Nanotherapeutics for the Treatment of Hepatocellular Carcinoma

Biswajit Mukherjee

• Verlag: Bentham Science Publishers
• Jahr: 2022
• ISBN:
  9789815039740
• Thema: Medizin
• Thema: Onkologie

Hepatocellular carcinoma (HCC) is a leading cause of death globally. Conventional chemotherapeutic agents are unable to penetrate cancerous hepatocytes completely and are toxic to non cancerous cells and tissues. This toxicity significantly compromises the therapeutic outcome of conventional chemotherapeutic agents which is also reflected in the high mortality of the disease. Nanotherapeutics have shed new light onto HCC treatment by enabling site-specific in vivo delivery of chemotherapeutics specifically to neoplastic hepatocytes without affecting normal hepatocytes. Thus, nanotherapeutics have shown considerable potential and there is tremendous impetus for rapid translation from the pre-clinical to the clinical domain to significantly prolong the survival in HCC. In Nanotherapeutics for the Treatment of Hepatocellular Carcinoma, authoritative experts of the field have explored the important aspects of nanotherapeutics against HCC. The book exhaustively, vividly and explicitly describes the molecular pathogenesis, diagnostic aspects and nanotherapy of HCC, while also highlighting the challenges of conventional therapy and the benefits of nanotherapeutics. Chapters of the book also cover recent investigations of nanotherapeutics against HCC, types of nanomedicines, recent patents, commercially available nanotherapeutics and a future perspective to give a comprehensive review of the topic to readers. In addition to these defining features, the book provides several references for further reading. The book is an ideal resource on HCC nanotherapeutics for medical and pharmacology postgraduate students, faculties, researchers, and biomedical scientists working on HCC and nanotherapy.

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.

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^* Corresponding author Biswajit Mukherjee: Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700032, India; Tel/Fax: [phone]; 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...