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Mechanisms of Hepatocarcinogenesis Development in an Acidic Microenvironment

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Cheng Jin, You-Yi Liu and Bo-Shi Wang

Reviewed: 12 October 2022 Published: 13 November 2022

DOI: 10.5772/intechopen.108559

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Liver Cancer - Genesis, Progression and Metastasis

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Abstract

Liver cancer represents one of the most common solid tumors globally. Despite curative improvements made in liver cancer therapy these years, the 5-year survival rate of liver cancer remains poor. Understanding the mechanisms involved in the initiation and progression of liver cancer is essential for optimizing therapeutic strategies. In recent years, it has been discovered that the acidic tumor microenvironment attributed to increased glycolysis, and hypoxia contributes to liver cancer progression through promoting cancer cell proliferation, metabolic adaptation, and migration and invasion. In this paper, research advances in the mechanisms of hepatocarcinogenesis development under an acidic microenvironment are reviewed.

Keywords

  • liver cancer
  • hepatocarcinogenesis
  • mechanism
  • acidic tumor microenvironment

1. Introduction

Liver cancer is the sixth most frequently identified cancer and the third most common cause of cancer death worldwide [1]. As the early diagnosis of liver cancer is difficult, most patients are diagnosed at advanced stages and even accompanied with tumor metastasis. It is critical to fully understand the molecular mechanisms of liver cancer metastasis, which would be helpful to improve the early diagnosis, treatment, and prognosis of liver cancer patients [2]. It has been reported that abnormal blood perfusion and hypoxia, coupled with a glycolytic phenotype, generate acidic microenvironment, which promotes cancer cell proliferation, metabolic adaptation, and migration and invasion, playing an important role in tumor development and progression. However, the molecular mechanisms that coordinate the formation of the acidic microenvironment in liver cancer remain to be adequately studied [3]. Given that the tumor treatment strategies targeting acidic microenvironment contribute to the management of many tumors types [4], the study of key molecular elements affecting the acidic microenvironment is of great importance for the diagnosis and intervention of liver cancer. This paper reviews the relevant research mechanisms of hepatocarcinogenesis and development under the acidic microenvironment, aiming to provide novel insight for further research studies.

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2. Development of the tumor acidic microenvironment

The acidic microenvironment is mainly produced by tumor energy metabolism and hypoxia in solid tumors. Stephen Paget proposed the “seed and soil” hypothesis, stating that metastasizing cancer cells “seed” only in certain especially hospitable tissues, akin to seeding in “fertile soil” [5]. Since then, subsequent studies have revealed several classes of metastasis causes, including the tumor acidic microenvironment. In the 1920s, Otto Warburg first described a phenomenon that cancer cells displayed an altered metabolism, attaining energy through glycolysis at disproportionately high rates even under hypoxic conditions (Figure 1) [6]. Glucose is converted into lactic acid through glycolysis. Nevertheless, energy can still be obtained through the glutaminolysis pathway instead of glycolysis. From both pathways, high amounts of lactic acid are generated and subsequently discharged into the extracellular space between cancer cells [7, 8]. Some key transporters and enzymes, including ras, src, p53, glut, etc., are regulated in cancer cells to ensure that the impact of expanded H+ is removed. These changes enhance the rate of glucose uptake to support the rapid proliferation of tumor cells [4].

Figure 1.

Energy metabolism in acidic microenvironment.

Hypoxia-inducible factors cannot be effectively degraded by enzymes under hypoxic conditions that are mainly caused by the rapid proliferation of tumor cells, resulting in stable and sustained expression in tumor cells [9]. The proliferation, invasion, migration, and energy metabolism of tumor cells are affected by these changes.

2.1 Energy metabolism

Normal cells consume oxygen for energy production. Liver cancer aerobic glycolysis, otherwise known as the Warburg effect, to produce energy [10]. The end products of aerobic glycolysis contribute to the establishment of the acidic microenvironment. In the acidic microenvironment, liver cancer cells regulate aerobic glycolysis by activating AMP-activated protein kinase (AMPK), PI3K/activity, and other related pathways, resulting in the increased expression of related proteins and enzymes, including glucose transporter, hexokinase, fructose-6-phosphate kinase, pyruvate kinase, and so on (Figure 2) [11]. As a carrier responsible for glucose transportation across the cell membrane, glucose transporter (GLUT) promotes higher glucose uptake in liver cancer cells [12]. Hexokinase, fructose-6-phosphate kinase, and pyruvate kinase are key enzymes of glycolysis. Relevant studies have shown that inhibition of the glucose transporter, hexokinase, and pyruvate kinase can attenuate the glucose metabolism of liver cancer cells, affecting the occurrence and development of liver cancer [13, 14, 15, 16]. Upregulation of the activation ratio of phosphofructokinase [17] facilitates the adaptation of liver cancer cells to the microenvironment and accelerates the proliferation and growth of liver cancer cells. The energy needed for the proliferation of liver cancer cells is provided by these changes, and the same with the material basis required for establishment of the acidic microenvironment. By adopting a pattern of energy metabolism that is different from normal cells, the internal and external microenvironment of liver cancer cells is changed, improving their survival advantage. From this perspective, inhibiting the activity of glycolysis-related proteases in liver cancer cells may be an effective way to treat liver cancer.

Figure 2.

Various enzymes related to glucose metabolism in acidic microenvironment.

2.2 Hypoxia

Hypoxia is a key feature of liver cancer, in which hypoxia-inducible factors (HIFs) play a key role [18, 19]. As the most studied hypoxia factor in liver cancer, the adaptive response of cells to the hypoxic microenvironment can be mediated by HIF-1, which is composed of HIF-1α and HIF-1β, as heterodimers that are expressed stably only in an anoxic environment but degraded rapidly in a normoxic environment [20, 21]. A variety of genes (such as Ras, C-MYC, p53, AMPK, etc.) and signaling pathways (such as PKB/Akt, PI3K, mTOR, etc.) can be transcriptionally regulated by HIF-1 and regulate the energy production of cancer cells to maintain their proliferation and survival [22]. It has been reported [23, 24, 25, 26] that lactic acid production from of liver cancer cells can be amplified by HIF-1, which results in altering the activity of enzymes associated with glycolysis that lead to microenvironment acidification of liver cancer tissues. This inhibition can affect the growth and proliferation of liver cancer by regulating the energy metabolism. In addition, it has also been reported that liver cancer cells and tissues can upregulate the expression of HIF-1 and vascular endothelial growth factor (VEGF) during hypoxia [27, 28, 29]. VEGF is central for neovascularization of expanding tumor nodules.

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3. Maintenance of tumor acidic microenvironment

The production of lactic acid causes the tumor microenvironment to be low in pH. Tumor cells excrete H+ and acid metabolites into the extracellular environment to avoid intracellular acidosis (Figure 3). To achieve this goal, tumor cells use transporters that mainly include vacuolar-H+ATPase (V-ATPase), Na+/H+ exchanger (NHE), monocarboxylic acid transporters (MCTs), bicarbonate transporters, and hydrochloric acid transporters to expel intracellular H+. In addition, the carbonic anhydrases (CAs) can be used to regulate pH by catalyzing the reversible hydration of CO2 to form bicarbonate and a proton in aqueous solutions. The reduction of extracellular pH is sensed by other complex mechanisms that include G-protein-coupled receptors, T-cell death-related gene 8 (TDAG8), acid-sensitive ion channels (ASICs), and the transient receptor potential channels, vanillin subfamily 1(TRPV1), to regulate the tumor microenvironment [30]. We can understand the occurrence and development of liver cancer and provide favorable conditions for targeted therapy of liver cancer by studying these transporters and complex pH-sensing molecular mechanisms in liver cancer.

