Skip to main content
Download PDF

Macrophages and hepatocellular carcinoma

Cell & Bioscience volume 9, Article number: 79 (2019) Cite this article

Abstract

Hepatocellular carcinoma (HCC) is among the most prevalent and lethal cancers in the human population. HCC is an inflammation-associated cancer caused by different etiological factors. The chronic inflammation leads to continuous cycles of hepatocytes destructive–regenerative process and contributes to HCC initiation and progression. Macrophages play a crucial role in chronic liver inflammation. The tumor microenvironment plays a key role in the progression of HCC. Tumor-associated macrophages are a well-known component of the tumor microenvironment and abundantly infiltrate HCC microenvironment. The roles of macrophages in the development and progression of HCC have been recognized. The deep understanding of macrophages in HCC will be critical for developing effective HCC therapy. Targeting of macrophages might provide novel therapeutic approaches for HCC patients and is an emerging field of interest. This review summarizes the knowledge on the contribution of macrophages in the development and progression of HCC, as well as potential immunotherapy being explored in targeting macrophages.

Background

Hepatocellular carcinoma (HCC) is one of the prevalent and leading lethal cancers in worldwide [1]. The survival of HCC remains poor despite recent advances in the diagnosis and treatment over the past decades [2]. HCC is an inflammation-associated cancer caused by different etiological factors such as hepatitis virus, non-alcoholic steatohepatitis and alcohol [3, 4]. After chronic liver injury, the damaged liver tissue initiates reparative processes to restore the liver structure and function. The chronic inflammation leads to continuous cycles of hepatocytes destructive–regenerative process and contributes to HCC initiation and progression [5, 6].

The tumor microenvironment, consisting of stromal cells, endothelial cells, immune cells, inflammatory cells, cytokines and extracellular matrix, plays a key role in initiation and progression of HCC [7, 8]. The tumor microenvironment promotes to HCC cells to acquire abnormal phenotypes and recruits immune cells (macrophages, T cells) [9, 10]. Tumor-associated macrophages (TAMs) are a well-known component of the tumor microenvironment, which take part in the cancer progression and metastasis [11]. Macrophages abundantly infiltrate HCC microenvironment and are often associated with poor prognosis of HCC patients. TAMs have important roles in uncontrolled malignant growth by regulating the immune responses to HCC cells and secreting various cytokines. The roles of TAMs in HCC have been recognized, including immunosuppressive function, enhancement of caner invasion and metastasis, angiogenesis, epithelial-mesenchymal transition (EMT) and maintenance of stemness. With this regard, the deep understanding of TAMs in HCC will be critical for developing effective HCC therapy [12]. Targeting of TAMs might provide novel therapeutic approaches for HCC patients and is an emerging field of interest [13].

In this review, we systematically summarize recent findings on the specific characteristic and role of macrophages in HCC progression. Subsequently, we address the potential possibilities of targeting macrophages for HCC immunotherapy.

Liver macrophages origin and heterogeneity

Macrophages are the end cells of the mononuclear lineage characterized by phagocytic nature according with mononuclear phagocytic system and arise from myeloid progenitors and circulating monocytes [14]. Several tissue-resident macrophage populations are seeded during waves of embryonic hematopoiesis and self-maintain independently of bone marrow contribution during adulthood [15]. Macrophages are found in all tissues of adult mammals and display incredibly anatomical plastic and functional diversity [16]. Macrophages play a crucial role in the initiation, maintenance, and resolution of inflammation [17]. Macrophages exert phagocytosis, antigen presentation capacity and immune regulation effect by releasing multiple growth factors and cytokines [18] (Fig. 1). Liver macrophages are composed of Kupffer cells and monocytes. Kupffer cells are self-sustaining, non-migratory tissue-resident phagocytes and originate from yolk sac-derived precursors during embryogenesis [19]. Kupffer cells are essential for hepatic and systemic homeostasis, as they are immunogenic in nature and receive signals from the local microenvironment that prompt their functional differentiation [20]. Following their activation by danger signals, Kupffer cells modulate inflammation and recruit immune cells—including large numbers of monocytes—to the liver [21].

Fig. 1
figure 1

Macrophages origin and heterogeneity. Macrophages are the end cells of the mononuclear lineage. Erythromyeloid progenitors from yolk sac and fetal liver and HSCs from bone marrow develop into the progenitor of macrophages. Macrophages can be induced two distinct polarization phenotypes according to the spectrum of their responses by different microenvironmental stimuli. M1 macrophages exert cytotoxic function by releasing IL-1α, IL-1β, IL-12, IL-18, iNOS, and TNF-α which are induced by LPS, IFN-γ and GM-CSF. M2 macrophages exert anti-inflammatory activities by express low IL-12, high IL-10, arginase 1 and PD-L1 which are induced by IL-4, IL-10, IL-13, M-CSF and helminth. Arg-1, arginine-1; HSCs, hematopoietic stem cells; iNOS, inducible nitric oxide synthase; IFN-γ, interferon-γ; LPS, lipopolysachharide; GM-CSF, granulocyte–macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; TNF-α, tumor necrosis factor α

Full size image

However, this definition is inadequate as macrophages have several origins during ontogeny and each of these different lineages persist into adulthood [22]. Other functional classifications of macrophages have included binary classifications that refer to inflammatory states. These include the activated macrophage and alternatively activated macrophage categories, and the derivative M1 and M2 categories for these types of macrophage in the non-pathoen-driven condition [23, 24]. Macrophages can be induced two distinct polarization phenotypes according to the spectrum of their responses by different microenvironmental stimuli, namely, the classically activated M1 and the alternatively activated M2 macrophages [25,26,27]. The two polarization phenotypes have almost contrarious functions on each other [28].

M1 phenotype is the classically activated macrophage which exerts pro-inflammatory properties, has high antigen presentation and promotes the function of T cells [29]. M1 macrophage exerts cytotoxic function by releasing nitric oxide (NO) and reactive oxygen species (ROS) [30,31,32]. M1 phenotype is stimulated by microbial products (e.g. lipopolysaccharide) or pro-inflammatory cytokines (e.g. IFN-γ, TNF, or Toll-like receptor ligands). M1 macrophage is characterized by high production of HLA-DR and many pro-inflammatory cytokines like IL-1, IL-6, IL-12, IL-23, TNFα, Type I IFN, CXCL1-3, CXCL-5, and CXCL8-10 [24, 33]. M2 phenotype is the alternatively activated macrophage which exerts anti-inflammatory activities, has immunoregulatory functions and promotes tissue repair [34]. M2 macrophage is induced by Th2 cytokine IL-4, IL-10, IL-13 and glucocorticoids. M2 macrophage is characterized by high production of CCR2, CXCR1, CXCR2, CD163, DC-SIGN, Dectin-1, mannose receptor, scavenger receptor A and B-1 [35]. M2 macrophage expresses high PD-L1 and anti-inflammatory cytokine IL-10, low level of pro-inflammatory cytokine IL-12 [36].

