**1.3 Liver cancer and its types**

202 Hepatocellular Carcinoma – Basic Research

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

produces bile which contains bile salts (sodium glycocholate, sodium taurocholate). The

involves in carbohydrate and fat metabolism, hemoglobin metabolism and lipid

converts circulating ammonia into urea by urea cycle (Ornithine cycle) and thereby

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

 stores many chemicals such as glycogens, vitamins, minerals and several metabolites. involves in detoxification and removal of many toxic chemicals, including drugs,

bile salts emulsify fats and oils and thus help in the digestion of them.

carcinogens, and various toxins through bile from the body.

produces serum proteins such as albumin, clotting factors.

known as the ito cell. These are adipose or stellate cells.

reduces ammonia level in blood.

Fig. 1. Histological structure of a liver lobule

**1.2 Hepatic regenerative capability** 

synthesis.

Liver undertakes several important functions in our body. It

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 cirrhosis and cirrhosis associated with genetic liver diseases.

### **1.3.1 Primary liver cancer**

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

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

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

#### **1.3.1.2 Cholangiocarcinoma**

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

#### **1.3.1.3 Angiosarcoma and hemangiosarcoma**

These are fast growing rare type liver cancers.

#### **1.3.1.4 Angiosarcoma**

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

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 205

The most common primary malignant tumor of liver is hepatocellular carcinoma. This primary liver cancer is also called hepatoma. As described above, liver has different types of cells such as hepatocytes, billiary cells, blood cells, Kupffer cells, ito cells, perisinusoidal cells etc. However, about more than 80% of liver tissue consists of hepatocytes. The majority of primary liver cancer (>90%) arises from hepatocytes and is called hepatocellular carcinoma. During hepatocarcinogenesis, initial carcinogen insult results in initiated cells from normal liver parenchyma cells or hepatocytes by genetic alteration following an interaction generally with DNA. Subsequent tumor promotion by chronic exposure of carcinogen or a tumor promoter such as phenobarbital develop clonally selected expansions of initiated cell populations called hepatic altered foci by fixing the mutations for further genetic changes. Additional accumulations of genetic changes within these foci produce hyperplastic nodules that ultimately lead to the development of hepatocellular carcinoma.

Transformation of the initiated hepatocytes into hepatocellular carcinoma is a multistage complex process. Based on the various morphological (such as appearance, size, shape, growth) and biochemical (such as variation in staining patterns, and altered enzyme expression patterns) changes of these hepatocytes, leading to hepatocellular carcinoma, various stages of development of the disease, namely *initiation*, *promotion* and *progression,* have been described to understand the progress of the disease in a more defined way and to

Exposure of genotoxic agents such as aflatoxins, 2-acetylaminofluorene, diethylnitrosamine, ionizing radiation etc. alters DNA sequence, causing mutations in the hepatocytes that

Fig. 2. Glycogen-stored early preneoplastic focal lesion (shown by yellow arrows) in rat

hepatic tissue with Periodic Acid Schiff reaction. (Mukherjee et al. 2005)

**3. Hepatocellular carcinoma** 

**3.1 Stages of hepatocellular carcinoma** 

develop better therapeutic strategies.

**3.1.1 Initiation** 

#### **1.3.1.5 Hemangiosarcoma**

This is also developed from the lining of blood vessel, however, with relatively a slow speed. Blood-filled channels and spaces can be delineated under microscope. This is highly invasive type of cancer. It is commonly found in children. In patients suffering from hemangiosarcoma, the rapture of tumor leads to bleeding to death.
