Hepatic stellate cells: Partners in crime for liver... : Hepatology (original) (raw)
The liver is an organ to which many primary malignant tumors commonly metastasize. These primary tumors include gastrointestinal cancers, melanoma, breast and lung carcinomas, neuroendocrine tumors, and sarcomas.1 Despite significant advances in the treatment of metastatic disease to the liver, hepatic metastases still remain a principal cause of patient death.2 Thus, understanding the molecular and/or cellular mechanisms of liver metastases and developing strategies to target liver-specific mechanisms that enhance metastatic growth may be most appropriate for preventing and treating tumors that show a preference for liver metastases, such as colorectal cancers and melanomas.
The liver is a common site of metastases, suggesting that it provides a prometastatic microenvironment for cancer cells. This prometastatic microenvironment consists of both noncellular and cellular components.1, 3 Noncellular components include growth factors and cytokines, such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF), extracellular matrix (ECM), proteolytic enzymes (e.g., matrix metalloproteinases [MMPs]), and tissue inhibitor of metalloproteinases (TIMP). Cellular components include hepatocytes, sinusoidal endothelial cells (ECs), hepatic stellate cells (HSCs), fibroblasts, and immune cells such as lymphocytes and Kupffer cells. HSCs, which are liver-specific pericytes, are particularly topical to the tumor microenvironment, and they will be the focus of this review.
HSCs are a key contributor to liver fibrosis and portal hypertension.4, 5 They were recently postulated as a component of the prometastatic liver microenvironment because they can transdifferentiate into highly proliferative and motile myofibroblasts that are implicated in the desmoplastic reaction and tumor growth.1, 3, 6 Besides HSCs, bone marrow–derived fibrocytes, portal fibroblasts, hepatocytes, or cholangiocytes are other potential origins of myofibroblasts.5 This review focuses on bidirectional interactions between tumor cells and HSCs in the liver microenvironment and discusses mechanisms whereby tumor derived factors activate HSCs, and in turn, activated HSCs promote metastatic growth (Fig. 1). In addition, we review currently available strategies that might be used to target the HSC activation process in the treatment of liver metastases.
A schema illustrating bidirectional interactions between tumor and HSCs that regulate HSC activation and metastatic growth in the liver. Bidirectional interactions may function as an “amplification loop” to enhance metastatic growth in the liver. Tumor-derived factors such as TGF-β and PDGF promote HSC activation and transdifferentiation into myofibroblasts. In turn, activated HSCs promote metastatic growth by multiple mechanisms: (1) production of growth factors and cytokines, (2) regulation of ECM turnover, (3) promotion of tumor angiogenesis, and (4) inhibition of immune cell functions. Tumor cells also modulate their growth by similar mechanisms. In addition to HSCs, other potential origins of myofibroblasts in the liver include portal fibroblasts, bone marrow–derived fibrocytes, hepatocytes, or cholangiocytes. EMT, epithelial–mesenchymal transition.
Abbreviations: α-SMA, alpha-smooth muscle actin; EC, endothelial cells; ECM, extracellular matrix; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; HSC, hepatic stellate cell; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinase; NO, nitric oxide; SDF-1, stromal cell-derived factor 1; TGF-β, transforming growth factor β; TIMP, tissue inhibitor of metalloproteinases; VEGF, vascular endothelial growth factor.
