Cancer Threat to Liver Homeostasis and the Liver Cancer Mechanism

Liver cancer is among the most popular malignancies in the world, such that it is ranked as the third leading cause of death in the world. Liver cancer pathologically mainly involves intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC). The two kinds of liver cancers have comparable hepatic microenvironment though they might contain different tumor microenvironments (TMEs) due to varying tumor cells biological characteristics. For example, in a significant cases proportion, ICC nurtures isocitrate dehydrogenase (IDH)  2 and IDH1 mutations that are unusual in HCC. IDH2 and IDH1 are essential enzymes engaged in cellular metabolism. Thus, mutations of IDH1/2 can considerably impact the metabolite profile in TMEs and cells. In this situation, the TME roles in progression of liver cancer might be altered greatly .

Read also Liver Physiology And Anatomy

Hepaocellular, hepatoblastoma, hepatocellular adenoma carcinoma (HCC) are three main neoplasms of hepatocellular. HCC is the basic liver tumor which contributes for over 80 percent of all liver tumors. HCC prognosis is however still highly poor, with 5 year survival rate being less than 5 years. Among the main HCC etiological causes include hepatitis C and hepatitis B infection, nonalcoholic and alcoholic fatty liver diseases, chemical carcinogens, and a number of metabolic genetic diseases that include alpha-1-antitryspin and hemochromotasis deficiency have been related with development of liver cancer, though the actual hepatocarcinogenesis mechanism is still unclear. In addition, a recent global metabolic diseases trend that includes diabetes and obesity are said to favor increase in incidences of HCC (4).  According to research HCC development involves two stages that include promotion and initiation. Initiation happens when cells having DNA mutation in a single or a number of dominant proto-oncogenes, malignant tumor suppressor genes that include Ras, p53 and Wnt signaling pathway components are generated. In cancer promotion stage, the initiated cells clonally expand via the cell proliferation increase or/and the apoptosis suppression.  In addition, reactive oxygen species (ROS) and additional cellular mutagens created in the cancer promotion stage will progressively add to the accumulation of extra genomic instability and genetic mutations, therefore increasing quantity of initiated cells (4). HCC cancer development is also associated with physiological conditions of inflammation and infection. Inflammation is currently acknowledged as a key player in promotion of liver tumor with identification of STAT3 and NF-kB pathways as important for establishing the results of liver inflammation, injury, and the following tumorigenesis.

NF-kB together with its upstream regulators such as IKKγ, IKKβ, and IKKα are known to be essential for liver homeostasis and hepatocyte survival. In recent times, the inflammatory and NF-κB pathways it controlled have been demonstrated to play an important roles promotion of cancer. The researchers noted that NF-κB activity inhibition in hepatocytes at HCC development later stages suppresses liver tumor development, demonstrating a NF-κB tumor-promotion impact. This might attribute to a distinguished NF-κB role in liver anti-apoptosis pathways (1). Actually, many targeted NF-κB genes that include JNK activation inhibitor (XIAP), caspase activator inhibitor (cFLIP), apoptosis inhibitor (c-IAPs) and Bel-2 family member Bcl-XL are key cell anti-apoptoss pathway components. It has also been established that IKK-β hepotocycte-specific deletion which is a kinase vital for the NF-κB activation result to stronger formation HCC, demonstrating the NF-κB tumor suppressor effect in liver. Correspondingly, IKKγ hepatocyte-specific deletion which regulates IKK complex subunit for activation of NF-κB results to death of liver cells, spontaneous and inflammation of HCC. The hepatocytes death is said to occur because in NF-κB absence, hepatocytes experiences accumulation of ROS and consequently, there is activation of JNK pathway in hepatocytes . This demonstrates that in varying types of liver cell and in HCC different stages NF-κB may influence tumor promotion differently. Based on the analysis, it is clear that chronic inflammation promotes liver carcinogenesis via a regeneration and death cell cycle, resulting to creation of cell proliferation and survival signals which enhance formation of dysplasia, regenerative nodules and cancer.

Normally, cell death induction works as a function of tumor suppression. However, in the liver, this function does not all the time works as tumor suppressor but on the contrary; it works as tumor promoter since hepatic mass loss as a result of hepatocyte death initiates the residue hepatocytes proliferation which might offer a promoting environment for the formation of the tumor. For instance, diethylnitrosamine (DEN) is a carcinogenic chemical that is normally applied to initiate HCC in rodents. DEN administration initiates acute DNA damage and liver injury in hepatocytes, and eventually resulting to neoplastic lesions, liver regeneration, and inflammation in the liver, which eventually promote tumor formation as explained above.

