Chronic liver inflammation and primary hepatocellular carcinoma
Many epidemiological studies and clinical observations have shown that, except for a few chronic HBV infections that can directly develop into primary hepatocellular carcinoma (HCC), the vast majority of chronic viral hepatitis (especially HCV infection), autoimmune liver disease, alcoholic and non-alcoholic fatty liver disease progress through the stages of chronic hepatitis, liver fibrosis and cirrhosis before developing into primary HCC. therefore, an in-depth study of the relationship between chronic The relationship between liver inflammation and HCC can help to understand the mechanism of HCC development and explore possible interventions and therapeutic targets.
I. The liver is an important immune organ
The liver is the largest visceral organ in the human body, and its main function is to regulate substance metabolism and energy metabolism of the whole body, and it is also an important immune organ. In addition to hepatocytes, bile duct epithelial cells, blood sinusoidal endothelial cells, and stellate cells, the liver also contains many immune cells such as Kupffer cells, dendritic cells (DC), natural killer (NK) cells, natural killer T (NKT) cells, and lymphocytes. Since the liver is mainly supplied with blood by the portal system, its low pressure and slow blood flow give the various immune cells in the blood an opportunity to interact in the liver.
The liver receives blood from the portal vein of the intestine and is therefore frequently exposed to a variety of foreign antigenic substances, while the liver is rich in natural and acquired immune cells capable of generating a moderate immune response to perform the function of identifying, monitoring and removing harmful antigens; at the same time the body keeps the immune system in the liver from being over-activated through a fine regulatory mechanism to ensure nutritional requirements and a stable internal environment
Second, chronic liver inflammation is the basis of primary HCC
Like anything, inflammation is a double-edged sword for the organism. On the one hand, inflammation is a defense or repair response of organ tissues against various harmful factors, and its physiological significance lies in limiting the extent of damage, healing damage, removing pathogens, and restoring parenchymal cell volume. However, on the other hand, persistent inflammation can disrupt tissue integrity, chromosomal stability, and promote apoptosis, proliferation, and carcinogenesis. Therefore, some foreign scholars have referred to the chronic inflammatory microenvironment as the 7th milestone event in malignant tumorigenesis.
Many infectious (hepatitis virus, etc.) and non-infectious (alcohol and obesity, etc.) factors can lead to inflammation in the liver. The pathological histological features of liver inflammation include degeneration, apoptosis, necrosis, regeneration of liver parenchymal cells, and immune/inflammatory cell infiltration, vascular proliferation, and stromal deposition. If the pathogen (hepatitis A or E virus) or other harmful factors (drugs, alcohol) are promptly removed or eliminated, the inflammation will subside, which is known as acute hepatitis. If liver inflammation persists for more than 6 months, it is generally referred to as chronic hepatitis. One of the important pathological features of chronic hepatitis is that on top of the inflammatory necrosis, there is a significant proliferation of collagen and other fibrous connective tissue, i.e. fibrosis; if further structural destruction of liver lobules occurs, cirrhosis is formed. Currently, both domestic and foreign academics agree that chronic hepatitis and its resulting liver fibrosis and cirrhosis are the most important risk factors for the development of HCC, but the specific role of inflammatory response/immune response in the development of HCC has not been fully elucidated.
III. Natural and acquired immune cells and chronic inflammation and HCC
The natural immune system mainly includes macrophages, Kuppfer cells, DCs, NK cells, NKT cells, etc., which are the first line of defense of the body. The natural immune system can not only promote angiogenesis and repair damage, but also recognize, analyze and transmit information about tissue damage to the acquired immune system. Early studies found that tumor tissues can be infiltrated by a variety of natural immune cells, and it is believed that these cells have a role in promoting tumor development. Recent studies have shown that their role is more complex and that immune cells may play different or even completely opposite roles in different tissue cells or extracellular matrix environments and at different stages of disease development. For example, tumor-associated macrophages (TAM) may promote tumorigenesis and progression in areas of hypoxia or in the stroma, while in tumor cell nests they may have tumor suppressive effects.
DCs are specialized antigen-presenting cells that play a key role in activating the acquired immune system. Early studies found that patients with DC infiltration in tumors survived longer, but later studies found that different subtypes and stages of maturation of DCs had different roles in tumor development. Animal experiments showed that NKT cells were lost in carbon tetrachloride-induced cirrhosis, suggesting that normal liver tissue structure is important for maintaining normal NK cells and NKT cells. It has been found that in HCV-induced cirrhosis and HCC, the number and antitumor activity of NK and NKT cells in both peripheral blood and liver are reduced.
Acquired immune cells are mainly various lymphocytes. An increasing number of studies have shown that the subtype, density and infiltration site of T lymphocytes are more related to the prognosis of tumor patients. For example, those with infiltration of CD8+ T cells (i.e. cytotoxic T cells, CTL) expressing granzyme in tumor cell nests have a better prognosis. Further studies revealed that CD4+ Thl cells enhanced the antitumor effect of CTL, while CD4+ regulatory T cells (Treg) attenuated the antitumor effect of CTL. Therefore, it has been suggested that the ratio of CTL to Treg in tumor tissues has a better predictive value than a single cell number.B lymphocytes are capable of producing autoantibodies against tumor antigens, and in general, B lymphocyte infiltration in tumors is mostly insignificant.Studies have shown that these autoantibodies against tumor antigens not only have no protective effect but are also associated with poor prognosis, and their mechanism of action may be through antibody The mechanism of action may be through the deposition of antibodies or immune complexes promoting the local inflammatory response, or B lymphocytes directly suppressing the Thl immune response.