Liver Metastases Are Dependent on Tumor Interactions with Liver-Specific Stromal Factors
Why do tumor cells preferentially metastasize to the liver? Two theories have been developed to explain the organ-specific spreading of cancer cells: (1) the Seed and Soil Theory, developed by Paget in 1889, which proposed that it was due to the dependence of the seeds (the cancer cells) on the soil (specific organs),7-9 and (2) Ewing's Theory, developed in the 1920s, which hypothesized that mechanical factors (circulatory patterns, blood flow patterns, and nonspecific trapping of cancer cells by the first capillary bed that they encounter) were sufficient for organ-specific metastasis.9, 10 However, recent studies have suggested that these two theories are not mutually exclusive, and that both mechanical and seed-soil compatibility factors may contribute to the ability of cancer cells to metastasize to specific organs such as the liver.1, 9
The combination of hemodynamic features of the liver and its unique microenvironment makes the liver one of the most targeted organs by cancer metastases. The liver is able to arrest circulating cancer cells (particularly gastrointestinal cancer cells) efficiently, because of its specific location and the slow and tortuous blood flow in the sinusoidal capillaries. However, not all tumor cells retained in the liver develop into metastases. Indeed, liver metastasis is a very inefficient process: an experimental liver metastasis model showed that less than 0.02% of intraportally injected B16F1 melanoma cells developed into macroscopic tumors in the mouse liver.11 Before they develop into macroscopic metastases, tumor cells must go through multiple selective steps in the liver, including (1) survival of anoikis or the innate immune response, (2) extravasation into the parenchyma, (3) formation of preangiogenic micrometastases, and finally (4) development of angiogenesis and macroscopic tumors.1, 2 Of all the steps, initiation of the growth of extravasated cancer cells and the development of macroscopic tumors from preangiogenic micrometastases are considered as rate-limiting.11 This suggests that liver metastases are highly dependent on the interactions between tumor cells (or tumor stem cells) and tumor-activated stromal factors in the liver. Recent studies indicate that HSCs may be one such important stromal factor and are discussed below.
How Do HSCs Contribute to the Prometastatic Liver Microenvironment?
HSCs Transdifferentiate into Myofibroblasts that Promote Tumor Growth.
Similar to the HSC activation process following liver injury, quiescent and nondividing HSCs acquire dramatic phenotypic changes upon activation by cancer cells, and transdifferentiate into myofibroblasts. The phenotypic changes include expression of α-smooth muscle actin (α-SMA) and tenascin C, development of actin stress fibers, increased motility and proliferation, and increased production of growth factors and ECM constituents. Liver metastases of pancreatic cancer in mice are surrounded by myofibroblasts (Fig. 2). Although myofibroblasts can derive from HSCs, bone marrow–derived fibrocytes, portal tract fibroblasts, hepatocytes, or cholangiocytes after epithelial–mesenchymal transition, HSCs are a predominant cell type that is activated and transdifferentiated into myofibroblasts when micrometastases develop in the sinusoidal area of liver lobules.1
Tumor cell–activated HSCs express α-SMA and contribute to the desmoplastic reaction of liver metastases. Human L3.6 pancreatic cancer cells were implanted into mouse livers by portal vein injection. α-SMA immunofluorescence (green) was performed on cryosections containing micrometastases (upper panels) or macrometastases (lower panels). Cell nuclei were counterstained by ToTo-3 (blue). Note that foci of micrometastases are surrounded by α-SMA positive myofibroblasts and that intrametastatic stroma contains abundant myofibroblasts. M: micrometastases; L: liver. Bars: 100 μM.
Accumulating in vitro and in vivo data suggest that activated HSCs promote tumor cell migration, growth, and survival. For example, coculture of HSCs with tumor cells in vitro significantly increased invasion and proliferation of tumor cells.12 Similarly, in a three-dimensional spheroid coculture system, HSCs promoted growth of tumor cells and diminished the extent of central necrosis of tumor cell spheroids.13 Consistent with these data, conditioned medium of activated HSCs was shown to promote the proliferation, migration, or invasion of tumor cells in vitro.13-17_In vivo_, coimplantation of HSCs or myofibroblasts with tumor cells into mice resulted in a larger tumor mass that correlated with enhanced angiogenesis.13-15, 18, 19 Furthermore, portal vein implantation of Lewis lung carcinoma cells into mouse livers demonstrated that metastatic growth in the liver was associated with higher densities of myofibroblasts.20 Ju et al. have evaluated the prognostic potential of activated HSCs in 130 human hepatocellular carcinoma (HCC) cases and found that activated HSCs independently contributed to high recurrence or death rates.21 Activated HSCs were also associated with higher rates of early recurrence, suggesting that they may potentiate the further dissemination of tumor cells into new areas of the liver.21 Similarly, patients with high α-SMA expression exhibited the worst outcome from intrahepatic cholangiocarcinoma.12 Taken together, these data suggest that activated HSCs may create a reactive stroma that facilitates tumor growth in the liver. A discussion of the mechanisms by which they do so follows (Fig. 1).
HSCs Supply Tumor Cells with Growth Factors and Cytokines.