The actual mechanism of macrophage polarization is entirely unclear by now because of the intense crosstalk between macrophage polarization and microenvironment. In recent years, researchers have clarified that macrophage polarization was involved in the progress of cancer. IL-6/STAT3 signaling pathway intermediates the polarization of macrophage during the development of HCC. The inhibition of IL-6/STAT3 pathway turned macrophages into M1-type and enhance the effects of M1 macrophages on HCC cells [37]. There is tentative evidence that macrophage polarization can be switched in response to tumor microenvironment [36]. The deep understanding of the role of macrophages in cancer is of vital importance to development of novel biological target therapies.

Macrophages as double-edged sword in hepatocarcinogenesis

Chronic liver inflammation which leads to fibrosis and cirrhosis is key in the progression of HCC [38]. Resident hepatic macrophages, termed Kupffer cells, play essential roles in the pathogenesis of chronic liver inflammation. Kupffer cells which predominantly localize within the lumen of the liver sinusoids become activated M1 or M2 macrophages in response to chronic liver injury. Chronic liver inflammation is regulated by a balance of between the two types of Kupffer cells: the anti-inflammatory of M1 macrophages and the pro-inflammatory of M2 macrophages [39]. It seems that M1 macrophages suppresses early HCC tumorigenesis by eliminating the cancer cells as soldiers of adaptive immunity. However, macrophages undergo an M2 to M1 phenotypic shift during the tumor progression of HCC [40, 41]. M2 macrophages promote cancer cells proliferation and invasion by suppressing the adaptive immune system.

Expression of NADPH oxidase 1 by liver macrophages induces the production of inflammatory cytokines and promotes tumor development in mice given injection of diethylnitrosamine (DEN) [42]. CCl4-induced chronic liver injury promotes HCC cells seeding and growth in liver. During the tumors developing, M2 pro-tumor monocyte-derived macrophages infiltrated within the tumors, associated with overexpression MMP-2 and -9 [43]. The proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a pivotal determinant of Kupffer cell, and controls the development and progression of HCC [44]. Hippo signaling is a major oncosuppressive pathway in HCC, and loss it in hepatocytes results in increased macrophage infiltration. Hippo signaling inhibits protumoural microenvironment by suppressing macrophage infiltration through the inhibition of Yap-dependent Mcp1 expression [45]. M2 macrophage activation was associated with chronic hepatitis C infection-induced liver fibrogenesis in a humanized mouse model, and HCV-activated monocytes/macrophages promoted hepatic stellate cell activation [46]. In the liver, steatosis often proceeds cancer formation. Debebe et al. demonstrated that infiltrating macrophages as a key source for steatosis-induced Wnt expression. Wnt/β-catenin is a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals [47]. Western diet-induced NASH accelerates HCC progression in a carcinogen initiated model via upregulation of hif-1α mediated IL-10 M2 macrophages polarization [48]. Leukocyte cell-derived chemotaxin-2 (LECT2) is a key player in liver tumorigenesis because LECT2 can controls inflammatory monocytes to constrain the growth and progression of HCC [49]. Increased expression of Six1 in macrophages can stimulate the growth and invasion of HCC by elevating MMP-9 expression [50].

Liver macrophages are also involved in the anti-tumor response of HCC development and progression. NAFLD causes selective intrahepatic CD4+ T lymphocyte loss and promotes hepatocarcinogenesis in mouse models and human samples. The interaction of hepatic macrophages with CD4+ T lymphocytes prevents hepatocarcinogenesis [51]. The CCL2-CCR2 axis is necessary for clearance of pre-cancerous senescent hepatocytes. Senescent hepatocytes secreted CCL2 in a mouse model of oncogene-induced senescence. CCL2 recruited CCR2+ pro-inflammatory monocyte-derived macrophages. Senescence-associated CCL2-CCR2 signaling acts as tumor suppressive in early stages of liver tumorigenesis [52]. The endocannabinoid system exerts key roles in the development of liver fibrosis and fatty liver. But cannabinoid receptor 2 that was predominantly expressed in macrophages seem to have antitumor effects by recruiting CD4+ T cells [53].

Tumor-associated macrophages and hepatocellular carcinoma

Recruitment of macrophages in HCC tissues

Macrophages were recruited into HCC tissue by up-regulation HMGB1 which was heightened expression by hypoxia via HIF1α. High expression of long non-coding RNA Hox antisense intergenic RNA (HOTAIR) is associated with poor prognosis in HCC. HOTAIR regulates CCL2 expression, which may be involved in the recruitment of macrophages and MDSCs to the tumor microenvironment [54]. Abundant macrophages infiltration is a common feature of malignant tumors and the macrophages around the tumoral region were termed tumor-associated macrophages (TAMs). A growing number of studies showed that TAMs promote tumor cell proliferation, angiogenesis, invasion and metastasis. TAMs represent the predominant type of leukocytes in HCC and play crucial roles during HCC progression. TAMs are located in the stroma of HCC tissue and are polarized toward M2 phenotype [55]. Until now, the contribution of TAMs to the development and progression of HCC has been only partially unraveled. The data of immunogenomic analysis by using The Cancer Genome Atlas (TCGA) show that HCC tissue enrich M2 macrophages and tumor microenvironment in HCC is usually dominated by immune regulatory cells [56, 57].

Increased TAMs are related to poor prognosis in HCC patients after the surgical resection [58]. Yeung et al. showed that M2 macrophages contribute to poor prognosis in HCC and promote tumor growth and invasiveness through CCL22-induced EMT [59]. In many studies, CD68 by immunohistochemical staining is frequently used as an indicator for TAMs. Additionally, CD86 (M1), or CD163 and CD206 (M2) are proposed to distinguish between M1 and M2 macrophages in cancers [60, 61]. Dong et al. showed that low presence of CD86+ M1 macrophages and high presence of CD206+ M2 macrophages were correlated with aggressive phenotypes of HCC, combined analysis of CD86 and CD206 provided a better indicator for prognosis [62]. HCC occurs more frequently and aggressively in males than in females in the transgenic zebrafish. These tumors of male Zebrafish were more heavily infiltrated with TAMs. This study showed that TAM infiltration was one of the primary factors in the gender disparity of HCC development [63]. ST18 is critical for liver cancer progression and maintenance in a mouse model. TAMs induced epithelial cells expression ST18, ST18 mediated mutual epithelium-macrophage dependency in liver carcinogenesis [64]. In a cohort from Australia, this study showed that soluble CD163 which is a specific macrophage activation marker may predict a rapid HCC progression [65]. The main role of TAMs is to prevent NK cells and other lymphocytes by cytokines of IL-10 and TGF-β [66]. The macrophages from intra-tumoral regions of HCC express CD48 proteins, which induced NK cell dysfunction by blocking CD48 receptor 2B4 on NK cells [67].