Molecular patterns and their recognition receptors with chronic hepatitis and HCC
Pathogen-associated molecular patterns (PAMPs) are conserved motifs on the surface of pathogens that can be recognized by pattern recognition receptors (PRRs) on the surface of natural immune cells (e.g., Kupffer cells), thereby initiating the natural immune response. (Patients with HBV, HCV infection, alcoholic liver disease and non-alcoholic steatohepatitis (NASH) often have low levels of endotoxemia and can activate TLR4 in Kupffer cells, thereby activating the NF-KB and JNK pathways; NF-KB in turn activates TNFcL thereby promoting tumor cell proliferation, and the JNK pathway promotes tumor proliferation by regulating matrix metalloproteinases and cyclins.
Damage/hazard associated molecular patterns (DAMPs) are also a natural class of alarm signals that trigger and amplify immune responses to deleterious events such as inflammation, cell death, and tumor metastasis. For example, high mobility group protein Bl (HMGBl), which belongs to the DAMPs family, is a DNA-binding protein passively released from necrotic tumor cell lysis or actively secreted from macrophages or hepatocytes at the tumor site, and it regulates the transcription of genes important for tumorigenesis (e.g., E selectin, TNFa, insulin receptor genes).
V. Mechanism of chronic liver inflammation leading to HCC: overlap of inflammatory and oncogenic pathways
In the development of multiple tumors, inflammation and tumor transformation regulatory networks overlap. For example, IL-6 and TNFa are acute inflammatory cytokines, and their levels are also elevated in cirrhotic and HCC tissues. It has been reported that IL-6 and TNFa can initiate the transcription factors STAT3 and NF-KB, respectively, and thus regulate the expression of downstream genes. NF-KB is an intracellular effector molecule for many pro-inflammatory cytokines (e.g. TNFa, IL-1 and TLRs) and is highly activated in many tumors. In hepatic parenchymal cells NF-KB functions to promote the survival of hepatic parenchymal cells, induce the expression of IL-6 and TNFa that favor the growth of tumor cells, and in non-parenchymal cells its function is mainly to promote tumor progression.
The transforming growth factor β (TGFβ) pathway is currently considered to play a key role in HCC development. the role of TGFβ in the development of fibrosis, cirrhosis and HCC is more complex and may have different roles in different stages. It has been found that knockdown of TGFβ receptor 2 (TGFBR2) and thus blocking the signaling pathway of TGFβ in a transgenic mouse model can inhibit the development of HCC due to p53 deficiency; however, treatment of HCC cell lines (with p53 mutation but still expressing TGFBR2) in vitro in culture with TGFβ can also inhibit their growth. Some literature shows that TGFβ expression is significantly higher in cirrhosis but significantly lower in HCC compared to normal subjects. This result has been explained as follows: in cirrhosis, in the presence of mutations in the oncogene p53, the upregulated TCFβ may promote the transformation and growth of newly developed cancer cells; while in those who have developed HCC, tumor cells escape the inhibitory effect of TGFβ on their growth by downregulating their own TGFβ receptors and the expression of TGFβ in the microenvironment.
The above different roles of TGFβ can be understood as follows: in acute inflammation, TGFβ mediates the Smad3 signaling pathway and thus terminates the proliferation of hepatocytes; however, in chronic inflammation, the long-term stimulation of pro-inflammatory cytokines alters the phosphorylation status of Smad2/3, leading to the continuous activation of proliferation-promoting and fibrosis-promoting signaling pathways, thus favoring the transformation and growth of tumor cells. growth.
VI. Summary and outlook
Various deleterious factors and events such as infection and stress can be recognized by pattern recognition receptors (e.g. TLRs) on the surface of natural immune cells through molecular patterns such as PAMPs and DAMPs, thus activating a series of natural or acquired immune cells, cytokines and inflammatory signaling pathways. In turn, oxidative stress during inflammation can alter cell structure and function by modifying proteins, lipids and amino acids. Sustained activation of inflammatory pathways can not only lead to liver fibrosis and cirrhosis, but can also affect hepatocyte and immune cell senescence, autophagy, apoptosis and proliferation by regulating tumor-associated gene expression, ultimately promoting cellular transformation and carcinogenesis. However, it is unclear whether there is a specific inflammatory pathway leading to tumorigenesis or whether chronic inflammation is only a non-specific background for tumorigenesis.
The most effective means of preventing HCC remains etiologic treatment of chronic liver disease, such as antiviral therapy for chronic hepatitis B/C, abstinence from alcohol in patients with alcoholic liver disease, and immunosuppressive therapy for autoimmune hepatitis. Encouragingly, studies have been reported on the treatment of hepatitis B/ C or HCC by modulating the body’s natural immunity through TLR agonists/antagonists or microRNAs (miRNAs). Therefore, we expect that in the future, we will be able to prevent HCC by intervening or modulating chronic inflammatory pathways to treat liver fibrosis and cirrhosis.