Liver tumors phenotype could also rely on interaction between immune microenvironment and oncogenes. Based on the recent animal research, various forms of liver tumors that include iCCAs, HCCs and HCC-iCCAs mix, arose through activation of distinctive oncology that includes CTNNB1 and AKT1 together with conditions of inflammatory microenvironment such as 4-dihydrocollidine, 3, 5-diethoxycarbonyl-1 or carbon tetrachloride. Tumors which generate through same oncogenes activation can still contain varying transcriptomes, based on the degree of inflammation and the microenvironment features . Immune system has been linked to the liver cancer development through various mechanisms. First cytokines secretion by immune cells that include interleukin (IL)-6 and factor of tumor necrosis, can initiate hepatocytes inflammatory signaling pathways through JAK-STAT and nuclear factor kB among others to enhance survival and proliferation of cells. The HCC immune microenvironment is typified by the immune responses coexistence resulting to both tolerance and immunogenicity. HCC enhances immunologic tolerance via cytokines release and transformation of beta (TGF)-β growth factor. The tumor-infiltrating and tumors immune cells also demonstrate immune regulators that include programmed cell death ligand PDL 1, cytotoxin t-lymphocyte protein 4 (CTLA4), and protein 1 (PD) that destroy the antitumor immune response, permitting progression and growth of tumor. Tumors containing immune infiltrates are said to have longer survival periods and minimized relapse rates after transplantation and resection. Factors which initiate inflammation that includes insulin receptor and nuclear factor kB, initiate carcinogenesis among patients suffering from nonalcoholic fatty liver diseases. In addition, the natural killer cells and CD4+ and CD8+ T cell are also said to enhance oncogenesis .

Liver cancer development demonstrates odd development situation. With limited supply of nutrient and rapid growth, the tumor cells survival is questionable. Nevertheless, the liver tumor demonstrates the ability of cellular metabolism reprograming for neoplastic proliferation. The cancer induced abnormal metabolism offers metabolites and energy for cell activity and also alters numerous associated pathways which influence a number of biological processes.  Metabolism is an important lifer function, and the liver metabolic disruption can result to spontaneous hepatocarcinogenesis. Profiling of the main metabolic modifications in the liver cancer through metabolomics analysis that demonstrated evaluated β-oxidation, gluconeogenesis and glycolysis with minimized activity of tricarboxylic acid cycle (TCA cycle) Aerobic glycolysis is observed frequently in different tumors . This theory designates that tumor cells mainly utilizes glycolysis, even when oxygen is enough. Glycolysis in addition plays a controlling role for liver cancer in glucose metabolism. Various researches have demonstrated the association between glycolysis and epigenetic as well as genetic changes. Mutant tumor supressors and activated oncogenes are also related with glycolysis. Lactate dehydrogenase (LDH), glucose transporters (GLUTs), pyruvate kinase M2 (PKM2) and glycolysis-associated enzyme hexokinase 2 (HK2) are in addition overexpressd in tissues of liver cancer, proposing an augmented glycolysis activity.  Oxidation of fatty β is also promoted in liver cancer to lower tumor glucose dependence and to overcome energy shortage. Metabolic modification increases glycerolipid metabolism and fatty acid biosynthesis, resulting to lipid and fatty acid accumulation. Moreover, approximately all amino acids are augmented in liver cancer as a result of reduction of catabolism of amino acid. These general changes together with various other factors might influence the metabolites levels in TME. Liver cancer is a serious health issue that is likely to result to death within 5 years after its manifestation. Early treatment is thus essential in saving the life of a patient. This cannot be done without clear diagnosis. Although most people do not demonstrate any symptom at the start, most of possible symptoms of liver cancer include chalky, white stool, jaundice, and unexplained loss of weigh, swelling of abdomen, loss of appetite, fatigue and general weakness, pain in upper abdomen, vomiting and nausea.  These symptoms can prompt to various liver cancer testes and procedures which include blood tests that is likely to demonstrate abnormalities in functions of a liver. Image testing such as magnetic resonance imaging (MRI), computerized tomography (CT) Scan, and ultrasound and liver biopsy may also assist in making more accurate diagnosis.  When diagnosis is positive more may need to be done to determine the stage of cancer development which may be done using bones scans, MRIs and CTs. Liver cancer test can also be run on individual with infectious and non-infectious diseases associated with liver cancer. These diseases include hepatitis C and B, cirrhosis, jaundice, obesity and diabetes.