Figure 3.

Molecular mechanism of transport in acidic microenvironment.

3.1 Study on the mechanism of intracellular pH regulation of liver cancer in an acidic microenvironment

3.1.1 Vacuolar H+-ATPase (V-ATPase)

Vacuolar H+-adenosine triphosphatase (V-ATPase) is ubiquitously expressed in eukaryotic cells [31], being situated not only in the membranes of many organelles but also in the plasma membrane [32]. Studies have demonstrated that V-ATPase is functionally expressed in some human tumor cell lines and plays an important role in the regulation of tumor acidic microenvironment [33, 34, 35]. V-ATPase has multiple subunits, and the C subunit of V-ATPase, ATP6L, is the most thoroughly studied. Xu et al. [36] showed that the expression of ATP6L, the C subunit of V-ATPase, was elevated on the plasma membrane of liver cancer cells. As it indiscriminately inhibits V-ATPase in both mammals and non-mammals, palomycin was used to inhibit V-ATPase, thereby reducing the acid load and pH of liver cancer cells. Further, in an orthotopic xenograft model, the growth of liver cancer cells was delayed [37]. Tang et al. [38] showed that the protein expressed by LASS2 can bind to ATP6L and can inhibit the transmembrane transport of H+ by V-ATPase proton pump. In this case, the mitochondrial apoptosis pathway is activated by increasing the concentration of hydrogen ions in the cell to induce apoptosis and inhibit the growth of tumor cells. These results imply that the expression of V-ATPase is increased in liver cancer cells and involved in the regulation of intracellular pH, while the growth of liver cancer cells can be effectively delayed by its corresponding inhibition.

3.1.2 Na+/H+ exchangers (NHEs)

Na+/H+ exchangers (NHEs) are a family of membrane proteins that contribute to exchanging one intracellular proton for one extracellular sodium. The family of NHEs consists of nine known members, NHE1-9. Each isoform represents a different gene product that has unique tissue expression, membrane localization, physiological effects, pathological regulation, and sensitivity to drug inhibitors [39]. NHE1 was the first to be discovered and is often referred to as the “housekeeping” isoform of the NHE family [40]. The NHE protein is activated by increased intracellular H+, can achieve a one-to-one exchange between intracellular H+ and extracellular Na+, and excess Na+ can be regulated by Na+/K+-ATPase in cells, which is a key ingredient in preventing cellular acidosis [40]. Enhanced glycolysis increases the amount of H+ in cancer cells, by which the NHE protein is effectively activated. Yang et al. [41] showed that the expression of NHE1 was increased in liver cancer and in cells and closely related to tumor size, venous invasion, and tumor stage. Kim et al. [42] showed that curcumin combined with GR was used to inhibit NHE1 expression in liver cancer cells characterized by low pH. In addition, Li et al. [43] showed that the growth and metastasis of liver cancer cells can be inhibited by Ginsenoside (Rg3), which blocks the EGF-EGFR-ERK1/2-HIF pathway by decreasing the expression of NHE1. As these results imply that NHE1 is involved in regulating intracellular pH and is upregulated in liver cancer cells, inhibition of it can effectively delay tumor cell growth and metastasis. Further study of NHE1 may effectively inhibit the progression of liver cancer. However, the role of other subtypes of NHEs in liver cancer is unclear and needs to be further studied.

3.1.3 Monocarboxylic acid transporters (MCTs)

MCTs belong to the SLC16 gene family and consist of 14 members, in which MCT1, MCT2, and MCT4 can act as proton transporters to participate in the transport of pyruvate and lactate [44]. In the process of glycolysis a lot of lactic acid is produced by tumor cells that require large amounts of monocarboxylic acid transporters to pump these acids out of the cell to regulate pH and maintain homeostasis in the tumor cell environment, which prevents cell apoptosis caused by lactic acid accumulation [45]. The distribution of MCTs in tissues is determined by the physiological requirements of lactate metabolism (Figure 4). In general, because it has a high affinity for lactic acid, MCT1 and MCT4, which are expressed in most tissues, are mainly responsible for the transport of lactic acid inside cells. However, glucose metabolism determines the level of MCT2 expression, where its affinity for pyruvate is much higher than other MCTs molecules, and intracellular pyruvate transport is mainly completed by it. In some literature reports, MCT1 and MCT4 are highly expressed in liver cancer, and the high expression of it was significantly correlated with the malignant phenotype and prognosis of the tumor, but MCT2 expression is low in hepatocellular carcinoma [46, 47]. Chen et al. found that the expression of MCT4 was positively correlated with the expression of GLUT1 and speculated that there was a positive feedback loop between the growth of HCC and the upregulation of MCT4/GLUT1 [48]. As an antitumor drug, lonidamine effectively inhibits MCTs, and it can impair the proliferation, metastasis, and invasion of liver cancer cells by reducing glycolysis [49]. These results imply that the specific molecular mechanism of MCTs involvement in the development of liver cancer may be related to MCTs mediating the shuttle of lactate and pyruvate in and out of liver cancer cells, which prevents lactic acid from accumulating in the liver cancer microenvironment and pyruvate from being transported extracellular that inhibits the proliferation and survival of HCC cells. However, the specific molecular pathways and related mechanisms remain unclear and need to be further studied.

Figure 4.

Related mechanism of MCT in acidic microenvironment.

3.1.4 Carbonic anhydrases (Cas)

Tumor tissues are often exposed to low oxygen that can activate CAs by which H2O and CO2 are reversibly converted to HCO3 so that the chemical reaction can maintain the normal pH of the cell. CAs can be divided into four categories according to their distribution location (cell and subcellular) [50], namely cytoplasmic type (CAI, II, III, VII, XIII), mitochondrial type (cava, VB), secretory type (CAVI), and membrane-related type (CAIX, XII, XIV, XV). Among them, CAII and CAXII are the most studied in liver cancer. Xing et al. [51] showed that the expression of carbonic anhydrase II (CAII) was significantly upregulated in liver cancer compared with serum CAII concentrations in the normal population and among patients with non-recurrent liver cancer. Further investigating the molecular mechanisms involved suggests that CaII increases the migration and invasion of liver cancer cells by activating the epithelial-mesenchymal transition (EMT) pathway. Finkelmeier et al. [52] showed that the serum CAXII level was significantly increased in patients with advanced liver cancer (BCLC and ALBI scores). Zeng et al. [53] showed that the high expression of CAXII was associated with poor prognosis in patients with liver cancer. UDA et al. [54] showed that the changes in intracellular pH can be caused by knocking out CAII, which inhibits the progression of liver cancer. Han et al. [55] showed that the proliferation of liver cancer can be inhibited by tiliroside by blocking CAXII. These findings suggest that CAXII may also be a prognostic indicator of poor prognosis in patients with liver cancer. The molecular mechanisms of CAII and CAXII affecting the progression of liver cancer need to be further explored, and the specific roles of other subtypes of CAs in the progression of liver cancer need to be further determined. However, according to current studies, CAII and CAXII may be potential treatment targets sites for liver cancer.