Activated HSCs produce an increased number of growth factors and cytokines to stimulate the proliferation, adhesion, and migration of cancer cells. Shimizu et al. have identified that conditioned medium of activated HSCs contained PDGF-AB, hepatocyte growth factor (HGF), and TGF-β, which were able to enhance the proliferation and migration of colon carcinoma LM-H3 cells in vitro.17 These data were confirmed by Amann et al., who showed that conditioned medium of activated HSCs contained HGF.13 Furthermore, TGF-β derived from HSCs acted on tumor cells and governed tumorigenesis in a paracrine fashion, leading to tumor-progressive and autocrine TGF-β signaling in tumor cells.18 Recently, stromal cell-derived factor 1 (SDF-1) was found to be released by activated HSCs within the liver metastases, and CXCR4 (chemokine [C-X-C motif] receptor 4), the ligand of SDF-1, was found to be expressed in colorectal cancer cells.22_In vitro_, this SDF-1/CXCR4 paracrine signaling promoted tumor cell invasion and protected tumor cells from apoptosis.22 In unpublished data, we have also demonstrated that myofibroblast-derived PDGF-BB is a potent survival factor for cholangiocarcinoma cells. Taken together, these data support the concept that activated HSCs promote tumor cell growth by supplying them with growth factors and cytokines.
HSCs Contribute to a Reactive Tumor Stroma by Regulating ECM Turnover.
A high degree of ECM remodeling favors tumor invasion and progression in the liver.23 Both MMP and TIMP2 play a key role in degrading basement membranes, thereby allowing cancer cells to cross tissue boundaries and develop into metastases. By performing in situ hybridization and zymography, Musso et al. found that both MMP2 and TIMP2 messenger RNA were expressed in activated HSCs at the invasive front of liver metastases, and a higher level of MMP2 messenger RNA and enzymatic activity was detected in liver metastases than in nontumoral liver samples.24, 25 In addition, activated HSCs at the invasive front of human liver metastases were found to express a secreted form of ADAM9 (a disintegrin and metallopeptidase 9).16 This molecule was shown to be able to cleave laminin and bind to tumor cells, thus promoting invasion of tumor cells.16 These data indicate that HSCs may facilitate tumor invasion by producing proteolytic enzymes involved in the degradation of ECM.
Activated HSCs are a major cell type for ECM production during the pathogenesis of liver fibrosis,4, 5 and this process may also contribute to the prometastatic growth effects of HSCs. In the liver tumor microenvironment, TGF-β1 released by tumor cells induces HSCs to produce increased amounts of ECM constituents such as fibronectin and collagen I. These ECM components constitute a microenvironment in which tumor cells adhere and grow. In addition to providing a physical support to tumor cells, these ECM components also regulate the adhesion, migration, and survival of tumor cells by binding to and activating integrins on the surface of tumor cells.26, 27 For example, ECM-mediated activation of phosphoinositide 3-kinase and its downstream targets in tumor cells protects tumor cells from genotoxin-induced cell cycle arrest and subsequent apoptosis, contributing to tumor chemoresistance.28 In addition, the poorly vascularized architecture associated with desmoplasia contributes to tumor chemoresistance by imposing a barrier to drug delivery.29 In summary, HSC-regulated ECM turnover may play a pivotal role for invasion and survival of tumor cells.
HSCs Promote Tumor Angiogenesis.
Upon activation, HSCs express not only α-SMA, but also a large panel of smooth muscle cell markers, including smooth muscle myosin heavy chain, hi-calponin, h-caldesmon, and myocardin, indicating that HSCs may mimic functions of pericytes during angiogenesis.30 Indeed, a functional three-dimensional spheroid coculture of ECs with HSCs resulted in differentiation into a core of HSCs and a surface layer of ECs, representing an inside-outside model of the physiological assembly of blood vessels.30 Similarly, liver sinusoidal ECs and HSCs formed capillary-like sprouts in gel angiogenesis assays.30, 31 Mechanistically, activated HSCs produce multiple angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietin 1 or 2, which stimulate EC function by activating their respective receptors on the surface of ECs.15, 32-35 Generation of VEGF by HSCs was also potentiated by hypoxia,34 an atmosphere that is common in the tumor microenvironment. In addition, HSC-derived ECM may also promote angiogenesis by activating integrin-mediated signaling cascades in ECs.28
Our laboratory has recently investigated the role of myofibroblasts in tumor angiogenesis and tumor growth by performing coimplantation of tumor cells and myofibroblasts into syngeneic mice. Perturbation of adhesion and migration signaling of myofibroblasts resulted in poor integration of coimplanted myofibroblasts into tumor stroma, which was associated with lower microvessel densities in tumors and impaired tumor growth in mice.19, 36 Thus, both in vitro and in vivo data suggest that myofibroblasts and/or activated HSCs may function as pericytes and play a proangiogenic role in liver metastases.
