**3.1.2 Promotion**

Initiated hepatocytes are unable to grow autonomously (Farber & Sarma 1987), although they gain the potential to favor proliferation by possessing alterations in gene and protein expressions. Upon exposure to an environment where initiated cells are at greater risk, further genetic alterations begin, causing some reversible changes in the initiated cell populations. Repeated or long-term exposure to a promoting agent (phenobarbital, dietary fat, ethanol, estrogens, chronic exposure of carcinogens) or by some processes (e.g., partial hepatectomy), or by physiological condition (e.g., the neonatal liver) or diseased liver (virus infected or cirrhotic liver), the initiated cells induce focal proliferations. It begins with a selective, clonal amplification of the initiated cells into focal proliferations.

### **3.1.3 Progression**

One or more focal lesions from the promotion phase further proceed for more genetic and enzymatic alterations in the constituted hepatocytes, forming enzyme-altered foci. Such a lesion may form from a single lesion or by merging several lesions and may be large enough to form a macroscopic structure (hepatic nodule) (Figure 3) in the liver. They sometimes

Fig. 3. An external morphology of liver tumor of a carcinogen-control rat showing multiple grayish-white and greenish-white hyperplastic nodules on the liver surface. (Das et al. 2010)

develop potential to begin the transformation of normal cells to cancer cells. The mutations generally activate proto-oncogenes and/or inactivate tumor suppressor genes to develop hepatocellular carcinoma in the carcinogenic mechanism. The chemicals that cause the process (initiation) are called "initiators". Initiation is an irreversible process for a small population of cells. It occurs with a single/ brief exposure to a carcinogen. Electrophilic moieties generated by genotoxic agents generally bind with DNA to form DNA adduct, hamper cellular DNA repair mechanism, and develop permanent DNA lesions. Thus, the normal cell becomes an initiated cell. The initiated cells can develop focal lesions (Figure 2), one or more of which can act as sites of origin for the subsequent development of malignant

Initiated hepatocytes are unable to grow autonomously (Farber & Sarma 1987), although they gain the potential to favor proliferation by possessing alterations in gene and protein expressions. Upon exposure to an environment where initiated cells are at greater risk, further genetic alterations begin, causing some reversible changes in the initiated cell populations. Repeated or long-term exposure to a promoting agent (phenobarbital, dietary fat, ethanol, estrogens, chronic exposure of carcinogens) or by some processes (e.g., partial hepatectomy), or by physiological condition (e.g., the neonatal liver) or diseased liver (virus infected or cirrhotic liver), the initiated cells induce focal proliferations. It begins with a

One or more focal lesions from the promotion phase further proceed for more genetic and enzymatic alterations in the constituted hepatocytes, forming enzyme-altered foci. Such a lesion may form from a single lesion or by merging several lesions and may be large enough to form a macroscopic structure (hepatic nodule) (Figure 3) in the liver. They sometimes

Fig. 3. An external morphology of liver tumor of a carcinogen-control rat showing multiple grayish-white and greenish-white hyperplastic nodules on the liver surface. (Das et al. 2010)

selective, clonal amplification of the initiated cells into focal proliferations.

neoplasia (Farber & Sarma 1987).

**3.1.2 Promotion** 

**3.1.3 Progression** 

look grey or whitish gray or greenish (because of the presence of bile in them). Eventually by a slow process through lots of biochemical and genetic alterations those hepatic altered foci or hepatic nodules develop increasingly malignant cellular characteristics and are transformed into neoplasia without any further external stimulus or intervention (Farber & Sarma 1987).
