Hepatocellular Carcinoma: Diagnosis, Molecular Pathogenesis, Biomarkers, and Conventional Therapy
Biswajit Mukherjee*, 1, Manasadeepa Rajagopalan2, Samrat Chakraborty1, Prasanta Ghosh1, Manisheeta Ray1, Ramkrishna Sen1, Iman Ehsan1 1 Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India
2 East West College of Pharmacy, Bangalore, Karnataka 560091, India
Abstract
Hepatocellular carcinoma (HCC), the most common liver malignancy, has been a significant cause of cancer-related deaths worldwide. Cirrhosis, hepatic viral infections, fatty liver, and alcohol consumption are notable risk factors associated with HCC. Furthermore, a crucial challenge in the therapeutic management of HCC patients is the late-stage diagnosis, primarily due to the asymptomatic early stage. Despite the availability of various preventive techniques, diagnoses, and several treatment options, the mortality rate persists. Ongoing investigation on exploring molecular pathogenesis of HCC and identifying different prognostic and diagnostic markers may intervene in the conventional mode of treatment option for better therapeutic management of the disease. Subsequently, tumor site and its size, extrahepatic spread, and liver function are the underlying fundamental factors in treating treatment modality. The development in both surgical and non-surgical methods has resulted in admirable benefits in the survival rates. Understanding the mechanism(s) of tumor progression and the ability of the tumor cells to develop resistance against drugs is extremely important for designing future therapy concerning HCC. This chapter has accumulated the current literature and provided a vivid description of HCC based on its classification, risk factors, stage-based diagnosis systems, molecular pathogenesis, prognostic/diagnostic markers, and the existing conventional treatment approaches.
Keywords: Cellular signaling pathway, Cirrhosis, HCC molecular pathogenesis, HCC- prognostic/diagnostic markers, HCC risk factors, Hepatocellular carcinoma (HCC), cell signaling during HCC development, Ongoing therapy against HCC, Stage-based diagnosis, Tumor microenvironment.
* Corresponding author Biswajit Mukherjee: Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India; Tel/Fax: +913324146677; Emails: [email protected], [email protected] INTRODUCTION
Hepatocellular carcinoma (HCC) is a malignant form of highly progressive primary liver cancer. It originates from hepatocytes. Around 0.9 million new cases and 0.8 million deaths of liver cancer patients globally have been reported in 2020 by the International Agency for Research on Cancer. Increasing mortality rates and late-stage diagnosis often make HCC a tremendous challenge for its better therapeutic management. Hence patients detected with early-stage HCC possess a greater chance of getting a positive response with different treatment protocols. HCC may not show any symptoms at an early stage of cancer. Still, with the disease's progress, the symptoms such as pain at the right side of the upper abdominal part, fatigue, bloating, loss of appetite, nausea, vomiting, fever, pale bowels, and dark urine may appear. Several risk factors are associated with infected livers, fatty liver, and chronic alcohol consumption in a high amount. In the case of cirrhotic liver, the treatment decisions become limited except the finding of liver transplantation. Due to cirrhosis, any planned liver resection gets limited since the remaining liver may not tolerate volume loss and regenerate. However, an effective treatment method for HCC and cirrhosis of the liver is orthotopic liver transplantation (OLT), but early-stage HCC detection is required for such cases. HCC and cirrhosis are more significant in patients with hepatitis C virus (HCV) infection.
Several upstream or downstream regulators in various signaling cascades activate/ inactivate to continue uncontrolled proliferation in the cancerous processes (Mello and Attardi 2018, Nam and van Deursen 2014, Dolgin 2017). Epigenetic alterations may cause DNA methylation and other histone modifications that confer significant alteration to the genome. The epigenetic modification may inactivate tumor suppressor genes or cause the sudden activation of oncogenes. These may ultimately cause cancer (Kanwal and Gupta, 2012). Thus, a vivid understanding of the tumor microenvironment only can lead to exploring molecular pathogenesis more accurately and minutely to access the more appropriate and convincing therapeutic management of HCC. Suitable diagnostic and prognostic biomarkers are still essential to identify the disease early as the treatment decisions strictly depend on the tumor stage.
Hence, in this chapter, we want to introduce HCC with its classification, risk factors, and various diagnostic staging based on current literature. Tumor microenvironment and molecular pathogenesis during HCC development and progression, along with prognostic/diagnostic HCC markers, have been explored here. The existing conventional treatment approaches give a better understanding of the current way of therapeutic management of HCC.
CANCER AND ITS TYPES
The liver is the largest organ that primarily undergoes detoxification, metabolism, break-down of blood cells, protein synthesis, and bile synthesis. The liver predominantly contains hepatocytes. However, other cell types such as perisinusoidal fat-storing cells or ito cells, hepatic stellate cells, Kupffer cells, and hepatic sinusoidal endothelial cells are also available in the liver (Guyton and Hall 2006, Fox 2011). Neoplasm that grows in epithelial cells is carcinoma, whereas mesenchymal (connective tissue) origin is a sarcoma. Both types appear in the liver.
Primary liver cancer begins in the liver and secondary liver cancer cells where neoplastic cells develop in a different organ and migrate to the liver.
Primary Liver Cancer
Hepatocellular Carcinoma (HCC)
The most common primary liver cancer that accounts for nearly 75 percent of all liver cancers in adults is HCC. It originates from hepatocytes. HCC usually metastasizes to the lungs, bone marrow, and other digestive organs, including the stomach, pancreas, and small and large intestines, including the colon.
Intrahepatic Cholangiocarcinoma (Bile Duct Cancer)
Intrahepatic cholangiocarcinomas originate from epithelial cells of the cell-lining present in small bile ducts. The type accounts for 10-20% of hepatic cancers (Gupta and Dixon 2017).
Angiosarcoma and Hemangiosarcoma
They are primarily rare forms of primary hepatic c...