3.2 Study on the mechanism of extracellular pH regulation of liver cancer in an acidic microenvironment

3.2.1 Acid sensing ion channels (ASICs)

Changes in extracellular pH can be sensed by acid-sensitive ion channels (ASICs). Six ASICs subunits are encoded by four genes have been cloned, which comprise ASIC1a, 1B, 2A, 2B, 3, and 4 [56]. A large number of crucial biological functions, such as inflammation, ischemia, and tissue acidification of tumors, are represented in ASICs. ASIC1a is of particular interest as one of its six subunits that play an important physiological and pathological role from mediating Ca2+influx [57]. Our team has been working on ASIC1a for many years since it is involved in the proliferation, invasion, and metastasis of liver cancer. When liver cancer tissues were in a pH 6.5 microenvironment, the expression of ASIC1a in liver cancer tissues was significantly higher than that in adjacent non-tumor tissues in previous studies [3]. ASIC1a protects against phosphorylation and ubiquitination of β-catenin and promotes β-catenin nuclear aggregation to stimulate the proliferation of HCC cells. ASIC1a can promote invasion and migration of liver cancer as demonstrated by cell scratch and trans-well assay data [58]. Downstream differentially expressed genes of ASIC1a were mainly concentrated in the transcription factor AP-1 in the MAPK-related signaling pathways [59]. These findings suggest that intracellular Ca2+ concentrations and changes in downstream AP-1 expression can be increased by ASIC1a to affect the migration and invasion of liver cancer. Thus, ASIC1a is an effective target for the treatment of liver cancer, and a precise study of the relevant mechanisms may provide a new diagnostic method or target.

3.2.2 Transient receptor potential channels vanillin subfamily 1 (TRPV1)

TRPV1 channel, which is a cation channel with high selectivity for Ca2+, is activated by excessive extracellular H+ in the absence of other stimuli [60]. Miao et al. [61] demonstrated that the high expression of TRPV1 in liver cancer patients with disease-free survival rate was significantly better than low TRPV1 expression from the variable analysis. In in vivo and in vitro experiments with dimethylnitrosamine (DEN)-induced gene models, combined with bioinformatics analysis of mouse and human liver cancer samples, were used to further study the molecular mechanism and related role of TRPV1 in liver cancer. The results showed that the liver microenvironment can be altered and the development of liver cancer be promoted from knockout of TRPV1 [62]. Some published papers have proved showed that TRPV1 can be activated by cannabinoid and capsaicin that may lead to apoptosis of liver cancer cells, which indicates that TRPV1 perhaps can be used as a therapeutic site and prognostic molecule for liver cancer [63].

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4. Tumor acidic microenvironment and the progress of liver cancer

The complex molecular mechanisms that generate an acidic microenvironment of liver cancer also affect autophagy [64] as well as the role of exosomes [65] in the occurrence and development of liver cancer. and Liver cancer cells also demonstrate immune escape, thereby developing the ability to migrate and metastasize [4].

4.1 The acidic tumor microenvironment promotes invasion and metastasis of liver cancer

Although the acidic tumor microenvironment has been shown to promote cancer metastasis, its potential regulatory mechanism remains unclear. In recent years, it has been confirmed that exosomes play an increasingly important role in promoting the invasion and metastasis of liver cancer in the acidic microenvironment [66, 67]. Exosomes are membrane vesicles that are 30–100 nm in size and are released by various cell types into the extracellular environment. Although initially considered as “garbage transporters” from parental cells, exosomes are now recognized as a new category of intercellular communicators. Cells constitutively sort envelope proteins and RNAs into exosomes, a process that can be stimulated by a variety of pathologic stimuli [68]. Tian et al.’s results showed that acidic microenvironment increased liver cancer cell–derived exosomal miR-21 and miR-10b levels, which could promote migration and invasion of recipient liver cancer cells cultured under normal conditions both in vivo and in vitro [69]. It has also been reported that exosomes can promote the progression and metastasis of liver cancer through epithelial-mesenchymal transition (EMT), which is a process in which cells gradually lose the morphological characteristics of epithelial cells and transform into mesenchymal types, which is often related to tumor invasion and metastasis [70]. Xia et al. proved that the expression of receptor tyrosine kinase-like orphan receptor 1 was upregulated in the acidic microenvironment, which led to the metastasis and invasion of liver cancer by promoting EMT [71]. It is proposed that the acidic microenvironment can promote the invasion and metastasis of liver cancer through exosomes. On the other hand, Takahashi et al. confirm that exosomes can regulate HIF-1 by transporting lincror-α expression levels in response to hypoxic conditions [72]. Further, the acidification of the liver cancer microenvironment is increased by hypoxia, while angiogenesis is promoted in response to the stress created by hypoxia [73, 74, 75]. Jin et al. showed that hepatic stellate cells are activated by an acidic tumor microenvironment and subsequently promote liver cancer metastasis via osteopontin [76], which indicates that the invasion and metastasis of liver cancer are regulated by the acidic microenvironment. In general, exosomes may alter cell matrix and promote epithelial mesenchymal transformation of hepatocellular carcinoma cells through their role as intercellular transporters and enhance the invasion and metastasis of liver cancer by influencing the acidification of HIF-1 microenvironment. The invasion and metastasis of liver cancer are influenced by an acidic microenvironment, on which further study may find an effective method to inhibit metastasis and invasion of liver cancer.

4.2 Tumor acidic microenvironment and immune escape

Tumor immunity is emerging as a crucial factor in cancer control and treatment. Spontaneous immune responses arising in cancer patients have been proved to condition disease course and positively impact prognosis [77]. If tumor cells have intrinsic antigenicity, which means that they cannot avoid being recognized by specific immune cell subsets, they do learn quite quickly how to escape immune recognition. Developing sophisticated mechanisms to shut down immunological responses, cancer cells not only survive in an immune competent host, but they proliferate, progress locally and disseminate systemically, often overcoming the control attempts of immune defense [78]. In fact, innate and adaptive immune cells are highly sensitive to the hypoxic microenvironment characterized by most solid cancers. Studies have demonstrated that hypoxia induces the expression of a range of chemokines and cytokines, such as TGF-β, IL-8, CCL26, and so on, regulating the recruitment and polarization of macrophages and neutrophils and aggravating immunosuppression and evasion [79]. The increase of lactic acid caused by hypoxia can reduce T cell metabolism and affect T cell differentiation and function [80, 81, 82, 83, 84, 85], by which NK cells can be inhibited and thus reduce NK cell production of IFN [86]. The tumor microenvironment can be further acidified by neutrophils by releasing an H+-pump ATPase that block NK and T cell activity, neutrophil apoptosis of which can be delayed, the inflammatory response of neutrophils be maintained, and can also stimulate the release of TGF by tumor cells and some immune cells [87, 88]. It has also been reported that the immune checkpoint can be upregulated hypoxia in TME and tumor immune escape be promoted [89]. These studies suggest that immune escape from solid tumors may be influenced by the acidic microenvironment, thereby promoting tumor proliferation and metastasis. However, less research has been done on immune escape in the acidic microenvironment of liver cancer. The impact of immune escape on liver cancer in an acidic microenvironment may have great potential in the treatment of liver cancer.