Recent investigations in innate immune memory revealed that macrophages could be trained by IGF-1 and IGF-2 with an altered responsiveness [68, 69]. These reprogramming processes of macrophages often occurred during their maturation [70]. Such remodeling of epigenetic landscape could result from a shift in the cellular metabolism of macrophages, since tricarboxylic acid cycle metabolites such as acetyl-CoA, α-ketoglutarate, and succinate are found to play important roles in modulating the enzymes responsible for epigenetic modification [71]. Liver is the major source for IGFs production in vivo. However, the relationship between IGFs-preprogrammed macrophages and HCC remained to be illustrated. Furthermore, the detailed signaling axis connecting metabolic reprogramming, epigenetic modification, and the altered responsiveness still merits further investigation.

TAMs regulate angiogenesis

The functionally distinct macrophage populations are the characteristics of HCC microenvironment. The CCR2+ inflammatory TAM subset accumulates at the highly vascularized HCC and has pro-angiogenic properties or tumor vascularization in fibrotic livers [72]. A nested case–control study based on chronic HBV infection cohort showed that the individuals with HCC outcome had higher serum levels of IL-23. IL-23 which was produced by inflammatory macrophages enhanced macrophage-mediated angiogenesis by upregulation IL-23 receptor expressions on macrophages. IL-23 consequently promoted HCC development after chronic hepatitis B virus infection [73]. The oxidored-nitro domain-containing protein 1 (NOR1) is overexpressed in human HCC tissues associated TAMs promotes M2 alternative polarization. Abnormal expression of NOR1 protein in TAMs contributes to the development of HCC induced by DEN [74]. The chemokine receptor CXCR3 regulates the polarization of TAMs and inhibits cancer growth and angiogenesis of HCC in mice. Macrophages could regulate the expression of CXCR4 via the ERK pathway, which is a novel vascular marker for angiogenesis in HCC tissues. The anti-tumor efficacy of sorafenib combined with zoledronic acid (ZA) was improved by significantly reducing the expression of CXCR4 in vessels [75].

TAMs promote HCC cells proliferation, invasion and metastasis

IL-6 derived by macrophages can induce EMT of HCC cells, and promote HCC invasion and metastasis [76]. The innate immune response of macrophages to LPS is regulated by miR-101 through targeting dual specificity phosphatase 1 (DUSP1). Macrophage polarization is altered by Sorafenib, and the growth, metastases and EMT driven by TGF-β of HCC in vitro are reduced [77]. miR-28-5p was down-regulated in clinical HCC samples, and its levels were inversely correlated with the number of TAMs and IL-34 expression. IL-34-mediated TAMs infiltration in HCC resulted an miR-28-5p-IL-34-macrophage feedback loop, and the feedback loop modulated HCC metastasis [78]. SPON2 promotes the recruitment of M1 polarization macrophages and inhibits the metastasis of HCC through different integrin-Rho GTPase-Hippo pathways. The study showed that SPON2 is a key factor mediating the immune response against HCC cells growth and migration [79]. Macrophages activating CXCL8 increased the expression of miR-17 cluster in HCC cells, and promoted HCC cells growth and metastasis [80]. Long non-coding RNA cox-2 inhibits immune evasion and metastasis of HCC by inhibiting the polarization of M2 macrophages [81]. Tim-3 expression was increased in TAMs of HCC, and correlated with the poor survival. Tim-3 promotes the development of HCC by enhancing TGF-β-mediated alternative activation of macrophages [82].

miR-98 play a vital role in regulating macrophage polarization by modulating from M2 to M1 in HCC, and suppresses the effects of TAMs on promoting invasion and EMT in hepatocellular carcinoma [83]. The necrotic debris of HCC cells induced potent IL-1β release by TAMs with an M2 phenotype in a hypoxic-inflammatory microenvironment. IL-1β, with its increasing in the local microenvironment, up-regulated the synthesis of HIF-1α in HCC cells by cyclooxygenase-2. And the overexpression of HIF-1α enhanced EMT of hepatoma cells [84]. Yao et al. found that TAMs with an M2 phenotype facilitated the migration and EMT of HCC cells through the TLR4/STAT3 signaling pathway [85]. Aberrant activation of the NTS/IL-8 pathway promoted a pro-oncogenic inflammatory microenvironment and tumor invasion of HCC cells by inducing M2 polarization of TAMs and indirectly promoting EMT [86].

TAMs affect liver cancer stem cells

Accumulating evidence prove that liver cancer stem cells (LCSCs) account for the substantial heterogeneity and hierarchical organization of liver cancer. LCSCs play a critical role in the recurrence, metastasis, chemotherapy and radiation resistance of HCC. CD44(+) cells isolated from human HCC tissues and cell lines have CSC activities in vitro and in vivo. TAMs produce interleukin 6 and signal via STAT3 to promote expansion of HCC stem cells in human [87]. Fan et al. indicate that the TAMs promote CSC-like properties via TGF-beta1-induced EMT and may contribute to investigate the prognosis of HCC [88]. Li et al. found chronic inflammation-elicited liver progenitor cells (LPCs) can convert to LCSCs, and demonstrated that macrophage-secreted TNF-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the TNF receptor 1/Src/signal transducer and activator of transcription 3 pathway [89]. Guo et al. demonstrated that tumor-initiating cells (TICs) actively recruit M2 macrophages from as early as the single-cell stage. Activation of the Hippo pathway effector Yes-associated protein (YAP) underlies macrophage recruitment by TICs [90]. TAMs exosomes promote HCC cell proliferation and stem cell properties. Significantly lower levels of miR-125a/b in exosomes and cell lysate isolated from TAMs by using miRNA profiles assay. miR-125a/b inhibits TAMs mediated in CSCs of HCC by targeting CD90 [91]. Chen et al. found that the Wnt/β-catenin pathway was a downstream target of TNF-α and that the Wnt/β-catenin inhibitor ICG-001 partially reversed EMT and attenuated cancer stemness. TNF-α derived from M2 TAMs promotes EMT and cancer stemness through the Wnt/β-catenin pathway in SMMC-7721 cells of HCC [92].

TAMs modulate therapeutic resistance

Sorafenib, an orally administered multikinase inhibitor, is limited due to individual differences and resistance. A natural CCR2 antagonist from Abies georgei could elevate the number of CD8+ T cells in tumors via blocking tumor-associated macrophage-mediated immunosuppression to potentiate the therapeutic effect of sorafenib for liver cancer [93]. Zhou et al. investigated the roles of tumor-associated neutrophils (TANs) in progression of HCC using cell lines and immune cells isolated from patients. The result demonstrated that TANs recruit macrophages and T-regulatory Cells to promote cells growth, progression and resistance to sorafenib of HCC [94]. Oxaliplatin-based chemotherapy is widely used in the treatment of HCC. The density of TAMs in HCC samples was found to associate with the efficacy of transarterial chemoembolization (TACE). TAMs modulate resistance to oxaliplatin by inducing autophagy to avoid apoptosis in HCC [95]. M2 macrophages significantly confer tumor resistance to sorafenib by secreting HGF in a feed-forward manner in HCC [96]. The immunoregulatory mechanism of sorafenib in the treatment of HCC is to induce pyroptosis of macrophages and release NK-cell mediated cytotoxicity [97].