Liver Cancer and its Treatment

The liver is famous for its amazing ability to regenerate following acute injury, that include loss of liver mass as experienced after partial hepatectomy (PHx)  or acetaminophen poisoning through compensatory hyperplasia , arbitrated by remaining healthy hepatocytes and just very restricted involvement of progenitor cell. However, prolonged hepatic damage as a result of constant carcinogenic, toxic, or viral injury compromises the hepatocytes negative capacity through replicative arrest induction and regeneration, depending on differentiation and activation of liver progenitor cells (LPCs). The growing international challenge of hepatocellular carcinoma and cirrhosis as a result of progressive prevalence of consumption of excessive alcohol, metabolic syndrome, obesity, and viral hepatitis has ignited interest in liver progenitor cells (LPCs) which is similar to stem cell as possible candidate for tissue engineering and cell therapy, as an alteration to organ transplantation (1). Nevertheless, LPCs normally multiply in chronic liver diseases with cancer predisposition, such that they have been proposed to play vital roles in disease progression, driving fibrosis, and might even signify tumor-initiating cells. A research conducted to enhance the understanding the LPCs role in liver cancer using a series of rodent experiment demonstrated that LPCs are just activated in hepatocyte replicative arrest or massive hepatocyte loss in humans. LPCs were found to be activated in most liver diseases, even in minimal level of liver damage. The research determining correlation of LPC proliferation in severe injured liver demonstrated minimization of tumor development with LPC inhibition, possibly connecting activation of LPC with HCC development proliferation (1). 

Non-alcoholic fatty liver disease (NAFLD) is identified as one of the leading cause of HCC as the secondary obesity pandemic consequence. NAFLD is identified in about 30 to 40% of the US general population, where about 95% of them have morbid obesity. Excess accumulation of fats triggers liver injury, regeneration and inflammation which advance to non-alcoholic steatohepatitis (NASH) in a percentage of patients (5). This additional stimulates cirrhosis and scar tissue (fibrosis) formation both of which are HCC predispose. The NAFLD and obesity in the society is coupled with chronic circadian epidemic disruption or social jet lag. A research was conducted to determine whether disruption of chronic circadian is enough to trigger spontaneous hepatocarcinogensis by driving persistent oncogenic activation and liver metabolic dysfunction. The research was carried out by inducing spontaneous HCC in wild-type of mice using chronic jet through mechanism that are very similar to these observed among obese humans. The process initiates NAFLD, which progresses to fibrosis and steorohepatitis before detection of HCC. This pathophysiological path is controlled by degeneration of jet-lag-trigged genome-wide gene and worldwide metabolic dysfunction of liver, with cholesterol/bile acid controlled nuclear receptor and xenobiotic metabolism amongst the deregulated top pathways. Farnesoid X receptor ablation dramatically augments levels of enterohepatic bile acid and Jet-lag-triggered HCC, while constitutive androstane receptor (CAR) loss inhibits HCC induced by NAFLD. CAR is well known promoter of liver tumor which mediates signaling of toxic bile acid. CAR is activated by circadian disruption through promoting sympathetic dysfunction, peripheral clock disruption, and promoting cholestasis (5).

Hepaticc stellate cells (HSCs) are also said to play significant role in HCC and liver fibroid. However, activation of vitamin D receptor (VDR) in HSCs suppresses liver fibrosis and inflammation. A protein p62/SQSTM2 upregulate parenchymal liver cells but downregulate in HCC-related to HSCs, controls activation of HSC negatively.  HSC-unique p62 ablation increases the effect of HSCCs and promotes HCC progression, fibrosis, and inflammation.  p62 interacts directly with RXR and VDR enhancing their heterodimerization that is vital for recruitment of target gene VDR:RXR. . P62 loss in HSCs destroys the inflammation and fibrosis repression through VDR agonists. This shows that p62 is a negative liver fibrosis and inflammation regulator, which achieves this through its aptitude to promote HSCs VDR signaling whose activation promote HCC (4).