4.3 Tumor acidic microenvironment and autophagy

Autophagy is a process wherein the double membrane is shed from the rough surface endoplasmic reticulum of the ribosomal area and forms an autophagosome, which can envelop part of the cytoplasm and cell organelle protein composition and merge with a lysosome to form an autolysosome, which eventually degrades the autophagosome contents [90]. The process produces the energy or material a cancer cell needs to survive. Many studies have shown that autophagy plays an important role in normal cell maintenance and in tumorigenesis, drug resistance, and other pathophysiological processes [91, 92, 93]. The increased autophagy in solid tumors is an adaptive behavior in response to the harsh microenvironment [94]. Fan et al. had demonstrated that activating autophagy in liver cancer cells could increase glucose consumption and lactate production; Conversely, inhibition of autophagy resulted in reduced glucose consumption and lactate production. Further studies demonstrated that adding up regulates MCT1 expression and activates Wnt/β-Catenin signaling that could enhance glucose uptake and lactate production, so as to promote the metastasis and invasion of liver cancer [95]. Lin et al. provided evidence that autophagy modulates the level of glycolysis through ubiquitin-mediated selective degradation of HK2 [96]. Wang et al. study demonstrated that acidic TME confers liver cancer cells anoikis resistance via downregulation of miR-3663-3p and finally drives liver cancer metastasis [97]. These results suggest that autophagy is closely related to the occurrence and development of liver cancer. The invasion and metastasis of liver cancer are regulated by this adaptation to the environment. Further study of the mechanism of autophagy in an acidic microenvironment may be an effective way to treat liver cancer.

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5. Perspectives of liver cancer therapy from tumor acidic microenvironment

The treatment of liver cancer is usually based on surgical treatment, of which early liver cancer can usually be resected, but systemic treatment of advanced liver cancer usually requires sorafenib in addition to local ablation, transcatheter chemoembolization, or external irradiation [98]. Multi-target tyrosine kinase inhibitor (TKI) Sorafenib has shown anti-angiogenesis and anti-proliferation effects in patients with advanced liver cancer and can inhibit tumor cell proliferation by inhibiting raf-1, B-Raf, and kinase activities in Ras/Raf/MEK/ERK signaling pathways, thus being used as an adjunctive therapy for advanced liver cancer [99, 100]. However, only approximately 30% of patients can benefit from sorafenib, and this population usually acquires drug resistance within 6 months [101]. Sorafenib inhibits the proliferation of liver cancer by anti-angiogenesis mainly by inhibiting the synthesis of hypoxia-inducible factor 1 (HIF-1), leading to the decrease of VEGF expression and tumor angiogenesis in liver cancer [102, 103]. A study by Liang et al. reported that hypoxia induced by continued sorafenib treatment conferred sorafenib resistance in liver cancer via HIF-1 and NF-κB activation [104]. Liver cancer glycolysis is promoted by this reverse-activated HIF-1, which further exacerbates the acidification of the microenvironment. It has also been reported that the structure and charge of drugs can be altered by acidic TME, which reduces their uptake by tumor cells and affects the delivery and efficacy of anticancer drugs as well as chemotherapy and radiotherapy [105, 106]. Therefore, the occurrence of sorafenib drug resistance may be caused, on the one hand, by the continuous treatment of hypoxia, which changes the expression of HIF-1 and increases drug resistance; but on the other hand, the change of HIF-1 aggravates the acidification of microenvironment, changes the physical and chemical properties of sorafenib to a certain extent, reduces the lethality of liver cancer, and aggravates the drug resistance of liver cancer. It has also been reported that changes in the microenvironment lead to increased resistance of gastric cancer cells to 5-fluorouracil and carboplatin [107]. Therefore, changes in the microenvironment are very important for the occurrence and development of tumors and drug treatment. It has been reported that urease can inhibit the development of human breast cancer and lung cancer by inducing extracellular pH alkalization [108]. Since the activity of immune cells can be inhibited by the acidification of microenvironment, the occurrence and development of tumor can be slowed down by using buffer to neutralize tumor acidosis and then immunotherapy, which has been reported in the literature as an effective method [109]. In addition, it has been reported that the progression of liver cancer can be slowed by inhibiting the activities of glycolic-related enzymes such as glucose transporter, hexokinase, pyruvate kinase, and 6-phosphofructokinase [12, 14, 16, 17]. Inhibition of V-ATPase by pavlomycin slowed the growth of liver cancer cells [37]. The growth and metastasis of liver cancer cells can be slowed down by inhibiting NHE1 activity, which can be inhibited by curcumin and GR in combination [42]. Lonidamine inhibits the proliferation, metastasis, and invasion of liver cancer cells by effectively inhibiting MCTs and thereby reducing glycolysis [49]. CAXII was inhibited by Tilroside and slowed down the proliferation of liver cancer [50]. The molecular mechanisms involved in glycolysis can be inhibited by these drugs, which inhibit the development of liver cancer. Therefore, the invasion and metastasis of liver cancer can be inhibited by changing the acidic microenvironment of liver cancer cells. Further study of the molecular mechanism of the acidic tumor microenvironment is a promising research direction for the treatment of liver cancer.

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6. Conclusion and future perspectives

Acidic microenvironment is a common phenomenon in solid tumors [8]. It has been proved that microenvironmental acidification is a key step in transforming solid tumors from noninvasive to invasive [110]. The enhancement of glycolysis of tumor cells leads to obvious acidification of the tissue microenvironment. As one of the indispensable members of solid tumors, liver cancer is no exception, and the pH value of its microenvironment is usually around 6.5 [3]. As shown in Figure 3, the expression of enzymes mediating glycolysis in liver cancer cells is altered by microenvironmental acidification, which increases the expression of related proteins and glycolysis. However, the proliferation of liver cancer cells leads to widespread hypoxia in which hypoxia factors cannot normally be degraded in liver cancer cells. Glycolysis is promoted by changes in glycolic-related proteins and hypoxia factors by which vascular endothelial growth factor can be also promoted to stimulate the formation of blood vessels and the supply of glucose to liver cancer tissues and further promote glycolysis of liver cancer cells. Liver cancer cells activate intracellular related acid transporters to maintain the internal pH disturbance caused by intracellular acidification exacerbated by increased glycolysis. Extracellular H+ excretion increases the extracellular hydrogen ion concentration, which activates extracellular hydrogen ion receptors such as ASICs, leading to further acidification of the liver cancer microenvironment. However, hydrogen ions cannot be discharged from cells indefinitely. When the regulation of hydrogen ions is impaired, TRPV1 will be actively activated in liver cancer tissue, by which cancer cells will be triggered into automatic apoptosis. On the other hand (Figure 5), epithelial-mesenchymal transition, invasion, and metastasis of hepatocellular carcinoma can be enhanced by selected exosomes that exchange information between hepatocellular carcinomas. Hypoxia-related factors can also further promote microenvironmental acidification. The activity of immune cells can be inhibited by an acidic microenvironment that causes the immune escape of liver cancer cells and facilitates the invasion and metastasis of liver cancer differently. The optimal pH value of the drug is changed by the acidification of the microenvironment that causes the tumors to develop drug resistance, which antitumor drugs generally have the right microenvironment to maximize their effects. Growth, proliferation, invasion, and metastasis of liver cancer are promoted by multiple molecular interactions implying that the liver cancer organization has accurate regulations and effective control and management.

Figure 5.

Mechanism diagram of molecular changes in liver cancer tissue under acidic microenvironment.

