Crosstalk between Hepatic Stellate Cells and Tumor Cells in the Development of Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a major global health concern, ranking sixth in age-standardized incidence (ASI) and fourth in age-standardized mortality (ASM) worldwide. In China, it holds an even more prominent position, being the fourth in ASI and the second in ASM among all cancers. The primary etiology of HCC in China is chronic hepatitis B, which often leads to persistent liver injury and inflammation. The tumor microenvironment (TME) plays a critical role in HCC progression, with increasing research focusing on the intercellular and molecular crosstalk between tumor cells and surrounding hepatic stromal cells, including hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs), and immune cells. Among these stromal cells, HSCs are central to the interaction between the tumor and stroma, significantly contributing to HCC progression.
Role of Hepatic Stellate Cells in HCC Development
HSCs reside in the space of Disse in a quiescent, non-proliferative state, storing vitamin A in a healthy liver. However, persistent liver injury and inflammation activate HSCs, transforming them into key players in the production of growth factors, extracellular matrix (ECM), matrix metalloproteinases (MMPs), and other cytokines. Activated HSCs are closely associated with fibrosis and cirrhosis, and the remodeling and reorganization of ECM create a stiff tumor microenvironment. As central modulators of the TME, activated HSCs, along with cancer-associated fibroblasts (CAFs) predominantly derived from HSCs, have multiple roles in HCC progression.
In vitro studies have demonstrated that HSCs directly induce the malignant phenotype of cancer cells through the secretion of growth factors, ECM, and MMPs. Activated HSCs also promote angiogenesis by upregulating the expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and fibroblast growth factor (FGF) during HCC development. Additionally, HSCs reduce immune surveillance by recruiting immunosuppressive inflammatory cells such as regulatory T-cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs), which drive tumor progression. Evidence suggests that HSCs induce MDSCs through interleukin-6 (IL-6) signaling and produce inhibitory enzymes to suppress T-cell immunity, thereby creating an immunosuppressive microenvironment.
Despite their pro-tumorigenic roles, some studies suggest that HSCs can act as negative regulators of HCC progression. For instance, HSCs upregulate endosialin expression in HCC, which inhibits tumor-promoting cytokines such as insulin-like growth factor 2, retinol-binding protein 4, dickkopf-1, and C-C chemokine ligand 5. This dual function of HSCs in HCC progression highlights the complexity of their role in the disease.
Mechanisms of HSC-HCC Crosstalk
The crosstalk between HSCs and HCC cells is mediated by the secretion of growth factors, ECM, MMPs, and other cytokines. TGF-β, primarily secreted by HSCs, is a key cytokine modulating this interaction. TGF-β binds to its receptors, TGF-beta receptor type I and TGF-beta receptor type II, and induces Smad and non-Smad signaling pathways, resulting in HSC activation, macrophage polarization, and LSEC capillarization. TGF-β has a dual role in cancer progression: it acts as a tumor suppressor in early phases of hepatocarcinogenesis by inducing cytostasis and apoptosis of hepatocytes, preventing inflammation, and counteracting stroma-released mitogens. However, in later phases of HCC, TGF-β promotes tumor progression by orchestrating processes such as fibrogenesis, invasion, migration, epithelial-mesenchymal transition (EMT), and tumor-stromal cell crosstalk, likely through upregulating nuclear β-catenin accumulation in malignant hepatocytes.
Growth differentiation factor 15 (GDF15), a TGF-β superfamily member, is upregulated in HCC cells by cisplatin and hypoxia treatment. GDF15 participates in HSC promotion and accelerates HCC progression by activating ERK1/2- and Smad3-dependent signaling pathways.
