**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

#### *Mechanisms of Hepatocarcinogenesis Development in an Acidic Microenvironment DOI: http://dx.doi.org/10.5772/intechopen.108559*

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.

### **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<sup>+</sup> 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.

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

*Mechanisms of Hepatocarcinogenesis Development in an Acidic Microenvironment DOI: http://dx.doi.org/10.5772/intechopen.108559*

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), alphafetoprotein (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.

#### **Acknowledgements**

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

### **Conflict of interest**

The authors declare no conflict of interests for this article.

#### **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).

*Liver Cancer - Genesis, Progression and Metastasis*
