Abstract
Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblast-like cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.
Highlights
Hepatocellular carcinoma (HCC) is the sixth leading cause of cancer related deaths in western countries (Choo et al, 2016; Bray et al, 2018), accounting for up to 90% of all primary liver cancers (Lozano et al, 2012)
This study showed in vitro evidence of early activated Hepatic stellate cells (HSCs) (4 days co-culture of HSCs and liver Natural Killer (NK) cells) induced NK cell activation via natural killer group 2 member D (NKG2D), whereas this was abolished in intermediately activated HSCs (8 days co culture of HSCs and liver NK cells) due to increased levels of TGFB1 and downregulation of NKG2D (Jeong et al, 2011)
Hepatic stellate cells activation is the central event of hepatic fibrosis and the development of cirrhosis and HCC
Summary
Hepatocellular carcinoma (HCC) is the sixth leading cause of cancer related deaths in western countries (Choo et al, 2016; Bray et al, 2018), accounting for up to 90% of all primary liver cancers (Lozano et al, 2012). These results establish that NK cells interact with activated HSCs to mitigate liver fibrosis during chronic liver injury, this process can be suppressed through increased TGFB and SOCS1 produced by activated HSCs in vitro.
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