Macrophages-targeted therapy in hepatocellular carcinoma

TAMs have a profound influence on the progression of HCC, so there is considerable interest in therapeutic targeting TAMs for HCC immunotherapy. These strategies can be roughly divided into those [98,99,100,101,102]: inhibition of monocytes recruitment, eliminating TAMs already present in tumor tissue, functionally re-educating TAMs polarization, neutralizing the tumor-promoting products of TAMs (Fig. 2). The preclinical of agents targeting TAMs for HCC treatment are listed in Table 1.

Fig. 2
figure 2

TAMs-targeted strategies in hepatocellular carcinoma. These strategies can be roughly divided into those: (i) inhibition of monocytes recruitment; (ii) eliminating TAMs already present in tumor tissue; (iii) functionally re-educating TAMs polarization; (iv) neutralizing the tumor-promoting products of TAMs

Full size image
Table 1 Preclinical of agents targeting TAMs for HCC treatment
Full size table

Inhibition of monocytes recruitment

Inhibition of monocytes recruitment to HCC is an approach to selectively deplete TAMs. CCL2-CCR2 signaling plays a crucial role in TAMs recruitment in most cancer types, and is new target to inhibit the recruitment of monocytes. One of the main sources of CCL2 is Kupffer cells [44]. So, Kupffer cells may participate in the recruitment and education of monocyte-derived macrophages. Li et al. showed that CCL2 is highly expressed and is a prognostic factor in patients with HCC. Blockade of CCL2/CCR2 signaling that inhibits tumor-infiltrating macrophages the switch towards a pro-tumor M2 phenotype, suppresses murine liver tumor growth via activating T cell antitumor immune response [103]. 747, as a natural product from Abies georgei, is an antagonist of CCR2. Yao et al. showed 747 exhibited anticancer properties by elevating tumor-infiltrated CD8+ T cells via blocking TAM-mediated immunosuppression and potentiated the efficacy of sorafenib in mouse models of HCC [93]. In addition, Teng et al. showed the tumor-inhibiting effect of a CCL2-neutralizing antibody by reducing the population of inflammatory myeloid cells and inhibiting expression of IL6 and TNFα in a mouse model liver of HCC [104]. MicroRNAs (miRNAs) are another class of small non-coding RNA molecules that can regulate the expression of proteins at the post-transcriptional level. Ectopic expression of miR-26a in a xenograft model of HCC suppressed tumor growth and recruitment of macrophages by down-regulating macrophage colony-stimulating factor (M-CSF) expression through the PI3 K/Akt pathway [105]. Glypican-3 is overexpressed in HCC cells [106] and involve in the recruitment of TAMs in HCC tissues by banding to CCL5 and CCL3 [107]. Antibodies targeting glypican-3 which could inhibit the recruitment of M2-polarized TAMs have shown promise for advanced HCC and have been performed in several Phase I clinical trials [108, 109]. GC33, a humanized antibody against glypican-3, was well tolerated in Japanese patients with advanced HCC [109]. This study showed GPC3 expression in HCC may be associated with the clinical benefit to GC33 [108].

Eliminating TAMs

As preclinical evidence largely supports the implementation of combinatorial approaches combining targeting TAMs strategies with specific immunotherapy approaches [110]. Sorafenib [111] which is an oral multikinase inhibitor approved for use in HCC inhibited polarized macrophage-induced EMT in human HCC and their migration via the HGF-Met signaling pathway [112]. Zoledronic acid (ZA) can cause a repolarization of the macrophage population by inducing apoptosis specifically in TAMs [113, 114]. Depletion of TAMs by clodrolip or ZA enhanced the inhibitory effect of sorafenib on tumor progression, tumor angiogenesis, and lung metastasis in HCC xenograft nude mouse models [115]. ZA treatment enhanced the effects of TACE through inhibiting TAMs infiltration and tumor angiogenesis in rat HCC models [116].

Re-educating TAMs

TAM towards M1 phenotype characterizes an immune-competent microenvironment that favors tumor regression. Baicalin, a natural flavonoid present, could block orthotopic growth of implanted HCC in a mouse model. Baicalin initiated TAM reprogramming to M1-like macrophage, and promoted pro-inflammatory cytokines production [117]. 8-Bromo-7-methoxychrysin (BrMC) suppressed the expression of the M2 macrophage marker CD163 and influenced the secretion profile of cytokines of TAMs. BrMC reversed M2 polarization of TAMs induced by liver cancer stem-like cells and may be a potentially novel flavonoid agent to cure HCC [118]. PLX3397, a competitive inhibitor for CSF-1R, could delayed tumor growth murine xenograft models. PLX3397-treated tumors were polarized toward an M1-like phenotype. CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs [119].

Neutralizing the tumor-promoting products of TAMs

IL6 which was produce by TAMs during HCC progression promotes expansion of CSCs and tumorigenesis. Tocilizumab is an anti-IL-6 receptor antibody. Tocilizumab was able to inhibit TAM-stimulated activity of human HCC stem cells in vitro and in vivo by blocking IL-6 signaling [87].

Conclusion

Although macrophages are essential for the normal activity of the immune system, their aberrant regulation are related to HCC. Macrophages abundantly infiltrate HCC microenvironment and have unexpected roles in uncontrolled malignant growth by regulating the immune responses and secreting various cytokines. Recent studies have shown that TAMs play unexpected roles in the development and progression of HCC, including immunosuppressive function, enhancement of caner invasion and metastasis, angiogenesis, inducing EMT and maintenance of stemness. With this regard, the deep understanding of TAMs in HCC will be critical for developing effective HCC therapy. Targeting of TAMs following hepatectomy or liver transplantation might provide novel concepts in adjuvant immunotherapy for HCC patients in the near future. Preliminary data on TAMs-targeted drug interventions suggest that these insights can be successfully translated into new treatment options for HCC patients.

Availability of data and materials

Not applicable.

Abbreviations

HCC:

hepatocellular carcinoma

TAMs:

tumor-associated macrophages

EMT:

epithelial-mesenchymal transition

ROS:

reactive oxygen species

DEN:

diethylnitrosamine

HOTAIR:

Hox antisense intergenic RNA

TCGA:

The Cancer Genome Atlas

LPCs:

liver progenitor cells

LCSCs:

liver cancer stem cells

TICs:

tumor-initiating cells

TANs:

tumor-associated neutrophils

TACE:

transarterial chemoembolization

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Cancer J Clin. 2018;68(6):394–424.

    Article  Google Scholar 

  2. Kulik L, El-Serag HB. Epidemiology and management of hepatocellular carcinoma. Gastroenterology. 2018;54(3):395–405.

    Google Scholar 

  3. Tu T, Buhler S, Bartenschlager R. Chronic viral hepatitis and its association with liver cancer. Biol Chem. 2017;398(8):817–37.

    CAS  PubMed  Article  Google Scholar 

  4. Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2013;2013:187204.