However, the specific mechanism of the related molecules and their exact role in the development of liver cancer need to be understood in the acidic microenvironment (1) Whether there are differences in the activities of various molecular protein subtypes induced by the acidic microenvironment of liver cancer remains to be shown. Whether these proteins have been mutated in the acidic microenvironment of liver cancer cells, and if so, whether these mutations can promote the occurrence and development of liver cancer requires further investigation. (2) Related experiments have proved that drugs that inhibit the acidic microenvironment of hepatocellular carcinoma can inhibit the invasion and metastasis. Whether these drugs can be used clinically to inhibit metastasis and invasion of liver cancer will be the focus of future studies. (3) In the acidic microenvironment, the expression levels of these diagnostic molecules that include alpha-fetoprotein Lens Culinaris agglutin-3 (AFP-L3), alpha-fetoprotein (AFP), Des-γ-carboxy Prothrombin (DCP), and other molecules related to the diagnosis of liver cancer have not been reported [111]. In the acidic microenvironment of liver cancer, the activities of related enzymes that maintain pH were changed, which has been confirmed by many experiments. Can one or more of these enzymes be used as a diagnostic basis for early liver cancer?

Although surgical treatment of liver cancer is commonly practiced [112, 113], surgical treatment cannot fundamentally cure liver cancer, after which recurrence and metastasis rates remain high. This is a major reason why the molecular mechanism contributing to the occurrence and development of liver cancer is not well understood [114]. The mechanisms of liver cancer cell microenvironment acidification, and the identification of key genes that are differentially expressed under those conditions, may provide a new theoretical basis and molecular targets for the development of drugs that will treat liver cancer.

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Acknowledgments

We are especially grateful for the training of 333 high-level talents in Jiangsu Province.

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Conflict of interest

The authors declare no conflict of interests for this article.

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Fund programs/support

333 High-level talents project of Jiangsu province (2022[2] in talent bureau of Jiangsu province); “Taihu lake” science and technology project of Wuxi (Y20212018); the first Outstanding Young and middle-aged Public Health talents project of Wuxi (BJ2020025).

