Historical Background and Zilber's Theory
For the first time, the etiological link between viruses and tumors was scientifically proven in 1910, when Peyton Rous established the viral nature of sarcoma in chickens. Subsequently, throughout the 1930s, researchers confirmed the involvement of specific "filterable agents" in the development of a number of pathologies: papilloma and skin cancer in rabbits, breast cancer in mice, and lymphoma in chickens.
A key contribution to understanding the true nature of viral oncogenesis was made by the prominent Russian researcher L.A. Zilber. In 1946, he published a large-scale monograph entitled "The Viral Theory of the Origin of Malignant Neoplasms." The central postulate of his viral-genetic theory states: for malignant transformation of a cell, it is absolutely necessary that the viral genome integrates into the cellular genome and closely interacts with it. In the 1970s, the development of molecular biology methods made it possible to fully confirm the validity of Zilber's theory.
Basic Principles of Oncovirus Classification
All oncogenic viruses share a proven ability to transform normal cells into malignant ones. They are conventionally classified by the type of nucleic acid and the mode of transmission.
According to the type of genome, two main categories are distinguished:
- RNA-containing viruses: represented by the family Retroviridae. It is using them as an example that the mechanisms of viral oncogenesis have been studied most thoroughly and deeply.
- DNA-containing viruses: include an extensive list of families, among which are Papillomaviridae, Polyomaviridae, Adenoviridae, Hepadnaviridae, Herpesviridae, and Poxviridae.
According to their mode of existence in the organism and routes of spread, oncoviruses are divided into two large groups:
- Endogenous oncoviruses: act as permanent elements of the cellular genome and are stably present in all tissues of the organism. They are transmitted vertically (from parents to offspring, much like ordinary genes). It is important to note that for their natural host, in whose genome they reside, they are usually non-oncogenic.
- Exogenous oncoviruses: spread horizontally, i.e., from an infected individual to a healthy one, and exist in the form of full-fledged infectious virions.
Molecular Mechanisms of Cell Transformation
The biological basis of viral oncogenesis is the onc gene theory. To understand the essence of the process, it is necessary to clearly distinguish between two basic states of the genetic apparatus:
- Proto-oncogenes: these are normal cellular genes that are in an inactive (dormant) state. In a healthy cell, they are responsible for the strict regulation of growth and division processes.
- Oncogenes (onc genes): activated forms of proto-oncogenes that directly cause malignant transformation of the cell. Modern science knows more than 20 types of such genes (examples include the src gene, which causes Rous sarcoma in chickens, and the ras gene, which causes sarcoma in rats).
A virus can activate a cellular proto-oncogene in several ways:
- Insertional mutagenesis: the integration of the proviral DNA into the cell genome automatically activates the nearby proto-oncogene.
- Oncogene transduction: the provirus can be excised (cut out) from the chromosome. In doing so, it can capture a cellular onc gene, incorporate it into its own genome structure, and transfer it to the next cell in a hyperactivated form.
- Trans-activation: there is a pathological increase in the transcription of normal cell genes under the influence of special viral promoters or enhancers. These regulatory elements are located in the long terminal repeats (LTRs) of the virus.
- Genetic rearrangement: the integration of viral DNA leads to major structural alterations in the cellular genome, which fatally disrupts the normal cell cycle.
Note: proto-oncogene activation can be triggered not only by oncogenic viruses, but also by various mutagens, as well as mobile genetic elements.
Physicochemical properties
Oncogenic viruses are characterized by specific resistance and sensitivity profiles to environmental factors. They exhibit high sensitivity to chemical reagents: they are rapidly destroyed by the action of ether, detergents, and formalin. They are also completely inactivated by temperature exposure at 56 °C. At the same time, oncoviruses demonstrate high resistance to ultraviolet radiation and tolerate low temperatures very well.
Briefly: answers to topical questions
What are the main histological types of tumors induced by the Epstein-Barr virus?
The Epstein-Barr virus is associated with the development of the following tumors:
- Burkitt lymphoma, including the endemic (African) form.
- Nasopharyngeal carcinoma.
- B-cell lymphoma.
- Certain forms of nodal T-cell lymphoma.
Which human papillomavirus proteins inactivate the p53 and Rb tumor suppressors?
The p53 and Rb tumor suppressors are inactivated by the viral E6 and E7 proteins. These proteins are encoded by early human papillomavirus genes, which serve as markers of oncogenicity and are always detected in transformed cells. As a result of the inactivation of the p53 and Rb tumor suppressor genes, the mechanism of uncontrolled cell proliferation is triggered, leading to the development of dysplasia and cancer.
What are the transmission routes of human T-cell leukemia virus?
Human T-cell leukemia virus is transmitted via three main routes. The following infection mechanisms are distinguished:
- Sexual route — transmission of the pathogen through sexual contact.
- Transfusion route — infection via contaminated blood.
- Transplacental route — vertical transmission of the virus from mother to fetus.
The infection is characterized by a long incubation period, reaching 20 years, and a slow progression of the pathological process with damage to the immune system.
To quickly memorize the four ways of proto-oncogene activation, use the mnemonic PITT (Rearrangement, Insertional mutagenesis, Transduction, Trans-activation).
Class and exam questions
What is the essence of Zilber's viral-genetic theory?
The essence of the theory is that to trigger malignant transformation, the viral genome must necessarily integrate into the host cell DNA and closely interact with it.
How do oncogenes differ from proto-oncogenes?
Proto-oncogenes are normal inactive genes that regulate cell growth. Oncogenes (onc genes) are their activated form, which leads to uncontrolled division and malignant transformation.
Are endogenous oncoviruses dangerous to the host organism?
Generally, no. They are permanent elements of the cellular genome, are transmitted vertically to offspring, and usually do not exhibit oncogenicity in the animal species in whose genome they reside.
What else to study on this topic
- Features of replication in members of the family Retroviridae.
- Structure and functions of long terminal repeats (LTRs) in the viral genome.
- Interaction of DNA-containing virus oncoproteins with tumor growth suppressors.
- Differences between vertical and horizontal transmission routes of oncoviruses at the population level.
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