    PubMed  Article  CAS  Google Scholar 

  5. Endig J, Buitrago-Molina LE, Marhenke S, Reisinger F, Saborowski A, Schutt J, et al. Dual role of the adaptive immune system in liver injury and hepatocellular carcinoma development. Cancer Cell. 2016;30(2):308–23.

    CAS  PubMed  Article  Google Scholar 

  6. Gao L, Lv G, Li R, Liu WT, Zong C, Ye F, et al. Glycochenodeoxycholate promotes hepatocellular carcinoma invasion and migration by AMPK/mTOR dependent autophagy activation. Cancer Lett. 2019;454:215–23.

    CAS  PubMed  Article  Google Scholar 

  7. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144(3):512–27.

    PubMed  Article  Google Scholar 

  8. Hou XJ, Ye F, Li XY, Liu WT, Jing YY, Han ZP, et al. Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis. Cell Immunol. 2018;326:52–9.

    CAS  PubMed  Article  Google Scholar 

  9. Ringelhan M, Pfister D, O’Connor T, Pikarsky E, Heikenwalder M. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–32.

    CAS  PubMed  Article  Google Scholar 

  10. Liu WT, Jing YY, Gao L, Li R, Yang X, Pan XR, et al. Lipopolysaccharide induces the differentiation of hepatic progenitor cells into myofibroblasts constitutes the hepatocarcinogenesis-associated microenvironment. Cell death and differentiation. 2019;16(14):1357–65.

    Google Scholar 

  11. Ostuni R, Kratochvill F, Murray PJ, Natoli G. Macrophages and cancer: from mechanisms to therapeutic implications. Trends Immunol. 2015;36(4):229–39.

    CAS  PubMed  Article  Google Scholar 

  12. Clappaert EJ, Murgaski A, Van Damme H, Kiss M, Laoui D. Diamonds in the rough: harnessing tumor-associated myeloid cells for cancer therapy. Front Immunol. 2018;9:2250.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  13. Petty AJ, Yang Y. Tumor-associated macrophages: implications in cancer immunotherapy. Immunotherapy. 2017;9(3):289–302.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496:445.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Ginhoux F, Guilliams M. Tissue-Resident Macrophage Ontogeny and Homeostasis. Immunity. 2016;44(3):439–49.

    CAS  PubMed  Article  Google Scholar 

  16. Gordon S, Plüddemann A, Martinez Estrada F. Macrophage heterogeneity in tissues: phenotypic diversity and functions. Immunol Rev. 2014;262(1):36–55.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. Vannella KM, Wynn TA. Mechanisms of organ injury and repair by macrophages. Annu Rev Physiol. 2017;79(1):593–617.

    CAS  PubMed  Article  Google Scholar 

  18. Arango Duque G, Descoteaux A. Macrophage cytokines: involvement in immunity and infectious diseases. Front Immunol. 2014;5:491.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol. 2017;17(5):306–21.

    CAS  PubMed  Article  Google Scholar 

  20. Scott CL, Zheng F, De Baetselier P, Martens L, Saeys Y, De Prijck S, et al. Bone marrow-derived monocytes give rise to self-renewing and fully differentiated Kupffer cells. Nat Commun. 2016;7:10321.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Okabe Y, Medzhitov R. Tissue biology perspective on macrophages. Nat Immunol. 2016;17(1):9–17.

    CAS  PubMed  Article  Google Scholar 

  22. Gautier EL, Shay T, Miller J, Greter M, Jakubzick C, Ivanov S, et al. Gene-expression profiles and transcriptional regulatory pathways that underlie the identity and diversity of mouse tissue macrophages. Nat Immunol. 2012;13(11):1118–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Gordon S. Alternative activation of macrophages. Nat Rev Immunol. 2003;3(1):23–35.

    CAS  PubMed  Article  Google Scholar 

  24. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Investig. 2012;122(3):787–95.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol. 2005;5:953.

    CAS  PubMed  Article  Google Scholar 

  26. Gordon S, Plűddemann A. Tissue macrophage heterogeneity: issues and prospects. Semin Immunopathol. 2013;35(5):533–40.

    CAS  PubMed  Article  Google Scholar 

  27. Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000 Prime Rep. 2014;6:13.

    Article  CAS  Google Scholar 

  28. Sica A, Erreni M, Allavena P, Porta C. Macrophage polarization in pathology. Cell Mol Life Sci. 2015;72(21):4111–26.

    CAS  PubMed  Article  Google Scholar 

  29. Galli SJ, Borregaard N, Wynn TA. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat Immunol. 2011;12:1035.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. Zimmerer JM, Liu XL, Blaszczak A, Avila CL, Pham TA, Warren RT, et al. Critical Role of Macrophage FcγR Signaling and Reactive Oxygen Species in Alloantibody-Mediated Hepatocyte Rejection. The Journal of Immunology. 2018:ji1800333.

  31. Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science. 2013;339(6116):172–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11(11):738–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Biswas SK, Mantovani A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889.

    CAS  PubMed  Article  Google Scholar 

  34. Sica A, Invernizzi P, Mantovani A. Macrophage plasticity and polarization in liver homeostasis and pathology. Hepatology. 2014;59(5):2034–42.

    PubMed  Article  Google Scholar 

  35. Martinez FO, Helming L, Gordon S. Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol. 2009;27:451–83.

    CAS  PubMed  Article  Google Scholar 

  36. Rhee I. Diverse macrophages polarization in tumor microenvironment. Arch Pharmacal Res. 2016;39(11):1588–96.

    CAS  Article  Google Scholar 

  37. Yin Z, Ma T, Lin Y, Lu X, Zhang C, Chen S, et al. IL-6/STAT3 pathway intermediates M1/M2 macrophage polarization during the development of hepatocellular carcinoma. J Cell Biochem. 2018;119(11):9419–32.

    CAS  PubMed  Article  Google Scholar 

  38. Li XY, Yang X, Zhao QD, Han ZP, Liang L, Pan XR, et al. Lipopolysaccharide promotes tumorigenicity of hepatic progenitor cells by promoting proliferation and blocking normal differentiation. Cancer Lett. 2017;386:35–46.

    CAS  PubMed  Article  Google Scholar 

  39. Yu LX, Ling Y, Wang HY. Role of nonresolving inflammation in hepatocellular carcinoma development and progression. NPJ Precis Oncol. 2018;2(1):6.

    PubMed  PubMed Central  Article  Google Scholar 

  40. Prieto J, Melero I, Sangro B. Immunological landscape and immunotherapy of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2015;12(12):681–700.

    CAS  PubMed  Article  Google Scholar 

  41. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331(6024):1565–70.

    CAS  PubMed  Article  Google Scholar 

  42. Liang S, Ma HY, Zhong Z, Dhar D, Liu X, Xu J, et al. NADPH oxidase 1 in liver macrophages promotes inflammation and tumor development in mice. Gastroenterology. 2018;156(4):1156–72.

    PubMed  Article  CAS  Google Scholar 

  43. Delire B, Henriet P, Lemoine P, Leclercq IA, Starkel P. Chronic liver injury promotes hepatocarcinoma cell seeding and growth, associated with infiltration by macrophages. Cancer Sci. 2018;109(7):2141–52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Can Res. 2012;72(16):3977–86.