HSCs Suppress the Antitumor Immune Response.
Although the desmoplastic reaction has been thought to create a physical barrier separating tumor cells from inflammatory cells, thereby protecting tumor cells from immune attack, the immunomodulatory role of HSCs has only recently begun to receive attention. Activated HSCs were able to inhibit T cell proliferation in vitro, and this effect was mediated by secretion of B7-homolog 1, a molecule that binds to its receptors on T cells, thereby inhibiting T cell proliferation and inducing T cell apoptosis.37, 38 Zhao et al. recently examined the lymphocyte infiltration of tumors and found fewer CD3+, CD4+, and CD8+ lymphocytes in tumor samples derived from coimplantation of HSCs and HCCs than in samples derived from HCC alone. Furthermore, they found that the apoptotic index of monocytes was two times higher in tumors derived from coimplantation than from HCC alone.15 In addition to these data, multiple studies have shown that activated HSCs produce TGF-β, which possesses a potent immunosuppressive activity.39 Thus, activated HSCs may contribute to a prometastatic microenvironment by suppressing the antitumor immune response.
HSCs Are Activated by Tumor Cells
Recent evidence suggests that HSCs are activated by tumor cells. The importance of this lies in the fact that activation of HSCs, in turn, can promote tumor growth through the aforementioned mechanisms. Shimizu et al. showed that intrasplenically injected tumor cells migrated into the space of Disse at 2 days after injection, where they proliferated in close association with HSCs, suggesting that tumor cells may interact with and activate HSCs directly in vivo.17 Their hypothesis was later supported by data showing that conditioned medium of tumor cells was able to induce HSC activation in vitro.14 Conditioned medium of tumor cells promoted HSC proliferation in a dose-dependent manner and induced the expression of α-SMA and formation of α-SMA–positive stress fibers in HSCs, which are characteristic of transdifferentiated myofibroblasts.14 In our laboratory, we found that treatment of quiescent HSCs with TGF-β1, a cytokine released by cancer cells that is abundant in the hepatic tumor microenvironment, induced myofibroblast transdifferentiation of HSCs in vitro.20 Taken together, these data suggest bidirectional interactions between tumor cells and HSCs in vivo.
The activation of HSCs in the tumor microenvironment is a complex process that requires participation of paracrine stimuli of tumor cells and intracellular factors within HSCs. TGF-β and PDGF are the two most potent factors regulating HSC activation in vivo. The action of TGF-β on HSC activation is mediated by the canonical TGF-β/Smad-dependent signaling pathway.20 PDGF is one of most powerful mitogens and survival factors for HSCs, which acts by activating key signaling pathways such as Ras/Erk (extracellular signal-regulated kinase) and phosphoinositide 3-kinase in HSCs.40, 41 In addition to TGF-β and PDGF, intracellular factors promoting HSC responsiveness to external stimuli include receptor-mediated signaling cascades, ECM-mediated integrin activation signaling, the Rho family of small guanosine triphosphatases, and transcription factors. Their roles in HSC activation remain active research topics and are reviewed in detail elsewhere.40, 42, 43 Given the complex nature of the hepatic microenvironment, it is likely that other components of liver may interact with HSCs and tumor cells, thus contributing to HSC activation and metastatic growth. For example, Kupffer cells may regulate HSC activation and tumor growth by releasing TGF-β1,44 and endothelial cells may suppress HSC activation by producing nitric oxide,45, 46 a multifunctional signaling molecule that possesses antifibrotic activity.
Are HSCs a New Therapeutic Target in the Treatment of Liver Metastases?
