are localized in the space of Disse, an area between hepatocytes and sinusoids, and thus are not directly exposed to the bloodstream.…”

“…These cells normally represent 5-8% of the total number of the liver cells. However, upon chronic inflammation, HSC undergo transformation to become myofibroblasts, the activated state of HSC [9][10][11]. Once activated, these cells proliferate and start secreting numerous components of the extracellular matrix creating a scarlike tissue [12].…”

“…Once activated, these cells proliferate and start secreting numerous components of the extracellular matrix creating a scarlike tissue [12]. However, during uncontrolled inflammation and scarring/healing process, the overproduction of extracellular matrix induces fibrosis, which can ultimately lead to cirrhosis and favor the development of hepatocellular carcinoma (HCC) [9,12]. Finally, Kupffer cells (KC), the liver resident macrophages, represent 80% of total macrophages population within the body [13].…”