    CAS  Article  Google Scholar 

  45. Kim W, Khan SK, Liu Y, Xu R, Park O, He Y, et al. Hepatic Hippo signaling inhibits protumoural microenvironment to suppress hepatocellular carcinoma. Gut. 2018;67(9):1692–703.

    CAS  PubMed  Article  Google Scholar 

  46. Bility MT, Nio K, Li F, McGivern DR, Lemon SM, Feeney ER, et al. Chronic hepatitis C infection-induced liver fibrogenesis is associated with M2 macrophage activation. Sci Rep. 2016;6:39520.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Debebe A, Medina V, Chen CY, Mahajan IM, Jia C, Fu D, et al. Wnt/beta-catenin activation and macrophage induction during liver cancer development following steatosis. Oncogene. 2017;36(43):6020–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Ambade A, Satishchandran A, Saha B, Gyongyosi B, Lowe P, Kodys K, et al. Hepatocellular carcinoma is accelerated by NASH involving M2 macrophage polarization mediated by hif-1alphainduced IL-10. Oncoimmunology. 2016;5(10):e1221557.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. L’Hermitte A, Pham S, Cadoux M, Couchy G, Caruso S, Anson M, et al. Lect2 controls inflammatory monocytes to constrain the growth and progression of hepatocellular carcinoma. Hepatology. 2019;69(1):160–78.

    PubMed  Article  CAS  Google Scholar 

  50. Zhang Y, Wang S, Liu Z, Yang L, Liu J, Xiu M. Increased Six1 expression in macrophages promotes hepatocellular carcinoma growth and invasion by regulating MMP-9. J Cell Mol Med. 2019;23(7):4523–33.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE, Jin P, et al. NAFLD causes selective CD4(+) T lymphocyte loss and promotes hepatocarcinogenesis. Nature. 2016;531(7593):253–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Eggert T, Wolter K, Ji J, Ma C, Yevsa T, Klotz S, et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell. 2016;30(4):533–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. Suk KT, Mederacke I, Gwak GY, Cho SW, Adeyemi A, Friedman R, et al. Opposite roles of cannabinoid receptors 1 and 2 in hepatocarcinogenesis. Gut. 2016;65(10):1721–32.

    CAS  PubMed  Article  Google Scholar 

  54. Fujisaka Y, Iwata T, Tamai K, Nakamura M, Mochizuki M, Shibuya R, et al. Long non-coding RNA HOTAIR up-regulates chemokine (C-C motif) ligand 2 and promotes proliferation of macrophages and myeloid-derived suppressor cells in hepatocellular carcinoma cell lines. Oncol Lett. 2018;15(1):509–14.

    PubMed  Google Scholar 

  55. Sprinzl MF, Reisinger F, Puschnik A, Ringelhan M, Ackermann K, Hartmann D, et al. Sorafenib perpetuates cellular anticancer effector functions by modulating the crosstalk between macrophages and natural killer cells. Hepatology. 2013;57(6):2358–68.

    CAS  PubMed  Article  Google Scholar 

  56. Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48(4):812–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Chew V, Lai L, Pan L, Lim CJ, Li J, Ong R, et al. Delineation of an immunosuppressive gradient in hepatocellular carcinoma using high-dimensional proteomic and transcriptomic analyses. Proc Natl Acad Sci USA. 2017;114(29):E5900–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. Zhou J, Ding T, Pan W, Zhu LY, Li L, Zheng L. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer. 2009;125(7):1640–8.

    CAS  PubMed  Article  Google Scholar 

  59. Yeung OW, Lo CM, Ling CC, Qi X, Geng W, Li CX, et al. Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma. J Hepatol. 2015;62(3):607–16.

    CAS  PubMed  Article  Google Scholar 

  60. Laoui D, Van Overmeire E, Movahedi K, Van den Bossche J, Schouppe E, Mommer C, et al. Mononuclear phagocyte heterogeneity in cancer: different subsets and activation states reaching out at the tumor site. Immunobiology. 2011;216(11):1192–202.

    CAS  PubMed  Article  Google Scholar 

  61. Elliott LA, Doherty GA, Sheahan K, Ryan EJ. Human tumor-infiltrating myeloid cells: phenotypic and functional diversity. Front Immunol. 2017;8:86.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. Dong P, Ma L, Liu L, Zhao G, Zhang S, Dong L, et al. CD86(+)/CD206(+), diametrically polarized tumor-associated macrophages, predict hepatocellular carcinoma patient prognosis. Int J Mol Sci. 2016;17(3):320.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. Yan C, Yang Q, Gong Z. Tumor-associated neutrophils and macrophages promote gender disparity in hepatocellular carcinoma in zebrafish. Can Res. 2017;77(6):1395–407.

    CAS  Article  Google Scholar 

  64. Rava M, D’Andrea A, Doni M, Kress TR, Ostuni R, Bianchi V, et al. Mutual epithelium-macrophage dependency in liver carcinogenesis mediated by ST18. Hepatology. 2017;65(5):1708–19.

    CAS  PubMed  Article  Google Scholar 

  65. Kazankov K, Rode A, Simonsen K, Villadsen GE, Nicoll A, Moller HJ, et al. Macrophage activation marker soluble CD163 may predict disease progression in hepatocellular carcinoma. Scand J Clin Lab Invest. 2016;76(1):64–73.

    CAS  PubMed  Article  Google Scholar 

  66. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Investig. 2007;117(5):1155–66.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  67. Wu Y, Kuang DM, Pan WD, Wan YL, Lao XM, Wang D, et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013;57(3):1107–16.

    CAS  PubMed  Article  Google Scholar 

  68. Bekkering S, Arts RJW, Novakovic B, Kourtzelis I, van der Heijden C, Li Y, et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell. 2018;172(1–2):135–46.

    CAS  PubMed  Article  Google Scholar 

  69. Du L, Lin L, Li Q, Liu K, Huang Y, Wang X, et al. IGF-2 preprograms maturing macrophages to acquire oxidative phosphorylation-dependent anti-inflammatory properties. Cell Metab. 2019;29(6):1363–75.

    CAS  PubMed  Article  Google Scholar 

  70. Saeed S, Quintin J, Kerstens HH, Rao NA, Aghajanirefah A, Matarese F, et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science. 2014;345(6204):1251086.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. Carey BW, Finley LWS, Cross JR, Allis CD, Thompson CB. Intracellular α-ketoglutarate maintains the pluripotency of embryonic stem cells. Nature. 2014;518:413.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  72. Bartneck M, Schrammen PL, Möckel D, Govaere O, Liepelt A, Krenkel O, et al. The CCR1 + macrophage subset promotes pathogenic angiogenesis for tumor vascularization in fibrotic livers. Cell Mol Gastroenterol Hepatol. 2018;7(2):371–90.

