Hepatocellular carcinoma (HCC) refers to cancer that originates in the liver, which is distinguished from "secondary" liver cancer that spreads from other organs to the liver. Hepatocellular carcinoma, which accounts for 90% of all primary liver cancers, is the sixth most common cancer in the world and the second leading cause of cancer death . It has the highest incidence in East Asia and other regions where HBV is prevalent.
3. What Affects Hepatocellular Carcinoma？
Hepatocellular carcinoma is the most common type of liver cancer in adults. It is usually diagnosed in people aged 50 or older.
The etiology of liver diseases is diverse, including chronic viral infection of hepatitis b or hepatitis c virus, alcohol toxicity, autoimmune and cholestasis liver diseases, and metabolic factors .
3.1 TNF-TNFR2 Signaling in Allergy
Hepatocellular carcinoma is more common in men than in women . But one of the subtypes, the fibroblast, which is very rare and accounts for less than 1% of HCC, is more common in women.
3.2 Chronic Viral Hepatitis
Liver cancer often occurs in the context of chronic hepatitis. Chronic (long-term) infection with either hepatitis b virus (HBV) or hepatitis C virus (HCV) is the most common risk factor for liver cancer  .These infections cause cirrhosis of the liver. Hepatitis C-induced progressive hepatic fibrosis and aging are recognized as high-risk conditions for liver cancer development .
Cirrhosis  is a disease in which liver cells are damaged and replaced by scar tissue. Most liver cancer patients have signs of cirrhosis.
3.4 Alcohol Abuse
Alcoholism  is one of the main causes of liver cirrhosis, which in turn increases the risk of liver cancer.
3.5 Obesity and Diabetes
Obesity can lead to nonalcoholic fatty liver disease, and people with nonalcoholic fatty hepatitis (NASH) can develop cirrhosis of the liver. Studies have shown that there is a close relationship between neuromodulation, endocrinology and liver cancer in obese patients .
The high risk of diabetes may be due to high insulin levels in diabetics or liver damage caused by diabetes. The choice of antidiabetic treatment may affect the development of liver cancer. Insulin therapy has been reported to increase the risk of liver cancer, while metformin seems to reduce the risk of liver cancer .
3.6 Iron Storage Related Diseases
Hemochromatosis, which causes the liver and other organs to store excess iron. People with the disease can develop hepatocellular carcinoma.
3.7 Exposure to Certain Hazardous Substances
Aflatoxin: Long-term exposure to aflatoxin is a major risk factor for liver cancer.
Vinyl chloride and cerium oxide: Exposure to these chemicals increases the risk of hepatic angiosarcoma.
Arsenic: Long-term consumption of arsenic-contaminated water increases the risk of certain types of liver cancer.
3.8 Some Rare Diseases
Diseases that increase the risk of liver cancer include:
Porphyria cutanea tarda.
Glycogen storage diseases.
3.9 Other Factors
Smoking  increases the risk of liver cancer
Recent findings suggest that adeno-associated virus 2 (AAV2) infection is a new cause of this disease, especially in people without cirrhosis .
Figure 2 The impact factors and processes of HCC
Treatment depends on the extent of cancer progression.
The most commonly used liver cancer comprehensive staging tool in the world is the Barcelona Clinical Liver Cancer (BCLC) system.
- (BCLC A): Patients with single tumours or up to three nodules that are 3 cm or smaller and preserved liver function are classified as having very early or early-stage hepatocellular carcinoma. The treatments available to patients at this stage are surgical resection, liver transplantation or local ablation.
- (BCLC B): In the mid-term, patients with compensatory cirrhosis have no tumor-related symptoms or vascular invasion. Transarterial chemoembolization (TACE) can be considered.
- (BCLC C): In advanced stages, the patient's symptoms at this stage are characterized by tumors or invasive tumors (extra-hepatic spread or vascular invasion), or both. This stage can be treated with the multi-kinase inhibitor sorafenib.
- (BCLC D): At the end of the period, there are serious cancer-related symptoms or severe liver damage, or both, and are not suitable for transplantation. Symptomatic treatment is recommended at this stage.
The best treatment opportunity for hepatocellular carcinoma is resection. When the tumor is single and less than 2 cm, the survival rate after resection is close to 70%. However, only 10% of patients met the criteria at the time of discovery. Therefore, early diagnosis is essential to improve prognosis.
7.2 Liver transplantation
The criteria for determining whether a liver cancer patient is eligible for a liver transplant are very different worldwide. However, MC remains the benchmark for patient selection .
During liver transplant surgery, the entire liver is removed and replaced with a healthy liver. After the transplant, you need to continue taking the drug to prevent the body from rejecting the new liver.
However, the current status is that the number of patients waiting for liver transplantation each year exceeds the number of patients undergoing liver transplantation.
7.3 Ablation therapy
Ablation therapy removes or destroys tissue.
Radiofrequency ablation (RFA) : the first line of ablation technique, which involves the use of a special needle to insert directly into the skin or through the abdominal incision to reach the tumor. High-energy radio waves heat needles and tumors that kill cancer cells.
Microwave therapy: A therapy that exposes a tumor to high temperatures generated by microwaves. This can destroy and kill cancer cells.
Percutaneous injection of ethanol: using ethanol kill cancer cells. The local control effect of ethanol injection is poor .
Cryoablation: A therapy that uses instruments to freeze and destroy cancer cells.
Electroporation treatment: An electrical pulse is sent through an electrode placed in a tumor to kill cancer cells. Electroporation therapy is being studied in clinical trials.