 Chronic liver damage sets hepatocytle fibrosis, inflammation and cell death in vicious cycle motion which results in cancer and cirrhosis, where a decisive role is played by hepatic stellate cells (HSCs). Quiescent HSCs express glial fibrillar and store retinoid droplets of lipid related to protein, never receptor p75 growth factor and synaptophysin. In reaction to injury, HSCs separate into α-smooth muscle actin (αSMA)- articulating myofibroblasts. The research was conducted to demonstrate HSCs critical role in the pro-inflammatory signal generation which is significant for development of HCC (2). The previous research has demonstrated a connection between autophagy substrate p62 and signaling adapter and liver cancer. p62 is hyaline granules and Mallory-Denk bodies (MDBs) component, which are aggregates of protein which accumulate in the damaged cytoplasm liver cells in HCC, cirrhosis, and NASH. P62 is significantly upregulated in liver cancer and a number of epithelial cancers which include the prostate, kidney, glioblastoma, and lung. The results strongly proposed that p62-driven paths could be regarded as possible therapeutic targets in HCC and NASH. Nevertheless, some studies handling the p62 role in cancer have centered on its function in epithelial cells transformation. P62 was found to inhibit prostate cancer (2).

 To determine if ablation of total body p62 inhibits development of HCC in mice, 2 week old of total p62 knockout (p62KO) and wild-type (WT) mice were injected with the hepatic carcinogen diethylnitrosamine (DEN) of 25 mg/kg. The mice were then fed with high-fat diet (HFD) as promoter of tumor under obesity conditions. Surprisingly the p62 global loss did not constrain HCC and on the contrary it promoted its development. Even if the multiplicity of the tumor was not impacted, the tumor size increased and there were larger tumor in p62KO compared to WT mice. Although edenomas with inflammation and steatosis developed in both genotypes, HCC only developed in p62KO mice. Tumors in p62K demonstrated higher α-fetoprotein (Afp) expression, a common marker of HCC (2).

There has been significant progress in the HCC treatment. However, success of poor treatment and high tumor incidences continue to be great challenge. Poor therapy has made HCC one of the main causes of death among common malignancies. In an effort to determine the best HCC intervention measure proteomic analysis was conducted to evaluate protein expression in HCC after it has been successfully applied in neoplastic disease. Prolonged hepatitis B virus (HBV) infection is regarded to be engaged in HCC pathogenesis (2). To advance HCC pathogenesis knowledge and to determine the possible new mass spectrometry, anticancer therapy and isobaric tag for absolute and relative quotation (iTARQ) were used. The research studied the variations between nine adjusted non-HCC and HBV-associated HCC tissues specimens. A total of 222 proteins were evaluated for disparity expression in the two kinds of samples. Among the analyzed proteins, a number were confirmed by real time RT-PCR, immunoblotting, and immunohistochemical analysis. Interference of RNA prompted glucose-6-phospahate dehydrogenase (G6PD) downregulation and reduce replication of HBV by fivefold through the IFN pathway. Reduced expression of G6PD resulted in reduction of migration of hepatoma cell and cell culture inversion. The investigation process in general offered new HBV infection pathogenesis information and proposes G6PD as a new target for anti-HCC. The suppression of G6PD might contribute to treatment approaches for inhibiting progression of tumor. The research process used proteomic analysis which is a helpful technology for protein expression evaluation, which has been widely used to neoplastic diseases. To contrast levels of protein expression in HCC, two-dimensional electrophoresis (2-DE), basic proteomic-founded technology is used. 2-DE and MALDI-TOF/MS were used to show that tubulin alpha-6 chain is a probable biomarker for effectively differentiated HCV-related HCC.  On the foundation of adjacent non –HCC and HCC 2-DE tissues specimens, SULT1A1 was said to be helpful in early HCC discovery and helped in the clinical outcome prediction for HCC patients. Nevertheless, 2-DE contains drawbacks that include high labor costs, excessive time, low sensitivity and integral variation (2).   