    PubMed  PubMed Central  Article  Google Scholar 

  73. Zang M, Li Y, He H, Ding H, Chen K, Du J, et al. IL-23 production of liver inflammatory macrophages to damaged hepatocytes promotes hepatocellular carcinoma development after chronic hepatitis B virus infection. Biochim Biophys Acta Mol Basis Dis. 2018;1864(12):3759–70.

    CAS  PubMed  Article  Google Scholar 

  74. Chen S, Zheng P, Wang W, Yi M, Chen P, Cai J, et al. Abberent expression of NOR1 protein in tumor associated macrophages contributes to the development of DEN-induced hepatocellular carcinoma. J Cell Physiol. 2018;233(6):5002–13.

    CAS  PubMed  Article  Google Scholar 

  75. Meng YM, Liang J, Wu C, Xu J, Zeng DN, Yu XJ, et al. Monocytes/macrophages promote vascular CXCR75 expression via the ERK pathway in hepatocellular carcinoma. Oncoimmunology. 2018;7(3):e1408745.

    PubMed  Article  Google Scholar 

  76. Jiang J, Wang GZ, Wang Y, Huang HZ, Li WT, Qu XD. Hypoxia-induced HMGB1 expression of HCC promotes tumor invasiveness and metastasis via regulating macrophage-derived IL-6. Exp Cell Res. 2018;367(1):81–8.

    CAS  PubMed  Article  Google Scholar 

  77. Wei X, Tang C, Lu X, Liu R, Zhou M, He D, et al. MiR-101 targets DUSP1 to regulate the TGF-beta secretion in sorafenib inhibits macrophage-induced growth of hepatocarcinoma. Oncotarget. 2015;6(21):18389–405.

    PubMed  PubMed Central  Article  Google Scholar 

  78. Zhou SL, Hu ZQ, Zhou ZJ, Dai Z, Wang Z, Cao Y, et al. miR-28-5p-IL-34-macrophage feedback loop modulates hepatocellular carcinoma metastasis. Hepatology. 2016;63(5):1560–75.

    CAS  PubMed  Article  Google Scholar 

  79. Zhang YL, Li Q, Yang XM, Fang F, Li J, Wang YH, et al. SPON2 promotes M1-like macrophage recruitment and inhibits hepatocellular carcinoma metastasis by distinct integrin-Rho GTPase-Hippo pathways. Can Res. 2018;78(9):2305–17.

    CAS  Article  Google Scholar 

  80. Yin Z, Huang J, Ma T, Li D, Wu Z, Hou B, et al. Macrophages activating chemokine (C-X-C motif) ligand 8/miR-17 cluster modulate hepatocellular carcinoma cell growth and metastasis. Am J Transl Res. 2017;9(5):2403–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Ye Y, Xu Y, Lai Y, He W, Li Y, Wang R, et al. Long non-coding RNA cox-2 prevents immune evasion and metastasis of hepatocellular carcinoma by altering M1/M2 macrophage polarization. J Cell Biochem. 2018;119(3):2951–63.

    CAS  PubMed  Article  Google Scholar 

  82. Yan W, Liu X, Ma H, Zhang H, Song X, Gao L, et al. Tim-3 fosters HCC development by enhancing TGF-beta-mediated alternative activation of macrophages. Gut. 2015;64(10):1593–604.

    CAS  PubMed  Article  Google Scholar 

  83. Li L, Sun P, Zhang C, Li Z, Cui K, Zhou W. MiR-98 modulates macrophage polarization and suppresses the effects of tumor-associated macrophages on promoting invasion and epithelial–mesenchymal transition of hepatocellular carcinoma. Cancer Cell Int. 2018;18:95.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  84. Zhang J, Zhang Q, Lou Y, Fu Q, Chen Q, Wei T, et al. Hypoxia-inducible factor-1alpha/interleukin-1beta signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment. Hepatology. 2018;67(5):1872–89.

    CAS  PubMed  Article  Google Scholar 

  85. Yao RR, Li JH, Zhang R, Chen RX, Wang YH. M2-polarized tumor-associated macrophages facilitated migration and epithelial-mesenchymal transition of HCC cells via the TLR4/STAT3 signaling pathway. World J Surg Oncol. 2018;16(1):9.

    PubMed  PubMed Central  Article  Google Scholar 

  86. Xiao P, Long X, Zhang L, Ye Y, Guo J, Liu P, et al. Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. Oncoimmunology. 2018;7(7):e1440166.

    PubMed  PubMed Central  Article  Google Scholar 

  87. Wan S, Zhao E, Kryczek I, Vatan L, Sadovskaya A, Ludema G, et al. Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology. 2014;147(6):1393–404.

    CAS  PubMed  Article  Google Scholar 

  88. Fan QM, Jing YY, Yu GF, Kou XR, Ye F, Gao L, et al. Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett. 2014;352(2):160–8.

    CAS  PubMed  Article  Google Scholar 

  89. Li XF, Chen C, Xiang DM, Qu L, Sun W, Lu XY, et al. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology. 2017;66(6):1934–51.

    CAS  PubMed  Article  Google Scholar 

  90. Guo X, Zhao Y, Yan H, Yang Y, Shen S, Dai X, et al. Single tumor-initiating cells evade immune clearance by recruiting type II macrophages. Genes Dev. 2017;31(3):247–59.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Wang Y, Wang B, Xiao S, Li Y, Chen Q. miR-125a/b inhibits tumor-associated macrophages mediated in cancer stem cells of hepatocellular carcinoma by targeting CD90. J Cell Biochem. 2019;120(3):3046–55.

    CAS  PubMed  Article  Google Scholar 

  92. Chen Y, Wen H, Zhou C, Su Q, Lin Y, Xie Y, et al. TNF-alpha derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/beta-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res. 2019;378(1):41–50.

    CAS  PubMed  Article  Google Scholar 

  93. Yao W, Ba Q, Li X, Li H, Zhang S, Yuan Y, et al. A natural CCR93 antagonist relieves tumor-associated macrophage-mediated immunosuppression to produce a therapeutic effect for liver cancer. EBioMedicine. 2017;22:58–67.

    PubMed  PubMed Central  Article  Google Scholar 

  94. Zhou SL, Zhou ZJ, Hu ZQ, Huang XW, Wang Z, Chen EB, et al. Tumor-associated neutrophils recruit macrophages and t-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology. 2016;150(7):1646–58.

    CAS  PubMed  Article  Google Scholar 

  95. Fu XT, Song K, Zhou J, Shi YH, Liu WR, Shi GM, et al. Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma. Cancer Cell Int. 2019;19:71.

    PubMed  PubMed Central  Article  Google Scholar 

  96. Dong N, Shi X, Wang S, Gao Y, Kuang Z, Xie Q, et al. M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br J Cancer. 2019;121(1):22–33.

    PubMed  PubMed Central  Article  Google Scholar 

  97. Hage C, Hoves S, Strauss L, Bissinger S, Prinz Y, Poschinger T, et al. Sorafenib induces pyroptosis in macrophages and triggers natural killer cell-mediated cytotoxicity against hepatocellular carcinoma. Hepatology. 2019. https://doi.org/10.1002/hep.30666.