References

  1. 1. Liu Y, Zheng J, Hao J, et al. Global burden of primary liver cancer by five etiologies and global prediction by 2035 based on global burden of disease study 2019. Cancer Medicine. 2022;11:1310-1323. DOI: 10.1002/cam4.4551
  2. 2. Han TS, Ban HS, Hur K, et al. The epigenetic regulation of HCC metastasis. International Journal of Molecular Sciences. 2018;19:3978. DOI: 10.3390/ijms19123978
  3. 3. Jin C, Ye QH, Yuan FL, et al. Involvement of acid-sensing ion channel 1α in hepatic carcinoma cell migration and invasion. Tumour Biology. 2015;36:4309-4317. DOI: 10.1007/s13277-015-3070-6
  4. 4. Boedtkjer E, Pedersen SF. The acidic tumor microenvironment as a driver of Cancer. Annual Review of Physiology. 2020;82:103-126. DOI: 10.1146/annurev-physiol-021119-034627
  5. 5. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Reviews. 1989;8:98-101
  6. 6. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. The Journal of General Physiology. 1927;8:519-530. DOI: 10.1085/jgp.8.6.519
  7. 7. Zhang Y, Yang JM. Altered energy metabolism in cancer: A unique opportunity for therapeutic intervention. Cancer Biology & Therapy. 2013;14:81-89. DOI: 10.4161/cbt.22958
  8. 8. Wang JX, Choi SYC, Niu X, et al. Lactic acid and an acidic tumor microenvironment suppress anticancer immunity. International Journal of Molecular Sciences. 2020;21:8363. DOI: 10.3390/ijms21218363
  9. 9. Jing X, Yang F, Shao C, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Molecular Cancer. 2019;18:157. DOI: 10.1186/s12943-019-1089-9
  10. 10. Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: Role of mitochondrial hexokinase. Proceedings of the National Academy of Sciences of the United States of America. 1977;74:3735-3739. DOI: 10.1073/pnas.74.9.3735
  11. 11. Feng J, Li J, Wu L, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. Journal of Experimental & Clinical Cancer Research. 2020;39:126. DOI: 10.1186/s13046-020-01629-4
  12. 12. Xiong T, Li Z, Huang X, et al. TO901317 inhibits the development of hepatocellular carcinoma by LXRα/Glut 1 decreasing glycometabolism. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2019;316:G598-G607. DOI: 10.1152/ajpgi.00061.2018
  13. 13. Chen X, She P, Wang C, et al. Hsa_circ_0001806 promotes glycolysis and cell progression in hepatocellular carcinoma through miR-125b/HK2. Journal of Clinical Laboratory Analysis. 2021;35:e23991. DOI: 10.1002/jcla.23991
  14. 14. Yoo JJ, Yu SJ, Na J, et al. Hexokinase-II inhibition synergistically augments the anti-tumor efficacy of sorafenib in hepatocellular carcinoma. International Journal of Molecular Sciences. 2019;20:1292. DOI: 10.3390/ijms20061292
  15. 15. Zhou Y, Lin F, Wan T, et al. ZEB1 enhances Warburg effect to facilitate tumorigenesis and metastasis of HCC by transcriptionally activating PFKM. Theranostics. 2021;11:5926-5938. DOI: 10.7150/thno.56490
  16. 16. Jia G, Wang Y, Lin C, et al. LNCAROD enhances hepatocellular carcinoma malignancy by activating glycolysis through induction of pyruvate kinase isoform PKM2. Journal of Experimental & Clinical Cancer Research. 2021;40:299. DOI: 10.1186/s13046-021-02090-7
  17. 17. Golinska M, Troy H, Chung YL, et al. Adaptation to HIF-1 deficiency by upregulation of the AMP/ATP ratio and phosphofructokinase activation in hepatomas. BMC Cancer. 2011;11:198. DOI: 10.1186/1471-2407-11-198
  18. 18. Yuen VW, Wong CC. Hypoxia-inducible factors and innate immunity in liver cancer. The Journal of Clinical Investigation. 2020;130:5052-5062. DOI: 10.1172/JCI137553
  19. 19. Bao MH, Wong CC. Hypoxia, metabolic reprogramming, and drug resistance in liver Cancer. Cell. 2021;10:1715. DOI: 10.3390/cells10071715
  20. 20. Liu Z, Wang Y, Dou C, et al. Hypoxia-induced up-regulation of VASP promotes invasiveness and metastasis of hepatocellular carcinoma. Theranostics. 2018;8:4649-4663. DOI: 10.7150/thno.26789
  21. 21. Chu Q , Gu X, Zheng Q , Zhu H. Regulatory mechanism of HIF-1α and its role in liver diseases: A narrative review. Annals of Translational Medicine. 2022;10:109. DOI: 10.21037/atm-21-4222
  22. 22. Moldogazieva NT, Mokhosoev IM, Terentiev AA. Metabolic heterogeneity of cancer cells: An interplay between HIF-1, GLUTs, and AMPK. Cancers (Basel). 2020;12:862. DOI: 10.3390/cancers12040862
  23. 23. Savic LJ, Schobert IT, Peters D, et al. Molecular imaging of extracellular tumor pH to reveal effects of locoregional therapy on liver cancer microenvironment. Clinical Cancer Research. 2020;26:428-438. DOI: 10.1158/1078-0432.CCR-19-1702
  24. 24. Maher JC, Wangpaichitr M, Savaraj N, et al. Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose. Molecular Cancer Therapeutics. 2007;6:732-741. DOI: 10.1158/1535-7163.MCT-06-0407
  25. 25. Ma CN, Wo LL, Wang DF, et al. Hypoxia activated long non-coding RNA HABON regulates the growth and proliferation of hepatocarcinoma cells by binding to and antagonizing HIF-1 alpha. RNA Biology. 2021;18:1791-1806. DOI: 10.1080/15476286.2020.1871215
  26. 26. Feng J, Dai W, Mao Y, et al. Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis. Journal of Experimental & Clinical Cancer Research. 2020;39:24. DOI: 10.1186/s13046-020-1528-x
  27. 27. Li H, Zhao B, Liu Y, Deng W, Zhang Y. Angiogenesis in residual cancer and roles of HIF-1α, VEGF, and MMP-9 in the development of residual cancer after radiofrequency ablation and surgical resection in rabbits with liver cancer. Folia Morphologica. 2020;79:71-78. DOI: 10.5603/FM.a2019.0059
  28. 28. Tian QG, Wu YT, Liu Y, et al. Expressions and correlation analysis of HIF-1α, survivin and VEGF in patients with hepatocarcinoma. European Review for Medical and Pharmacological Sciences. 2018;22:3378-3385. DOI: 10.26355/eurrev_201806_15159
  29. 29. Lin J, Cao S, Wang Y, et al. Long non-coding RNA UBE2CP3 enhances HCC cell secretion of VEGFA and promotes angiogenesis by activating ERK1/2/HIF-1α/VEGFA signalling in hepatocellular carcinoma. Journal of Experimental & Clinical Cancer Research. 2018;37:113. DOI: 10.1186/s13046-018-0727-1
  30. 30. Damaghi M, Wojtkowiak JW, Gillies RJ. pH sensing and regulation in cancer. Frontiers in Physiology. 2013;4:370. DOI: 10.3389/fphys.2013.00370
  31. 31. Nishi T, Forgac M. The vacuolar (H+)-ATPases—Nature's most versatile proton pumps. Nature Reviews. Molecular Cell Biology. 2002;3:94-103. DOI:10.1038/ nrm729
  32. 32. Jefferies KC, Cipriano DJ, Forgac M. Function, structure and regulation of the vacuolar (H+)-ATPases. Archives of Biochemistry and Biophysics. 2008;476:33-42. DOI: 10.1016/j.abb.2008.03.025
  33. 33. Martinez-Zaguilan R, Lynch RM, Martinez GM, Gillies RJ. Vacuolar-type H(+)-ATPases are functionally expressed in plasma membranes of human tumor cells. The American Journal of Physiology. 1993;265:C1015-C1029. DOI: 10.1152/ajpcell.1993.265.4.C1015
  34. 34. Sennoune SR, Bakunts K, Martínez GM, et al. Vacuolar H+-ATPase in human breast cancer cells with distinct metastatic potential: Distribution and functional activity. American Journal of Physiology. Cell Physiology. 2004;286:C1443-C1452. DOI: 10.1152/ajpcell.00407.2003
  35. 35. Fais S, De Milito A, You H, Qin W. Targeting vacuolar H+-ATPases as a new strategy against cancer. Cancer Research. 2007;67:10627-10630. DOI: 10.1158/0008-5472.CAN-07-1805
  36. 36. Xu J, Xie R, Liu X, et al. Expression and functional role of vacuolar H(+)-ATPase in human hepatocellular carcinoma. Carcinogenesis. 2012;33:2432-2440. DOI: 10.1093/carcin/bgs277
  37. 37. Lu X, Chen L, Chen Y, Shao Q , Qin W. Bafilomycin A1 inhibits the growth and metastatic potential of the BEL-7402 liver cancer and HO-8910 ovarian cancer cell lines and induces alterations in their microRNA expression. Experimental and Therapeutic Medicine. 2015;10:1829-1834. DOI: 10.3892/etm.2015.2758
  38. 38. Tang N, Jin J, Deng Y, et al. LASS2 interacts with V-ATPase and inhibits cell growth of hepatocellular carcinoma. Sheng Li Xue Bao. 2010;62:196-202 Chinese