Animal Models to Study the Role of HSCs in Liver Metastases.
Current in vivo models that are employed to study the role of HSCs in liver metastases include subcutaneous coimplantation of tumor cells and HSCs/myofibroblasts in mice, portal vein implantation of tumor cells into the liver of mice, and portal vein coimplantation of tumor cells and HSCs/myofibroblasts into the liver of mice. Subcutaneous or portal vein coimplantation of HSCs/myofibroblasts and tumor cells in mice often resulted in larger tumors.13-15, 18, 19 We recently performed portal vein implantation of tumor cells in mice and found that nitric oxide inhibited metastatic growth of pancreatic cancer cells in mouse livers by inhibiting tumor–stroma interactions,47 and that mice with deficiency of IQ motif–containing guanosine triphosphatase activating protein 1 (IQGAP1) developed significantly more liver metastases that contained higher densities of activated HSCs/myofibroblasts than did wild-type mice.20 These in vivo studies suggest that HSCs could present a new therapeutic target in the treatment of liver metastases.
Pharmacological Inhibitors Targeting HSC Activation.
Although the role of TGF-β in cancer biology is complex and involves both tumor suppression and tumor promotion, depending on the stage of malignant progression, overexpression of TGF-β is generally accepted to be associated with metastasis and poor prognosis.39, 48 In mouse models, TGF-β pathway antagonists (1D11, a mouse monoclonal pan-TGF-β neutralizing antibody; LY2109761, a chemical inhibitor of both TGF-β receptor I (TβRI) and TβRII; and TβRII:Fc fusion protein) inhibited metastases in multiple organs, including the liver.49-51 Because TGF-β is one of the most potent cytokines for HSC activation and tumor desmoplasia, anti–TGF-β pathway therapy may provide therapeutic benefits by targeting both tumor cells and tumor stroma. Currently, several agents that target TGF-β signaling are being tested in phase 1 and 2 trials in patients with metastatic malignant tumors. These include GC1008, a human TGF-β–neutralizing monoclonal antibody capable of neutralizing all three TGF-β isoforms; AP12009, an antisense molecule against TGF-β2; and LY2157299, a newly developed inhibitor of TβRI kinase.52 Thus, TGF-β antagonists may have potential for clinical use in the prevention of liver metastases, in part through inhibiting effects on the liver microenvironment.
The approved anticancer drugs imatinib mesylate (Gleevec, formerly referred to as STI571 or CGP57148B), sunitinib, and sorafenib are small molecules that specifically target multiple protein tyrosine kinases, including PDGF receptors. These drugs may inhibit the desmoplastic reaction and tumor–stroma interactions in the liver. Indeed, numerous studies using experimental liver fibrosis animal models have already demonstrated that these drugs inhibited HSC activation and liver fibrosis in vivo.31, 53-55 These small molecules are currently approved to treat cancer in patients, making it feasible to test whether they help prevent or reduce metastatic liver diseases through their inhibiting effects on desmoplasia.
Conclusions and Prospects for Future Studies
In summary, HSCs are postulated as a component of the prometastatic liver microenvironment. Tumor cells induce HSC activation, and activated HSCs in turn stimulate tumor growth. Bidirectional interactions between tumors and HSCs may function as an “amplification loop” to further enhance metastatic growth in the liver. Because the evidence in vivo that activated HSCs promote the growth of tumor cells is still scarce, recently developed mice that harbor floxed TβRII alleles56 will help us define a precise role of HSCs in liver metastases in vivo by generating HSC-specific TβRII knockout mice. The activation of HSCs is a complex process regulated by multiple factors such as TGF-β and PDGF signaling pathways, which may present as therapeutic targets in the prevention and treatment of liver metastases. As shown in multiple studies, targeting the tumor stroma may improve the efficacy of standard chemotherapy by reducing tumor interstitial fluid pressure and increasing vascular density and drug uptake by cancer cells.29, 57 It is worth investigating if targeting HSCs/myofibroblasts with TGF-β or PDGF antagonists in coordination with chemotherapy, radiotherapy, or surgery would be more effective at reducing liver metastases and increasing the survival benefit of patients by targeting both tumor cells and the tumor microenvironment.
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