Hepatic stellate cells: central modulators of hepatic carcinogenesis

Abstract

Hepatocellular carcinoma (HCC) represents the second most common cause of cancer-related death worldwide, and is increasing in incidence. Currently, our therapeutic repertoire for the treatment of HCC is severely limited, and therefore effective new therapies are urgently required. Recently, there has been increasing interest focusing on the cellular and molecular interactions between cancer cells and their microenvironment. HCC represents a unique opportunity to study the relationship between a diseased stroma and promotion of carcinogenesis, as 90% of HCCs arise in a cirrhotic liver. Hepatic stellate cells (HSC) are the major source of extracellular proteins during fibrogenesis, and may directly, or via secreted products, contribute to tumour initiation and progression. In this review we explore the complex cellular and molecular interplay between HSC biology and hepatocarcinogenesis. We focus on the molecular mechanisms by which HSC modulate HCC growth, immune cell evasion and angiogenesis. This is followed by a discussion of recent progress in the field in understanding the mechanistic crosstalk between HSC and HCC, and the pathways that are potentially amenable to therapeutic intervention. Furthermore, we summarise the exciting recent developments in strategies to target HSC specifically, and novel techniques to deliver pharmaceutical agents directly to HSC, potentially allowing tailored, cell-specific therapy for HCC.

Fig. 1

Crosstalk between HSC and HCC. HSC-secreted factors such as HGF may promote hepatocarcinogenesis. Similarly, HCC signalling results in further HGF production from activated HSC. TGF-β demonstrates both tumour-suppressive and tumour-promoting functions, depending on context. HSC produce angiogenic cytokines, supporting new vessel growth. HCC cells contribute to angiogenic signalling, and HSC also possess receptors for some of these factors. Gut-derived LPS induces HSC activation, resulting in epiregulin and HGF production, with mitogenic effects on HCC

Fig. 2

Immunomodulatory effects of HSC in HCC. Intratumoural HSC (iHSC) promote HCC progression through i) an increase in Treg cell induction and immunosuppressive function and ii) upregulation of B7-H1 on iHSC resulting in increased ligation of its receptor (PD-1) on activated T-cells, leading to increased apoptosis of activated T cells with subsequent inhibition of T-cell-mediated tumour cell apoptosis. This results in HCC immunotolerance and a permissive environment for tumour growth. PD-1, programmed death ligand; B7-H1 human B7 homolog 1; ECM, extracellular matrix

Fig. 3

Therapeutic approaches to targeting HSC. HSC have been targeted by coupling a compound to a carrier possessing either a HSC-specific receptor-binding ligand or an antibody. Carriers utilised include: a monoclonal human single chain antibody (scAb) fragment to synaptophysin [155]; a sugar moiety that binds the mannose-6-phosphate (M6P) insulin-like growth factor receptor [157]; a liposome specific to the vitamin A (retinol-binding protein) receptor [156]; PDGFβ-peptide [160]; PDGFβ receptor recognising peptide (PPB) [164]; an RGD peptide bound to a liposome or coupled to human serum albumin (HSA) [159, 162] scAb Fv, single chain antibody variable fragment; PEG, polyethylene glycol; pCVI, 10 cyclic peptide moieties that recognise collagen type VI receptors