According to Viral Gene Hypothesis, certain viruses are responsible for the oncogenesis. Virus which are causes cancer called oncogenic virus. First evidence of a relationship between viruses and cancer was obtained by demonstration of transmission of leukemia by cell free filtrate of blood of diseased chickens to healthy chickens.
In 1911, Rous also transmitted chicken sarcoma from diseased chicken to healthy one. The viral etiology of various cancers in animals like fishes, dogs, mice, rats, rabbits, frog, horses etc. is clearly evidenced.
Many viruses are found to be associated with many cancers in humans also. Viruses that are capable of producing cancer are called 'oncogenic viruses' or 'tumor viruses'.
There are two classes of tumor viruses as DNA and RNA tumor viruses. A common characteristic of both these viruses is that the viral genome is some way becomes integrated into the host cell DNA and replicates along with host cell chromosome.
I] DNA Tumor Viruses :
There are five groups of DNA viruses causing cancer in humans. They include -
a. Papova
b. Adeno
c. Pox
d. Herpes and
e. Hepatitis viruses.
Among these, Papova viruses have been received more attention because they are known to cause tumors in a variety of animals.
a) Papova Viruses :
- Name papova is derived from first two letters of three viruses as Papilloma, Polyoma and Simian vacuolating 40 virus ( SV 40 virus).
- They belong to the papovaviridiae family.
- Papovaviridiae family includes two genera - Papiloma viruses and Polyoma viruses.
- SV40 virus is now placed in the genus Polyoma viruses.
- All papova viruses are small, naked, icosahedral, circular double stranded DNA viruses.
- They are commonly found in humans and other mammals.
- Their size ranges from 45nm to 55nm in diameter.
- They contain 5 to 7 genes. The icosahedral capsid is constructed from 2 to 3 polypeptides
i) Papilloma virus :
- Small, non enveloped, icosahedral, circular, ds DNA viruses.
- They are about 55 nm in diameter.
- Their capsid contains 72 capsomers.
- Capsomers made from two types of proteins as L,(Major)and L2(Minor).
- These are wart causing viruses.
- Natural infection results in formation of benign warts in humans and other animals.
- These viruses induce tumor only in natural host.
- They transform normal cells into cancer cells in vitro very rarely.
- Warts produced by these viruses are usually benign But they may convert into malignant carcinomas.
- Also found to be associated with human penile, uterine and cervical carcinomas.
- They replicate exclusively in the keratinocytes.
- Keratinocytes form the outermost layer of the skin as well as some mucosal surfaces of the genitals, anus and mouth.
ii) Polyoma Viruses :
- Name polyoma refers to multiple (poly) tumors (oma) producing viruses.
- They are also small, naked, circular, ds DNA viruses, about 45nm in diameter.
- Capsid is made from three proteins as - VP1, VP2 and VP3.
- These three proteins form pentameric capsomers.
- There are about 72 pentameric capsomers.
- These viruses also encode a protein called 'T antigen'. The polyoma viruses do not induce tumors in the natural hosts like monkey and mouse.
- For example - Simian vacuolating virus (SV 40) replicates in the kidneys of monkeys ( natural host ) without causing any disease.
- However, the SV 40 virus cause the sarcomas in the hamster. They also transform the cells in vitro.
- The SV 40 virus is most thoroughly studied oncogenic DNA virus.
- It is a monkey polyoma virus.
- It can't induce tumor in monkey (natural host) but induce tumors in experimental hamsters as well as rodents.
- The two other examples of human polyoma virus are JC and BK virus.
JC Virus - It causes progressive multifocal leukoencephalopathy – damage or inflammation of white matter of brain at multiple locations. Symptoms include- weakness, paralysis, loss of vision, impaired speech, coma and death.
BK virus - Associated with renal diseases in kidney transplanted patients.
II] RNA Tumor Viruses :
- Oncogenic RNA containing viruses are called "OncoRNA viruses'.
- They are classified as 'retroviruses' because the viral RNA produces intermediate DNA by using reverse transcriptase enzyme.
- From this DNA copy, viral RNA are produced which are accommodated in viral capsid while DNA copies are integrated into host genome.
- Retroviruses have been isolated from many vertebrates like fishes, reptiles, birds and mammals.
- They cause leukemia and sarcoma in chicken while lymphoma and mammary carcinoma in mice.