Embolization therapy: Embolization treatment is to block or reduce the flow of blood through the hepatic artery to the tumor. Thereby inhibiting the growth of the tumor.
7.4 Targeted therapy
Targeted therapy is a method that uses drugs or other substances to specifically recognize and attack specific cancer cells without harming normal cells.
Hepatocellular carcinoma is associated with abnormal activation of multiple cellular signaling pathways , which leads to the complexity of its etiology. The current therapeutic targets for hepatocellular carcinoma include:
Figure 3 The targets involved in hepatocellular carcinoma
Cell membrane receptors: such as tyrosine kinase receptor, vascular endothelial growth factor receptor.
Growth factors: Wnt/beta-catenin, Ras /Raf /MEK /ERK and PI3K /Akt /mTOR.
Cell cycle regulatory proteins: p53, p16 /INK4, cyclin /CDK complex.
Unfortunately, currently there are so few clinically effective HCC targeted therapies that multiple kinase inhibitors are the only HCC therapy drugs approved by FDA.
Sorafenib is currently approved as a first-line systemic therapy for unresectable liver cancer . It is a multi-kinase inhibitor and is the only advanced HCC-targeted drug currently marketed in the United States and the European Union.
Sorafenib inhibits kinases such as RAF kinase, VEGFR-2, VEGFR-3, PDGFR-β, KIT and FLT-3. It can also directly inhibit tumor growth through the RAF / MEK / ERK signaling pathway; it also inhibits tumor cell growth indirectly by inhibiting VEGFR and PDGFR.
7.5 Radiation therapy
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill or prevent cancer cells from growing.
7.6 New therapy
Studies on microflora and HCC have found that in the mouse model of liver cancer induced in the laboratory, intestinal microorganisms influence the development of tumors and induce the occurrence of tumors .One study found that a specific probiotics (inulin type fructan) can reduce the proliferation of hepatocellular carcinoma cells in mice by stimulating the production of short-chain fatty acid propionate .
 Jemal A, Bray F, Center M M, et al. Global cancer statistics [J]. Ca Cancer J Clin, 2011, 61(2): 69-90.
 Hemming A W, Berumen J, Mekeel K. Hepatitis B and Hepatocellular Carcinoma [J]. Gastroenterologist, 2016, 20(4): 703-720.
 Ibrahim G A, Khan S A, Toledano M B, et al. Hepatocellular carcinoma: Epidemiology, risk factors and pathogenesis [J]. World Journal of Gastroenterology, 2008, 14(27): 4300-.
 Yang D, Hanna D L, Usher J, et al. Impact of sex on the survival of patients with hepatocellular carcinoma: A Surveillance, Epidemiology, and End Results analysis [J]. Cancer, 2015, 120(23): 3707-3716.
 Bosetti C, Turati F, La Vecchia C. Hepatocellular carcinoma epidemiology [J]. Best Practice & Research Clinical Gastroenterology, 2014, 28(5): 753-770.
 Stanaway J D, Flaxman A D, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013 [J]. The Lancet, 2016: 1081-1088.
 Hoshida Y, Fuchs B C, Bardeesy N, et al. Pathogenesis and prevention of hepatitis C virus-induced hepatocellular carcinoma [J]. Journal of Hepatology, 2014, 61(1): S79-S90.
 Bolondi L. Surveillance programme of cirrhotic patients for early diagnosis and treatment of hepatocellular carcinoma: a cost effectiveness analysis [J]. Gut, 2001, 48(2): 251-259.
 Turati F, Galeone C, Rota M, et al. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies [J]. Annals of Oncology, 2014, 25(8): 1526-1535.
 Gan L, Liu Z, Sun C. Obesity linking to hepatocellular carcinoma: A global view [J]. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 2018, 1869(2): 97-102.
 Chen H P, Shieh J J, Chang C C, et al. Metformin decreases hepatocellular carcinoma risk in a dose-dependent manner: population-based and in vitro studies [J]. Gut, 2013, 62(4): 606-615.
 Chuang S C, Vecchia C L, Boffetta P. Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection [J]. Cancer Letters, 2009, 286(1): 0-14.
 Nault J C, Datta S, Imbeaud S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas [J]. Nature Genetics, 2015.
 Hayes C, Kazuaki C. MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma [J]. International Journal of Molecular Sciences, 2016, 17(3): 280-.
 Lai C L, Yuen M F. Prevention of hepatitis B virus-related hepatocellular carcinoma with antiviral therapy [J]. Hepatology, 2013, 57(1): 399-408.
 Webster D P, Klenerman P, Dusheiko G M. Hepatitis C [J]. Lancet, 2015, 385(9973): 1124-1135.
 Clavien P A, Lesurtel M, Bossuyt P M, et al. Recommendations for liver transplantation for hepatocellular carcinoma: an international consensus conference report [J]. Lancet Oncology, 2012, 13(1): e11-e22.
 Lencioni R, Crocetti L. Local-Regional Treatment of Hepatocellular Carcinoma [J]. Radiology, 2012, 262(1): 43-58.
 Lin S M. Randomised controlled trial comparing percutaneous radiofrequency thermal ablation, percutaneous ethanol injection, and percutaneous acetic acid injection to treat hepatocellular carcinoma of 3 cm or less [J]. Gut, 2005, 54(8): 1151-1156.
 Cervello M, Mccubrey J A, Cusimano A, et al. Targeted therapy for hepatocellular carcinoma: novel agents on the horizon [J]. Oncotarget, 2012, 3(3).