    Article  PubMed  Google Scholar 

  98. Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology. 2013;138(2):93–104.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Zheng X, Turkowski K, Mora J, Brune B, Seeger W, Weigert A, et al. Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget. 2017;8(29):48436–52.

    PubMed  PubMed Central  Google Scholar 

  100. Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017;14(7):399–416.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Sawa-Wejksza K, Kandefer-Szerszen M. Tumor-Associated Macrophages as Target for Antitumor Therapy. Arch Immunol Ther Exp (Warsz). 2018;66(2):97–111.

    CAS  Article  Google Scholar 

  102. Degroote H, Van Dierendonck A, Geerts A, Van Vlierberghe H, Devisscher L. Preclinical and clinical therapeutic strategies affecting tumor-associated macrophages in hepatocellular carcinoma. J Immunol Res. 2018;2018:7819520.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR103 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut. 2017;66(1):157–67.

    CAS  PubMed  Article  Google Scholar 

  104. Teng KY, Han J, Zhang X, Hsu SH, He S, Wani NA, et al. Blocking the CCL2-CCR104 axis using CCL2-neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model. Mol Cancer Ther. 2017;16(2):312–22.

    CAS  PubMed  Article  Google Scholar 

  105. Chai ZT, Zhu XD, Ao JY, Wang WQ, Gao DM, Kong J, et al. microRNA-26a suppresses recruitment of macrophages by down-regulating macrophage colony-stimulating factor expression through the PI3 K/Akt pathway in hepatocellular carcinoma. J Hematol Oncol. 2015;8:56.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. Yao M, Wang L, Dong Z, Qian Q, Shi Y, Yu D, et al. Glypican-3 as an emerging molecular target for hepatocellular carcinoma gene therapy. Tumour Biol. 2014;35(6):5857–68.

    CAS  PubMed  Article  Google Scholar 

  107. Takai H, Ashihara M, Ishiguro T, Terashima H, Watanabe T, Kato A, et al. Involvement of glypican-3 in the recruitment of M2-polarized tumor-associated macrophages in hepatocellular carcinoma. Cancer Biol Ther. 2009;8(24):2329–38.

    CAS  PubMed  Article  Google Scholar 

  108. Zhu AX, Gold PJ, El-Khoueiry AB, Abrams TA, Morikawa H, Ohishi N, et al. First-in-man phase I study of GC33, a novel recombinant humanized antibody against glypican-3, in patients with advanced hepatocellular carcinoma. Clin Cancer Res. 2013;19(4):920–8.

    CAS  PubMed  Article  Google Scholar 

  109. Ikeda M, Ohkawa S, Okusaka T, Mitsunaga S, Kobayashi S, Morizane C, et al. Japanese phase I study of GC33, a humanized antibody against glypican-3 for advanced hepatocellular carcinoma. Cancer Sci. 2014;105(4):455–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27(4):462–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.

    CAS  PubMed  Article  Google Scholar 

  112. Deng YR, Liu WB, Lian ZX, Li X, Hou X. Sorafenib inhibits macrophage-mediated epithelial-mesenchymal transition in hepatocellular carcinoma. Oncotarget. 2016;7(25):38292–305.

    PubMed  PubMed Central  Article  Google Scholar 

  113. Rogers TL, Wind N, Hughes R, Nutter F, Brown HK, Vasiliadou I, et al. Macrophages as potential targets for zoledronic acid outside the skeleton-evidence from in vitro and in vivo models. Cell Oncol (Dordr). 2013;36(6):505–14.

    CAS  PubMed  Article  Google Scholar 

  114. Coscia M, Quaglino E, Iezzi M, Curcio C, Pantaleoni F, Riganti C, et al. Zoledronic acid repolarizes tumour-associated macrophages and inhibits mammary carcinogenesis by targeting the mevalonate pathway. J Cell Mol Med. 2010;14(12):2803–15.

    CAS  PubMed  Article  Google Scholar 

  115. Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX, et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res. 2010;16(13):3420–30.

    CAS  PubMed  Article  Google Scholar 

  116. Zhou DY, Qin J, Huang J, Wang F, Xu GP, Lv YT, et al. Zoledronic acid inhibits infiltration of tumor-associated macrophages and angiogenesis following transcatheter arterial chemoembolization in rat hepatocellular carcinoma models. Oncol Lett. 2017;14(4):4078–84.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. Tan HY, Wang N, Man K, Tsao SW, Che CM, Feng Y. Autophagy-induced RelB/p52 activation mediates tumour-associated macrophage repolarisation and suppression of hepatocellular carcinoma by natural compound baicalin. Cell Death Dis. 2015;6:e1942.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Sun S, Cui Y, Ren K, Quan M, Song Z, Zou H, et al. 8-bromo-7-methoxychrysin reversed M2 polarization of tumor-associated macrophages induced by liver cancer stem-like cells. Anticancer Agents Med Chem. 2017;17(2):286–93.

    CAS  PubMed  Article  Google Scholar 

  119. Ao JY, Zhu XD, Chai ZT, Cai H, Zhang YY, Zhang KZ, et al. Colony-stimulating factor 1 receptor blockade inhibits tumor growth by altering the polarization of tumor-associated macrophages in hepatocellular carcinoma. Mol Cancer Ther. 2017;16(8):1544–54.

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was supported by the National Key R&D Program of China (Grant No. 2018YFA0107502); National Natural Science Foundation of China (Grant Nos. 81772940, 81702320, 81630070, 81673641, 81572444, 31700788, 81872243, 81802737); Special Funds for National Key Sci-Tech Sepcial Project of China (Grant Nos. 2018ZX10723204-005-004); Shanghai Science and Technology Committee (Grant Nos. 16ZR1400200, 16JC1405200, 16YF1415000); Science Fund for Creative Research Groups, NSFC, China (Grant No. 81521091) and Science Foundation of Wuxi People’s Hospital (Grant No. RKA201822).

Author information

Author notes

  1. Zhiqiang Tian and Xiaojuan Hou contributed equally to this work

Authors and Affiliations

  1. Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, 225 Changhai Road, Shanghai, 200438, China

    Zhiqiang Tian, Xiaojuan Hou, Wenting Liu, Zhipeng Han & Lixin Wei

  2. Department of General Surgery, Wuxi People’s Hospital Affiliated Nanjing Medical University, 299 Qingyang Road, Wuxi, 214000, China

    Zhiqiang Tian

Authors
  1. Zhiqiang Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaojuan Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wenting Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhipeng Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lixin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZT and XH designed the study and drafted the manuscript. WL performed the literature review. ZH and LW performed the literature review and edited the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhipeng Han or Lixin Wei.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Tian, Z., Hou, X., Liu, W. et al. Macrophages and hepatocellular carcinoma. Cell Biosci 9, 79 (2019). https://doi.org/10.1186/s13578-019-0342-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13578-019-0342-7

Keywords

  • Hepatocellular carcinoma
  • Macrophage
  • Tumor microenvironment
  • Immunotherapy

Cell & Bioscience

ISSN: 2045-3701

Contact us