Based on the host range and disease type, there are five categories of Oncorna viruses They include -
a) Avian leukosis complex -
- e.g. Rous sarcoma virus of chickens.
b) Murine leukosis virus -
- e.g. Murine leukemia & sarcoma virus.
c) Mammary tumor virus of Mice -
- e.g. Bittner virus that causes breast cancer and multiplies in mammary glands. It is transmitted to the offsprings through the breast milk.
d) Leukosis sarcoma virus -
- It produces sarcoma in the animals such as cat, hamster, guinea pigs and monkey.
e) Human T cell lymphotrophic virus ( HTLV) -
- It causes T cell lymphoma.
- There are two types of HTLV as HTLV type 1 and HTLV type 2.
- Type Icauses adult T cell lymphoma and Type 2 causes hairy cell leukemia.
- In hairy cell leukemia - the bone marrow has difficulty in producing enough normal cells like WBCs, RBCs and platelets.
Retrovirus :
- Retroviruses are icosahedral with envelope. They have diploid genome i.e. they carry two identical segments of RNA genome.
- RNA molecules are plus sense single stranded. Consists of 3 important genes- gag, env & pol.
- Name retroviruses refers to participation of reverse transcriptase in their multiplication.
- Multiplication of these viruses requires the transcription of RNA into DNA and its subsequent integration into a host genome.
- Only an integrated viral DNA can be transcribed into viral RNA.
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| Retrovirus replication |
- Replication of positive sense ssRNA occurs as shown in figure.
- Virus multiplication is not lytic and does not kill the cell.
- Integrated genome of the retroviruses replicate along with host genome and therefore, it is present in all cancer cells.
- Oncogenic development is due to the expression of a viral gene known as 'src' gene.
- Base sequence of viral 'src' gene is similar to that of the host cell gene whose product plays a role in the regulation of growth of the normal cells.
- This suggests that the oncogenes of retroviruses are of cellular origin. Thus, the retroviruses cause the cancer as they introduce the new genetic material into host DNA and cause transformation.
- Three theories have been proposed which are concerned with the oncogenesis by RNA viruses in human beings.
a). Oncogene theory
b). Protovirus theory and
c). Provirus theory
a) Oncogene Theory :
Oncogene Theory is Proposed by Huebner & Todaro.
- According to this, the genetic information for cancer is present in each of the body cell and it is transmitted from parent to offspring through the germ cells.
- Infection of body cells by RNA viruses has occurred millions of years ago during evolution.
- Therefore, every cell is assumed to contain oncogene i.e. viral gene responsible for oncogenesis.
- This oncogene is normally kept in repressed condition (prevented from functioning by the regulatory genes of the host cell).
- When the oncogene becomes derepressed either by a physical, chemical or biological agent, it gets expressed itself by the formation of a transforming protein.
- This protein could change the normal cell into a malignant one although no virus could be recovered from it.
b) Protovirus Theory :
Protovirus Theory was Proposed by Temin.
- According to this, certain DNA regions of normal cells are transcribed to RNA & reverse transcribed to DNA by reverse transcriptase enzyme.
- Such newly formed DNA segments get back integrated into original DNA either at the same site or at different sites.
- This leads to the amplification of genetic regions.
- In this flow of genetic information from DNA to RNA & back to DNA, the genetic information becomes independent of cell genome.
- At this stage with or without effect of mutations, the protoviruses may arise which would direct synthesis of RNA tumor viruses or alternatively the integration of newly formed DNA could produce new gene alignment leading to oncogenesis.
- Thus, this theory postulates that the normal back & forth flow of genetic information during amplification process, with or without the effect of mutation or due to alignment of new gene sequences may generate RNA tumor viruses or genes necessary to induce oncogenesis.
c) Provirus theory :
This theory was Proposed by Spiegelman.
- It states that some cancers are caused by direct infection with oncogenic viruses.
- It further states that tumor viruses are transmitted horizontally from individual to individual entering in provirus states.
- They may cause the cancer as a result of chance activation of their transforming genes.
- Occasionally, they may be transmitted vertically i.e. from one generation to other.
- Thus, this theory is different from the oncogene and protovirus theory which state that the spontaneous mutation in animals and humans cells may cause oncogenic events.
- Among these three hypothesizes, the oncogene hypothesis is consistent with number of observations. They include -
- Spontaneous intracellular appearance of oncogenic RNA viruses after repeated sub-culturing of cells.
- This gave no indication of previous virus infection.
- The appearance of oncogenic RNA viruses upon exposure to oncogenic agents in the cells.
- The demonstration of the occurrence of oncogenic viral genetic material in the cells by hybridization studies.