Role of PDGF and HGF in HSC-HCC Interaction
PDGF is a key element in HSC signaling and acts synergistically with TGF-β to activate HSCs. PDGF binds to its receptors, PDGF-Rα or PDGF-Rβ, to activate phosphatidylinositol-3-kinase, rat sarcoma, and phospholipase C-gamma signaling pathways. PDGF also plays a pro-tumorigenic role in various stages of HCC development by upregulating TGF-β receptors and inducing pro-carcinogenic factors such as β-catenin, VEGF, and FGF. A recent study in transgenic mice overexpressing PDGF-C indicates that PDGF-C activates the TGF-β/Smad3 signaling pathway to promote HSC activation, leading to HCC progression.
Hepatocyte growth factor (HGF), mostly produced by HSCs, is another crucial growth factor regulating the HSC-HCC interaction. HGF binds to its receptor, c-Met, and triggers subsequent phosphorylation cascades. The HGF/c-Met signaling pathway promotes hepatocarcinogenesis by accelerating tumor cell proliferation, angiogenesis, invasion, and EMT in HCC. Evidence suggests that HSC-derived HGF regulates Keratin 19 expression via a MET-ERK1/2-AP1 and SP1 axis to promote aggressive hepatoma growth.
Connective Tissue Growth Factor (CTGF) in HCC Development
CTGF, mainly derived from HSCs, is a downstream mediator of TGF-β signaling and is induced by TGF-β via STAT3 and Smad2/3 signaling pathways. CTGF plays a pro-carcinogenic role in HCC development by increasing DNA synthesis, cell-cycle progression, and invasion and migration abilities. It also induces resistance to doxorubicin and TNF-related apoptosis-inducing ligand apoptosis in HCC cells. CTGF secreted by tumor cells promotes HSC activation and accelerates HCC development. Additionally, CTGF-mediated crosstalk between HSCs and HCC induces IL-6 production, which stimulates hepatoma advancement.
ECM Components and Other Cytokines in HSC-HCC Crosstalk
Proteoglycans, laminins, and fibronectin, major components of the ECM mostly secreted by HSCs, interact with tumor cells. HSC-derived cartilage oligomeric matrix protein stimulates HCC development by inducing MEK/ERK and phosphatidylinositol-3-kinase/AKT signaling pathways in a CD36-dependent manner. Fibrinogen promotes HSC activation by binding to integrin αvβ5 to induce hepatocarcinogenesis, indicating a novel interaction between HCC and HSCs in a zebrafish HCC model.
Other cytokines secreted by HSCs also mediate the HSC-HCC crosstalk. For instance, the senescence-associated secretory phenotype (SASP) in HSCs plays a pro-tumorigenic role by downregulating cytoplasmic DNases. Blocking the SASP in HSC senescence results in a decline of obesity-associated HCC development in mice.
STMN1 and Exosomes in HSC-HCC Interaction
STMN1, an oncogene, mediates the HSC-HCC crosstalk by inducing the HGF/c-Met signaling pathway. STMN1 overexpression in HCC cells enhanced by HGF converts HSCs into CAFs, which promote HCC development. The HSC-HCC interaction is also modulated by tumor-derived exosomes. Tumor-secreted miRNA-21 facilitates HSC activation to acquire CAF features via the PTEN/PDK1/AKT signaling pathway. CAFs exhibit increased angiogenic factors like VEGF, MMP2/9, TGF-β, and FGF, accelerating HCC development.
Conclusion
The crosstalk between HSCs and tumor cells is indispensable for HCC progression. This interaction is bidirectional: HSCs directly affect tumor growth by secreting growth factors, ECM, MMPs, and other cytokines. HSCs also influence HCC advancement by altering ECM components, promoting angiogenesis, and reducing immune surveillance. Simultaneously, tumor cells secrete multiple factors that alter HSCs towards a more pro-tumoral phenotype, creating a vicious feedback loop that drives HCC progression. The complex molecular network of HSC-HCC cell crosstalk is crucial for HCC development, and innovative therapeutic strategies targeting this interaction need to be explored to improve the treatment of this deadly cancer.
doi.org/10.1097/CM9.0000000000001726
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