  39. 39. Li T, Tuo B. Pathophysiology of hepatic Na+/H+ exchange (review). Experimental and Therapeutic Medicine. 2020;20:1220-1229. DOI: 10.3892/etm.2020.8888
  40. 40. Sardet C, Franchi A, Pouysségur J. Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporter. Cell. 1989;56:271-280. DOI: 10.1016/0092-8674(89)90901-x
  41. 41. Yang X, Wang D, Dong W, Song Z, Dou K. Expression and modulation of Na(+)/H(+) exchanger 1 gene in hepatocellular carcinoma: A potential therapeutic target. Journal of Gastroenterology and Hepatology. 2011;26:364-370. DOI: 10.1111/j.1440-1746.2010.06382.x
  42. 42. Kim SW, Cha MJ, Lee SK, et al. Curcumin treatment in combination with glucose restriction inhibits intracellular alkalinization and tumor growth in hepatoma cells. International Journal of Molecular Sciences. 2019;20:2375. DOI: 10.3390/ijms20102375
  43. 43. Li X, Tsauo J, Geng C, Zhao H, Lei X, Li X. Ginsenoside Rg3 decreases NHE1 expression via inhibiting EGF-EGFR-ERK1/2-HIF-1 α pathway in hepatocellular carcinoma: A novel antitumor mechanism. The American Journal of Chinese Medicine. 2018;46:1915-1931. DOI: 10.1142/S0192415X18500969
  44. 44. Payen VL, Mina E, Van Hée VF, Porporato PE, Sonveaux P. Monocarboxylate transporters in cancer. Molecular Metabolism. 2020;33:48-66. DOI: 10.1016/j.molmet.2019.07.006
  45. 45. de la Cruz-López KG, Castro-Muñoz LJ, Reyes-Hernández DO, García-Carrancá A, Manzo-Merino J. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Frontiers in Oncology. 2019;9:1143. DOI: 10.3389/fonc.2019.01143
  46. 46. Alves VA, Pinheiro C, Morais-Santos F, Felipe-Silva A, Longatto-Filho A, Baltazar F. Characterization of monocarboxylate transporter activity in hepatocellular carcinoma. World Journal of Gastroenterology. 2014;20:11780-11787. DOI: 10.3748/wjg.v20.i33.11780
  47. 47. Halestrap AP, Wilson MC. The monocarboxylate transporter family—Role and regulation. IUBMB Life. 2012;64:109-119. DOI: 10.1002/iub.572
  48. 48. Chen HL, OuYang HY, Le Y, et al. Aberrant MCT4 and GLUT1 expression is correlated with early recurrence and poor prognosis of hepatocellular carcinoma after hepatectomy. Cancer Medicine. 2018;7:5339-5350. DOI: 10.1002/cam4.1521
  49. 49. Nath K, Guo L, Nancolas B, et al. Mechanism of antineoplastic activity of lonidamine. Biochimica et Biophysica Acta. 2016;1866:151-162. DOI: 10.1016/j.bbcan.2016.08.001
  50. 50. Waheed A, Sly WS. Carbonic anhydrase XII functions in health and disease. Gene. 2017;623:33-40. DOI: 10.1016/j.gene.2017.04.027
  51. 51. Xing X, Yuan H, Liu H, et al. Quantitative secretome analysis reveals clinical values of carbonic anhydrase II in hepatocellular carcinoma. Genomics, Proteomics & Bioinformatics. 2021;19:94-107. DOI: 10.1016/j.gpb.2020.09.005
  52. 52. Finkelmeier F, Canli Ö, Peiffer KH, et al. Circulating hypoxia marker carbonic anhydrase IX (CA9) in patients with hepatocellular carcinoma and patients with cirrhosis. PLoS One. 2018;13:e0200855. DOI: 10.1371/journal.pone.0200855
  53. 53. Zeng X, Yin F, Liu X, et al. Upregulation of E2F transcription factor 3 is associated with poor prognosis in hepatocellular carcinoma. Oncology Reports. 2014;31:1139-1146. DOI: 10.3892/or.2014.2968
  54. 54. Uda NR, Stenner F, Seibert V, et al. Humanized monoclonal antibody blocking carbonic anhydrase 12 enzymatic activity leads to reduced tumor growth in vitro. Anticancer Research. 2019;39:4117-4128. DOI: 10.21873/anticanres.13570
  55. 55. Han R, Yang H, Lu L, Lin L. Tiliroside as a CAXII inhibitor suppresses liver cancer development and modulates E2Fs/Caspase-3 axis. Scientific Reports. 2021;11:8626. DOI: 10.1038/s41598-021-88133-7
  56. 56. Carattino MD, Montalbetti N. Acid-sensing ion channels in sensory signaling. American Journal of Physiology. Renal Physiology. 2020;318:F531-F543. DOI: 10.1152/ajprenal.00546.2019
  57. 57. Storozhuk M, Cherninskyi A, Maximyuk O, Isaev D, Krishtal O. Acid-sensing ion channels: Focus on physiological and some pathological roles in the brain. Current Neuropharmacology. 2021;19:1570-1589. DOI: 10.2174/1570159X19666210125151824
  58. 58. Jin C, Yuan FL, Gu YL, et al. Over-expression of ASIC1a promotes proliferation via activation of the β-catenin/LEF-TCF axis and is associated with disease outcome in liver cancer. Oncotarget. 2017;8:25977-25988. DOI: 10.18632/oncotarget.10774
  59. 59. Jin C, Zhu MQ , Yuan FL, et al. The expressions of acid sensing ion channel la and activator protein-1 in hepatocellular carcinoma and their relationships with clinical features. Chinese Journal of Hepatobiliary Surgery. 2018;24:376-380. DOI: 10.3760/cma.j.issn.1007-8118.2018.06.005
  60. 60. Bujak JK, Kosmala D, Szopa IM, Majchrzak K, Bednarczyk P. Inflammation, cancer and immunity-implication of TRPV1 channel. Frontiers in Oncology. 2019;9:1087. DOI: 10.3389/fonc.2019.01087
  61. 61. Miao X, Liu G, Xu X, et al. High expression of vanilloid receptor-1 is associated with better prognosis of patients with hepatocellular carcinoma. Cancer Genetics and Cytogenetics. 2008;186:25-32. DOI: 10.1016/j.cancergencyto.2008.05.011
  62. 62. Xie C, Liu G, Li M, et al. Targeting TRPV1 on cellular plasticity regulated by Ovol 2 and Zeb 1 in hepatocellular carcinoma. Biomedicine & Pharmacotherapy. 2019;118:109270. DOI: 10.1016/j.biopha.2019.109270
  63. 63. Scheau C, Badarau IA, Caruntu C, et al. Capsaicin: Effects on the pathogenesis of hepatocellular carcinoma. Molecules. 2019;24:2350. DOI: 10.3390/molecules24132350
  64. 64. Wong MM, Chan HY, Aziz NA, et al. Interplay of autophagy and cancer stem cells in hepatocellular carcinoma. Molecular Biology Reports. 2021;48:3695-3717. DOI: 10.1007/s11033-021-06334-9
  65. 65. Li X, Li C, Zhang L, et al. The significance of exosomes in the development and treatment of hepatocellular carcinoma. Molecular Cancer. 2020;19:1. DOI: 10.1186/s12943-019-1085-0
  66. 66. Wang H, Lu Z, Zhao X. Tumorigenesis, diagnosis, and therapeutic potential of exosomes in liver cancer. Journal of Hematology & Oncology. 2019;12:133. DOI: 10.1186/s13045-019-0806-6
  67. 67. Liu Y, Shi K, Chen Y, et al. Exosomes and their role in cancer progression. Frontiers in Oncology. 2021;11:639159. DOI: 10.3389/fonc.2021.639159
  68. 68. Panagiotou N, Neytchev O, Selman C, Shiels PG. Extracellular vesicles, ageing, and therapeutic interventions. Cell. 2018;7:110. DOI: 10.3390/cells7080110
  69. 69. Tian XP, Wang CY, Jin XH, et al. Acidic microenvironment up-regulates exosomal miR-21 and miR-10b in early-stage hepatocellular carcinoma to promote cancer cell proliferation and metastasis. Theranostics. 2019;9:1965-1979. DOI: 10.7150/thno.30958
  70. 70. Greening DW, Gopal SK, Mathias RA, et al. Emerging roles of exosomes during epithelial-mesenchymal transition and cancer progression. Seminars in Cell & Developmental Biology. 2015;40:60-71. DOI: 10.1016/j.semcdb.2015.02.008
  71. 71. Meng X, Xu Y, Ning X. Tumor microenvironment acidity modulates ROR1 to promote epithelial-mesenchymal transition and hepatocarcinoma metastasis. Journal of Cell Science. 2021;134:jcs255349. DOI: 10.1242/jcs.255349
  72. 72. Takahashi K, Yan IK, Haga H, Patel T. Modulation of hypoxia-signaling pathways by extracellular linc-RoR. Journal of Cell Science. 2014;127:1585-1594. DOI: 10.1242/jcs.141069
  73. 73. Ludwig N, Whiteside TL. Potential roles of tumor-derived exosomes in angiogenesis. Expert Opinion on Therapeutic Targets. 2018;22:409-417. DOI: 10.1080/14728222.2018.1464141
  74. 74. Shao C, Yang F, Miao S, et al. Role of hypoxia-induced exosomes in tumor biology. Molecular Cancer. 2018;17:120. DOI: 10.1186/s12943-018-0869-y
  75. 75. Lee TK, Poon RT, Yuen AP, et al. Regulation of angiogenesis by Id-1 through hypoxia-inducible factor-1alpha-mediated vascular endothelial growth factor up-regulation in hepatocellular carcinoma. Clinical Cancer Research. 2006;12:6910-6919. DOI: 10.1158/1078-0432.CCR-06-0489
