**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

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

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 [73–75]. 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 [80–85], 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 [91–93]. 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.
