Biological Carcinogenesis Notes

Biological Carcinogenesis

Epidemiological studies on different types of cancers indicate the involvement of transmissible biologic agents in their development, chiefly viruses.

Other microbial agents implicated in carcinogenesis are as follows:

• Parasites: Schistosoma haematobium infection of the urinary bladder is associated with high incidence of squamous cell carcinoma of the urinary bladder in some parts of the world such as In Egypt.
  Clonorchis sinensis, the liver fluke, lives in the hepatic duct and is implicated in the etiology of cholangiocarcinoma.
• Fungus: Aspergillus flavus grows in stored grains and liberates aflatoxin; its human consumption, especially by those with hepatitis B virus infection, is associated with development of hepatocellular carcinoma.

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• Bacteria: Helicobacter pylori, gram-positive spiral-shaped bacteria, colonises the gastric mucosa and has been found in cases of chronic gastritis and peptic ulcer. Its prolonged infection may lead to gastric lymphoma and gastric carcinoma.

However, the role of viruses in the etiology of cancer is more significant. Therefore, biologic carcinogenesis is largely viral carcinogenesis, described below.

Viral Carcinogenesis

It has been estimated that about 20% of all cancers worldwide are due to the persistence of virus infection. The association of oncogenic viruses with neoplasia was first observed by an Italian physician Sanarelli in 1889 who noted the association between myxomatosis of rabbits with poxvirus.

The contagious nature of the common human wart was first established in 1907. Since then, a number of viruses capable of inducing tumours (oncogenic viruses) in experimental animals, and some implicated in humans, have been identified.

Most of the common viral infections (including oncogenic viruses) can be transmitted by one of the 3 routes:

1. Horizontal transmission: Horizontal transmission is more common in which viral infection passes from one to another by direct contact, by ingestion of contaminated water or food, or by inhalation as occurs in most contagious diseases.
   Most of these infections begin on the epithelial surfaces, spread into deeper tissues, and then through haematogenous or lymphatic or neural routes disseminate to other sites in the body.
2. Parenteral route of transmission: Parenteral route of transmission is by inoculation as happens in some viruses by interhuman spread, and from animals and insects to humans.
3. Vertical transmission:  Vertical transmission when the infection is genetically transmitted from infected parents to the offspring.

Based on their nucleic acid content, oncogenic viruses fall into 2 broad groups:

1. Those containing deoxyribonucleic acid are called DNA oncogenic viruses.
2. Those containing ribonucleic acid are termed RNA oncogenic viruses or retroviruses.

Both types of oncogenic viruses usually have 3 genes and are abbreviated according to the coding pattern by each gene:

• Gag gene: codes for group antigen
• Pol gene: codes for polymerase enzyme
• Env gene: codes for envelope protein

Natural history of viral infection can be categorised into primary and persistent:

• Primary viral infections are a majority of the common viral infections in which the infection lasts for a few days to a few weeks and produces clinical manifestations.
• Primary viral infections are generally cleared by the body’s innate immunity and specific immune responses.
• Subsequently, an immunocompetent host is generally immune to the disease or reinfection by the same virus.
• However, the body’s immune system is not effective against surface colonization or deep infection or persistence of viral infection.
• Persistence of viral infection or latent infection in some viruses may occur by acquiring mutations in viruses which resist immune attack by the host, or virus per se induces immunosuppression in the host such as HIV.

Viral Oncogenesis: General Aspects

Support to the etiologic role of oncogenic viruses in causing human cancers is based on the following:

• Epidemiologic data
• Presence of viral DNA in the genome of a host target cell.
• Demonstration of virally induced transformation of human target cells in culture.
• In vivo demonstration of expressed specifically transforming viral genes in premalignant and malignant cells.
• In vitro assay of specific viral gene products which produce effects on cell proliferation and survival.

In general, persistence of DNA or RNA viruses may induce mutation in the target host cell, although persistence of viral infection alone is not sufficient for oncogenes is but is one step in the multistep process of cancer development. Generally, RNA viruses have a very high mutation rate (for example, HIV, HCV) than DNA viruses.

Mechanisms as to how specific DNA and RNA viruses cause mutation in the host cell are varied, but in generally continued presence of DNA or RNA virus in the cell causes activation of growth-promoting pathways or inhibition of tumor suppressor pathways in the infected cells.

Thus, such virus-infected host cells after having undergone genetic changes enter the cell cycle and produce the next progeny of transformed cells which have characteristics of autonomous growth and survival completing their role as oncogenic viruses.

General mode of oncogenesis by each group of DNA and RNA oncogenic viruses is briefly considered below:

1. Mode of DNA viral oncogenesis:

Host cells infected by DNA oncogenic viruses may have one of the following 2 forms :

1. Replication In permissive cells, the virus replicates in the host cell with consequent lysis of the infected cell (i.e. cell death) and release of virions.
2. Integration In non-permissive cells, the viral DNA is integrated into host cell genome, induces mutation and thus neoplastic transformation of the host cell.

An essential feature for host cell transformation is the expression of virus-specific T- (transforming protein) antigens immediately after infection of the host cell by DNA oncogenic virus (discussed later).

2. Mode of RNA viral oncogenesis:

RNA viruses or retroviruses contain two identical strands of RNA and the enzyme, reverse transcriptase :

• Reverse transcriptase is RNA-dependent DNA synthetase that acts as a template to synthesize a single strand of matching viral DNA i.e. the reverse of the normal in which DNA is transcribed into messenger RNA

• The single strand of viral DNA is then copied by DNA-dependent DNA synthetase to form another strand of complementary DNA resulting in double-stranded viral DNA or provirus.
• The provirus initially remains unintegrated but later viral integrase protein inserts the viral DNA integrates into the host cell DNA and may induce mutation and thus transform the cell into a neoplastic cell.
• Retroviruses are replication-competent. The host cells which allow replication of integrated retrovirus are called permissive cells. Non-permissible cells do not permit replication of the integrated retrovirus.
• Viral replication begins after the integration of the provirus into the host cell genome. Integration results in transcription of proviral genes or progeny into messenger RNA which then forms components of the virus particle—virion core protein from gag gene, reverse transcriptase from the pol gene, and envelope glycoprotein from the env gene.

These components of virus particles are then assembled at the plasma membrane of the host cell and the virus particles are released by budding off from the plasma membrane, thus completing the process of replication.

With these general comments, we now turn to specific DNA and RNA oncogenic viruses and their specific oncogenic role.