  76. 76. Song J, Ge Z, Yang X, et al. Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin. Cancer Letters. 2015;356:713-720. DOI: 10.1016/j.canlet.2014.10.021
  77. 77. Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: A randomised, double-blind, multicentre, phase 2, dose-ranging study. The Lancet Oncology. 2010;11:155-164. DOI: 10.1016/S1470-2045(09)70334-1
  78. 78. Huber V, Camisaschi C, Berzi A, et al. Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation. Seminars in Cancer Biology. 2017;43:74-89. DOI: 10.1016/j.semcancer.2017.03.001
  79. 79. Veglia F, Sanseviero E, Gabrilovich DI. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nature Reviews. Immunology. 2021;21(8):485-498. DOI: 10.1038/s41577-020-00490-y
  80. 80. Labiano S, Palazon A, Melero I. Immune response regulation in the tumor microenvironment by hypoxia. Seminars in Oncology. 2015;42:378-386. DOI: 10.1053/j.seminoncol.2015.02.009
  81. 81. Cubillos-Ruiz JR, Mohamed E, Rodriguez PC. Unfolding anti-tumor immunity: ER stress responses sculpt tolerogenic myeloid cells in cancer. Journal for Immunotherapy of Cancer. 2017;5:5. DOI: 10.1186/s40425-016-0203-4
  82. 82. Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. Hypoxic stress: Obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 2017;36:439-445. DOI: 10.1038/onc.2016.225
  83. 83. Egners A, Erdem M, Cramer T. The response of macrophages and neutrophils to hypoxia in the context of cancer and other inflammatory diseases. Mediators of Inflammation. 2016;2016:2053646. DOI: 10.1155/2016/2053646
  84. 84. Chen J, Cao X, Li B, et al. Warburg effect is a cancer immune evasion mechanism against macrophage immunosurveillance. Frontiers in Immunology. 2021;11:621757. DOI: 10.3389/fimmu.2020.621757
  85. 85. Lim AR, Rathmell WK, Rathmell JC. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. eLife. 2020;9:e55185. DOI: 10.7554/eLife.55185
  86. 86. Pötzl J, Roser D, Bankel L, et al. Reversal of tumor acidosis by systemic buffering reactivates NK cells to express IFN-γ and induces NK cell-dependent lymphoma control without other immunotherapies. International Journal of Cancer. 2017;140:2125-2133. DOI: 10.1002/ijc.30646
  87. 87. Mollinedo F. Neutrophil degranulation, plasticity, and cancer metastasis. Trends in Immunology. 2019;40:228-242. DOI: 10.1016/j.it.2019.01.006
  88. 88. Trevani AS, Andonegui G, Giordano M, et al. Extracellular acidification induces human neutrophil activation. Journal of Immunology. 1999;162:4849-4857
  89. 89. Worsley CM, Veale RB, Mayne ES. The acidic tumour microenvironment: Manipulating the immune response to elicit escape. Human Immunology. 2022;83:399-408. DOI: 10.1016/j.humimm.2022.01.014
  90. 90. Jiang P, Mizushima N. Autophagy and human diseases. Cell Research. 2014;24:69-79. DOI: 10.1038/cr.2013.161
  91. 91. Ghavami S, Gupta S, Ambrose E, Hnatowich M, Freed DH, Dixon IM. Autophagy and heart disease: Implications for cardiac ischemia-reperfusion damage. Current Molecular Medicine. 2014;14:616-629. DOI: 10.2174/1566524014666140603101520
  92. 92. Hashimoto D, Bläuer M, Hirota M, Ikonen NH, Sand J, Laukkarinen J. Autophagy is needed for the growth of pancreatic adenocarcinoma and has a cytoprotective effect against anticancer drugs. European Journal of Cancer. 2014;50:1382-1390. DOI: 10.1016/j.ejca.2014.01.011
  93. 93. Ryter SW, Choi AM. Autophagy in lung disease pathogenesis and therapeutics. Redox Biology. 2015;4:215-225. DOI: 10.1016/j.redox.2014.12.010
  94. 94. Chao X, Qian H, Wang S, Fulte S, Ding WX. Autophagy and liver cancer. Clinical and Molecular Hepatology. 2020;26:606-617. DOI: 10.3350/cmh.2020.0169
  95. 95. Fan Q , Yang L, Zhang X, et al. Autophagy promotes metastasis and glycolysis by upregulating MCT1 expression and Wnt/β-catenin signaling pathway activation in hepatocellular carcinoma cells. Journal of Experimental & Clinical Cancer Research. 2018;37:9. DOI: 10.1186/s13046-018-0673-y
  96. 96. Jiao L, Zhang HL, Li DD, et al. Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2). Autophagy. 2018;14:671-684. DOI: 10.1080/15548627.2017.1381804
  97. 97. Wang S, Lv Y, Zhou Y, et al. Acidic extracellular pH induces autophagy to promote anoikis resistance of hepatocellular carcinoma cells via downregulation of miR-3663-3p. Journal of Cancer. 2021;12:3418-3426. DOI: 10.7150/jca.51849
  98. 98. Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet. 2018;391:1301-1314. DOI: 10.1016/S0140-6736(18)30010-2
  99. 99. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. The New England Journal of Medicine. 2008;359:378-390. DOI: 10.1056/NEJMoa0708857
  100. 100. Tang W, Chen Z, Zhang W, et al. The mechanisms of sorafenib resistance in hepatocellular carcinoma: Theoretical basis and therapeutic aspects. Signal Transduction and Targeted Therapy. 2020;5:87. DOI: 10.1038/s41392-020-0187-x
  101. 101. Colagrande S, Regini F, Taliani GG, Nardi C, Inghilesi AL. Advanced hepatocellular carcinoma and sorafenib: Diagnosis, indications, clinical and radiological follow-up. World Journal of Hepatology. 2015;7:1041-1053. DOI: 10.4254/wjh.v7.i8.1041
  102. 102. Liu LP, Ho RL, Chen GG, Lai PB. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: Implications for antiangiogenic activity in hepatocellular carcinoma. Clinical Cancer Research. 2012;18:5662-5671. DOI: 10.1158/1078-0432.CCR-12-0552
  103. 103. Xu M, Xie XH, Xie XY, et al. Sorafenib suppresses the rapid progress of hepatocellular carcinoma after insufficient radiofrequency ablation therapy: An experiment in vivo. Acta Radiologica. 2013;54:199-204. DOI: 10.1258/ar.2012.120249
  104. 104. Liang Y, Zheng T, Song R, et al. Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology. 2013;57:1847-1857. DOI: 10.1002/hep.26224
  105. 105. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Research. 2016;76:1381-1390. DOI: 10.1158/0008-5472.CAN-15-1743
  106. 106. Fais S, Marunaka Y. The acidic microenvironment: Is it a phenotype of all cancers? A focus on multiple myeloma and some analogies with diabetes mellitus. Cancers (Basel). 2020;12:3226. DOI: 10.3390/cancers12113226
  107. 107. Bhattacharya B, Low SH, Soh C, et al. Increased drug resistance is associated with reduced glucose levels and an enhanced glycolysis phenotype. British Journal of Pharmacology. 2014;171:3255-3267. DOI: 10.1111/bph.12668
  108. 108. Wong WY, DeLuca CI, Tian B, et al. Urease-induced alkalinization of extracellular pH and its antitumor activity in human breast and lung cancers. Journal of Experimental Therapeutics & Oncology. 2005;5:93-99
  109. 109. Bhattacharya B, Huang DQ , Low SHH, et al. Effect of cell microenvironment on the drug sensitivity of hepatocellular cancer cells. Oncotarget. 2021;12:674-685. DOI: 10.18632/oncotarget.27910
  110. 110. Bergers G, Fendt SM. The metabolism of cancer cells during metastasis. Nature Reviews. Cancer. 2021;21:162-180. DOI: 10.1038/s41568-020-00320-2
  111. 111. Piñero F, Dirchwolf M, Pessôa MG. Biomarkers in hepatocellular carcinoma: Diagnosis, prognosis and treatment response assessment. Cells. 2020;9:1370. DOI: 10.3390/cells9061370
  112. 112. Kremer M, Manzini G, Hartel M. Lebermetastasen: aktueller Stand der chirurgischen Behandlungsmöglichkeiten [Current surgical treatment options for liver metastasis]. Therapeutische Umschau. 2021;78:597-603. DOI: 10.1024/0040-5930/a001316
  113. 113. Li YM, Wei YC. Reconsideration of surgical treatment for liver cancer. Zhonghua Yi Xue Za Zhi. 2021;101:2179-2184. DOI: 10.3760/cma.j.cn112137-20210411-00865
  114. 114. Song TQ. Changes and challenges of surgical treatment strategy for hepatocellular carcinoma. Zhong hua Wai Ke Za Zhi. 2021;59:447-451. DOI:10.3760/cma.j.cn112139-20201209-00849

Written By

Cheng Jin, You-Yi Liu and Bo-Shi Wang

Reviewed: 12 October 2022 Published: 13 November 2022

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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