Preface

Hepatocellular cancer (HCC) is among the ten most common tumor types worldwide. It is associated with chronic hepatitis B and C virus infections, chronic alcoholism, and with nonalcoholic steatohepatitis (NASH). HCC most often develops against a background of chronic liver disease (CLD), in which hepatitis progressively develops into fibrosis, cirrhosis, and finally cancer. This suggests that regardless of etiology, the pathogenesis of HCC is immune-mediated. Early-stage HCC is usually asymptomatic, and in most cases, by the time diagnosis is made, HCC is often in advanced stages, resulting in high mortality. A major limitation in achieving an early diagnosis, as well as developing and assessing the efficacy of therapeutics targeting HCC, is the lack of reproducible biomarkers. Major efforts are underway to develop such markers as an understanding of the molecular pathogenesis of HCC increases. Given that HCC, like most other tumor types, is a multi-step process, it has been challenging to develop effective therapeutics. A variety of local and systemic therapies are currently in use to treat HCC, but the patient response rate is modest. However, the renin-angiotensin system, insulin resistance, cancer stem cells, and specific epigenetic changes in hepatocellular gene expression are putative targets for the development of new therapies. Altered expression patterns of miRNAs may also contribute to the pathogenesis of HCC and serve as therapeutic targets. Dysbiosis of the gut microbiome, which is characterized by alterations in the ratios of microbes in the intestine, may also mediate alterations in gene expression in hepatocytes and immune cells that are important to the pathogenesis of CLD. However, it is not always clear whether altered patterns of gene expression mediate HCC development or reflect the outcome of tumorigenesis. The HCC microenvironment is also characteristically tolerogenic, which attenuates the efficacy of newer treatments, such as cancer immunotherapy. The application of immunotherapy and/ or the resolution of dysbiosis prior to the development of cancer may also be a viable option to alter the progression of CLD. The tumor microenvironment is also altered by changes in glucose metabolism in which oxidative metabolism is replaced by aerobic glycolysis in tumor cells. Future research will determine whether the biological properties of tumor cells, the tumor microenvironment, the gut microbiome, and/or immune effector cells will be the best target in developing more effective therapies against HCC.

> **Mark Feitelson** Department of Biology, Temple University, Philadelphia, PA, USA

#### **Alla Arzumanyan**

Temple University, Philadelphia, PA, USA

**1**

**Chapter 1**

**Abstract**

Dysbiosis, hepatitis B and C

viduals will die from this ailment [2].

**1. Introduction**

Etiology, Mechanism and

Treatment of Liver Cancer

*Aqsa Nazir, Muhammad Aqib and Muhammad Usman*

Liver cancer or hepatocellular carcinoma (HCC) is a malignant tumor in liver tissue and worldwide it is fourth leading death cause among all cancers. The most common causes of liver cancer are hepatitis B or C virus infections, alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH), smoking and obesity. The development and metastasis of liver cancer is a multistage and branched process of morphological and genetic traits. Various corresponding signaling pathways such as Yes-Associated Protein-Hippo Pathway (YAP-HIPPO), Wnt/β-catenin and inflammation by interleukin-6 (IL-6), tumor necrosis factor (TNF), nuclear factor-Κb (NF-κB), biological pathways including epithelial–mesenchymal transition (EMT), tumor microenvironment, tumor-stromal interactions and cancer stem cells and gut microbial dysbiosis are allied to both origination, progression and metastasis of liver cancer. Numerous therapeutic approaches are classified into different categories such as pharmacological therapy including sorafenib, lenvatinib and ramuciruma, surgery of HCC patients includes surgical resection, adjuvant therapy after surgical resection and liver transplantation. Locoregional ablative therapy includes cryotherapy, ethanol injection and radiofrequency ablation, cytotoxic chemotherapy, natural compounds such as piperine, as curcumin and oleocanthal, oncolytic virus therapy, immunotherapies and nanotechnology.

**Keywords:** hepatocellular carcinoma (HCC), inflammation, disease progression,

Liver cancer is a malignant tumor which is commonly occurs in cirrhosis and chronic liver disease patients. Liver cancer comprises of different types, the most common type is hepatocellular carcinoma (HCC) or primary liver cancer and other rarely occurring types includes hepatoblastoma and intrahepatic cholangiocarcinoma depend upon their origin such as liver stem cells, hepatocytes, cholangiocytes, and hepatoblasts [1]. Worldwide, the fourth leading cause of all cancers related deaths is primary liver cancer or HCC and its prevalence is 75% of all types of liver cancers. Out of all types of cancer related patients, every fifth male and seventh in female is diagnosed with liver cancer. Moreover, World Health Organization (WHO) declared that if it is not properly treated then ultimately in 2030 more than one million indi-