Liver cancer has been associated to a number of changes in its homeostasis reaction and presence of different receptors in its surrounding. One of the receptors associated with liver cancer is CD151 receptor which is regarded as a member of the tetraspanin receptors family. CD151 is a lateral modulator and organizer of activities of various transmembrane proteins families. This receptor has been associated with the progression and development of various cancers, though its contribution to chronic inflammatory diseases remains unclear. In a research conducted to determine CD151 role in liver cancer established that CD151 is up-regulated by different   signals of microenvironment in a range of prime liver cancer and in various inflammatory liver diseases, where it supports recruitment of lymphocyte. CD151 was highly demonstrated in hepatic neovessels and sinusoids endothelial cells developing in tumor margins and fibrotic septa. Human hepatic sinusoidal endothelial cells (HSECs) primary cultures showed CD151 at the intercellular vesicles and cell membrane (3). There was upreglation of CD151 by HepG2 and VEGF conditioned media through not by proinflammatory cytokines. It was confirmed through confocal microscope that colonization of CD151 happens with superfamily member of endothelial adhesion immunoglobulin/molecule, VCAM-1. Evaluation of functional flow-founded connection with HSECs and basic human lymphocytes illustrated a 40% lymphocccyte adhesion reduction with blockade of CD151. Lymphocyte adhesion inhibition was similar between CD151/VCAM-I blockade combination and CD151 blockade, proposing a collaborative role in the two receptors. The research thus demonstrated that there is upregulation of CD151 in the liver where during prolonged inflammation, where CD151 supports recruitment of lymphocyte through live endothelium. The research thus suggests that the VCAM-1 activity is regulated by the CD151 in the recruitment of lymphocyte to human liver and this could be a new target of anti-inflammatory target in hepatocellular cancer and liver disease prevention. Chronic hepatitis which is one main cause of liver cancer is characterized accumulation of lymphocyte in liver tissues, which drives carcinogenesis and fibrosis. CD151 tetraspanin support connection of lymphocyte to liver endothelium. The research demonstrates upregulation of CD151 in hepatocellular carcinoma (HCC) and liver disease and is controlled on endothelium by procarcinogenic and tissues remodeling factors. These functional and regulatory studies identify CD151 as a possible therapeutic target for HCC and liver fibrosis treatment (3).


Liver is one of the largest and most important human organs in enhancing effective operation of human body and human general health and safety. The organ has extensive important responsibilities that ensure effective operation of various body mechanisms that include metabolism of carbohydrates, fatty acids and proteins, bile secretion, blood storage, detoxification of blood, storage and distribution of nutrients and vitamins, and enhance immunity. It also has a complex anatomy that promotes its ability to execute its responsibilities, with its primary functional unit being lobule that has substructures which include hepatocytes plates, portal triads, liver sinusoids and bile canaliculi. However, its main role is to control safety and flow of food substances absorbed from the digestive system before they are circulated in the entire circulatory system. The liver is position in right upper abdomen where it is protected by the lib cage and the diaphragm. Its healthy operation ensures general body health, with its failure in operation increasing death risk. Liver can suffer from various health conditions which include jaundice, Hepatitis B and C, cirrhosis and cancer, which is a condition that can be initiated by the other liver diseases especially when the diseases advance to chronic cases.     

Liver cancer is ranked among the most popular solid cancers in the globe and the leading cause of cancer related death. Liver cancer cause death at a very high rate, while its disease burden and global incidences are increasing steadily. HCC symbolizes liver cancer major subtype that accounts for about 90% of all cases of liver cancers, with the main risk factors including HCV and HBV infection, NAFLD, prolonged and continuous excessive consumption of alcohol among other metabolic disorders. Studies have demonstrated various mechanisms that can influence the development of liver cancer, especially sever inflammation that results to cells mutation and extensive growth of mutated cells creating liver tumor. It has also been established that development of HCC among patients with metabolic syndrome as the main risk factor might generate from malignant alteration of preexisting adenomas liver cell in the absence of important liver cirrhosis and fibrosis. Due to the increasing prevalence of Type 2 diabetes and obesity globally, that essentially predispose patients to progression of metabolic fatty liver disorder, thus NAFLD has been of specific concern.

Today, arthotopic liver transplantation, radio-frequency ablation surgical resection, small-molecule tyrosine kinase sorafenib inhibitor and transcatheter arterial chemoebolization are the main treatment of HCC. However,, research still continue to determine other therapeutic methods that can be used to inhibit growth and development of HCC in the liver which include CD151 and glucose-6-phospahate dehydrogenase (G6PD) among other therapeutic measures that are being discovered with advanced research. The second most popular basic liver cancer is ICC which accounts for about 10% of cancer cases, with its main causes being environmental factors. However, the research development in this cancer is considerably minimal and thus, making it complex to handle. Generally, cancer is initiated by sequential mutations of genes resulting to either change in the genes epigenetic signature such as tumor genes suppressor and oncogenes, or sequence alterations. The genes that are most impacted play main roles in differentiation, self-renewal,, cell proliferation, and cell cycle control mechanisms. Both ICC and HCC develop from central precursor lesions, demonstrating the hepatic carcinogenesis multistep process.

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