**Chemically Induced Hepatocellular Carcinoma and Stages of Development with Biochemical and Genetic Modulation: A Special Reference to Insulin-Like-Growth Factor II and Raf Gene Signaling**

Biswajit Mukherjee\*, Miltu Kumar Ghosh and Chowdhury Mobaswar Hossain *Department of Pharmaceutical Technology, Jadavpur University, Kolkata India* 

#### **1. Introduction**

200 Hepatocellular Carcinoma – Basic Research

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#### **1.1 Liver and its physiology**

The liver, the largest organ in the body, predominantly functions as a biochemical laboratory where metabolism takes place. It has both endocrine and exocrine functions; and is also involved in numerous metabolic activities and acting as a storage depot. Once the nutritional substances and other chemicals such as drugs, carcinogens etc. reach in liver, they are metabolized by hepatic enzymes. The organ is located on the right side of the abdomen just beneath the diaphragm in human. Liver is a solid organ consisting of several lobes. Each lobe is constituted with numerous lobules which are in general hexagonal in shape (Figure 1). The center of each lobule is occupied by the central vein and the periphery of the lobule is delineated by a close arrangement of hepatic artery, portal vein, and bile duct; called "portal triads". The portal triads appear at the vertices of the hexagonal lobules. The vessels generated from the portal triads ramify and distribute along the sides of the lobule, and open into the sinusoids which have thin epithelial lining, a discontinuous layer of fenestrated endothelial cells. The liver has different types of cells. Oval cells are generally found near the portal triad. This rare cell-type has been claimed as hepatic stem cells by some researchers (Zamule et al., 2011). However, the major cell-type in liver is the polygonal hepatic parenchymal cells (hepatocytes). Hepatic lobules are made up of more than 80% hepatocytes which have an average size of 25 and occupy 70-90% of liver mass, depending on the species. They have clear cell membrane; sometimes with two nuclei. They have large deposits of glycogen, often with lipid droplets and basophilic materials. They also contain other cellular organelles such as mitochondria, rough endoplasmic reticulum (granular) and smooth endoplasmic reticulum (agranular), golgi apparatus, and lysosomes. The hepatocytes are arranged in stacks of anastomosing plates, separated by an anastomosing

<sup>\*</sup> Corresponding Author

Chemically Induced Hepatocellular Carcinoma and Stages of Development with Biochemical and Genetic Modulation: A Special Reference to Insulin-Like-Growth Factor II and Raf Gene Signaling 203

appear. Normal hepatic function suffers and hepatic homeostasis decreases.

cirrhosis and cirrhosis associated with genetic liver diseases.

**1.3.1.1 Hepatocellular carcinoma (also called hepatoma)** 

cause primary liver cancer. Primary liver cancer has different types, too.

children and teenagers, similar pattern of the disease is called hepatoblastoma.

When primary liver cancer occurs in bile ducts it is called cholangiocarcinoma.

**1.3 Liver cancer and its types** 

**1.3.1 Primary liver cancer** 

**1.3.1.2 Cholangiocarcinoma** 

**1.3.1.4 Angiosarcoma** 

vessel of the liver.

**1.3.1.3 Angiosarcoma and hemangiosarcoma**  These are fast growing rare type liver cancers.

increase in hepatic cells by rapid cell division (hyperplasia) or increase in cell-size (hypertrophy) primarily causes enlargement of the tissue (Michalopoulos & DeFrances, 1997). Exposure to high levels of chemical toxicants causes increase in liver-size about 2-3 times of its normal size to combat the enhanced metabolic pressure exerted by chemical exposure (Michalopoulos & DeFrances, 1997). By regeneration process liver replaces the necrotic/ dead cells or the cells damaged due to toxicity. During hepatic continual regeneration process, the increased collagen synthesis and deposition result in fibrosis. This alongwith further continual hepatic cell damage due to various stress conditions cause liver cirrhosis (Lv et al., 2006). In cirrhosis, liver morphology alters. Scarring and nodularity

Cancer is the uncontrolled proliferation of cells that is caused by the multi-genetic defects. When the phenomenon occurs in liver cells, this is called hepatic cancer or liver cancer. The cancerous process begins in a few cells and the cells become immortal. They invade adjacent cells, intrude other nearby tissues (sometimes tissues at a distance) and metastasize. Uncontrolled proliferation of the cells causes solid mass formation in liver, resulting hepatic tumor. The predominant risk factors and etiological agents responsible for hepatocellular carcinoma in humans have been identified as chronic infection with hepatitis B virus or hepatitis C virus, exposure to aflatoxin B1 or other chemical carcinogens, and alcoholic

Primary liver cancer means that the cancerous process occurs and develops primarily in liver and does not start from the spread of cancerous cells located outside the liver. It is the most common type of hepatic cancer. There may be several causes of primary liver cancer. Chronic viral infections such as hepatitis B or C, some toxins, chemical induced hepatic damage, radiation-induced hepatic damage, and chronic liver diseases such as cirrhosis can

Hepatocellular carcinoma is the incidence of primary liver cancer in liver parenchyma cells or hepatocytes. People suffering from liver chronic diseases such as cirrhosis of liver are more prone to hepatocellular carcinoma. This is common to adult patients. However, in

This rare form of rapidly growing fatal tumor develops in the endothelial cells of blood

system of sinusoids. One or two cells thick hepatocytes appear radiating from central vein towards the periphery. They metabolize and excrete into sinusoids or bile canaliculi. They can undergo cell division to produce more hepatocytes. Other than the endothelial cells, the liver sinusoids contain phagocytic cells derived from monocytes, known as Kupffer cells. These macrophages phagocytize particulates and cell debris. Another hepatic cell-type is known as the ito cell. These are adipose or stellate cells.

Liver undertakes several important functions in our body. It


#### **1.2 Hepatic regenerative capability**

Under normal condition in an adult, liver maintains its size. However, liver has the regenerative capacity. Under various stress conditions, liver-size may increase. Numerical

Fig. 1. Histological structure of a liver lobule

increase in hepatic cells by rapid cell division (hyperplasia) or increase in cell-size (hypertrophy) primarily causes enlargement of the tissue (Michalopoulos & DeFrances, 1997). Exposure to high levels of chemical toxicants causes increase in liver-size about 2-3 times of its normal size to combat the enhanced metabolic pressure exerted by chemical exposure (Michalopoulos & DeFrances, 1997). By regeneration process liver replaces the necrotic/ dead cells or the cells damaged due to toxicity. During hepatic continual regeneration process, the increased collagen synthesis and deposition result in fibrosis. This alongwith further continual hepatic cell damage due to various stress conditions cause liver cirrhosis (Lv et al., 2006). In cirrhosis, liver morphology alters. Scarring and nodularity appear. Normal hepatic function suffers and hepatic homeostasis decreases.
