Infectious theory of carcinogenesis
The infectious theory was pioneered by the Russian oncologist L. A. Zilber. The essence of his concept is that certain neoplasms arise under the influence of specific oncogenic viruses.
The evidence base was built over decades. A crucial milestone was experiments in which cell-free filtrates of tumor tissue were injected into healthy recipient animals, causing them to develop neoplasias.
- In 1908, researchers first managed to experimentally induce leukemia in chickens.
- In 1911, P. Rous described the first oncogenic filterable agent, the Rous sarcoma virus.
- In 1976, it was in this retrovirus that the first gene triggering malignant transformation was discovered — the src oncogene. Today, science knows of over 100 such viral oncogenes.
DNA-containing oncoviruses
The genetic apparatus of DNA oncoviruses includes two groups of genes: those responsible for replication and those encoding structural viral proteins.
Their mechanism of action is based on complete or partial integration into the host cell genome. However, malignant transformation occurs extremely rarely (approximately one case in a million). This is because for a tumor to develop, the virus must infect a susceptible cell without killing it. In the overwhelming majority of cases, infection ends in lysis — the death of the cell due to the destruction of its membrane as new viral particles exit. This is precisely why DNA viruses provoke common infectious diseases far more often than tumor growth.
This group includes:
- Epstein-Barr virus: associated with endemic (African) Burkitt lymphoma and nasopharyngeal carcinoma.
- Human papillomavirus: causes papillomas, skin and genital cancers.
- Adenoviruses, hepatitis B viruses, and the herpes group (including the chickenpox causative agent).
RNA-containing oncoviruses (retroviruses)
RNA oncoviruses belong to the retrovirus family. Unlike their DNA-containing counterparts, they rarely cause acute infections (except for HIV and hepatitis C) and are capable of persisting asymptomatically in the body for years.
Their genome consists of three key gene groups:
- gag — encodes the virus's own proteins.
- pol — responsible for the synthesis of reverse transcriptase. This enzyme creates viral DNA based on an RNA template for subsequent integration into the host genome.
- env — encodes viral capsid proteins.
RNA viruses are extremely efficient agents of malignant transformation. The reason lies in the fact that they leave the cell without destroying its membrane. The cell survives and gives rise to sarcomas, leukemias, or solid tumors (for example, the RNA virus HTLV-1 causes certain types of T-cell leukemias and lymphomas).
Microbial carcinogenesis
Tumors can be provoked not only by viruses but also by bacteria. A classic example is Helicobacter pylori, which inhabits the acidic environment of the gastric mucosa. It has been proven to be an etiological factor in gastric cancer and MALT lymphoma.
Pathogenesis of lymphoma development:
- Chronic Helicobacter pylori infection attracts reactive T-lymphocytes into the tissue.
- T-cells begin actively producing cytokines.
- Cytokines stimulate the uncontrolled proliferation of B-lymphocytes.
- Mutations accumulate in actively dividing B-cells, leading to malignant transformation.
- Tumor growth acquires a monoclonal character and is no longer regulated by T-cells.
Polyetiological theory
Modern science integrates all existing views into a single polyetiological theory. It states that tumors are a multitude of different diseases in whose development various etiological factors may participate, with their effects capable of summing up and potentiating each other.
The main mechanism of carcinogenesis is the emergence of mutations in somatic cells due to DNA damage under the influence of carcinogens. The mutational nature is confirmed by the presence of strict correlations between chromosomal abnormalities and specific tumor types, as well as the fact that transfection (transfer) of viral oncogenes into normal cells inevitably leads to the development of a tumor phenotype.
Briefly: answers to topical questions
Which strains of human papillomavirus belong to the high-oncogenic-risk group?
Human papillomavirus types 16, 18, 31, 33, 45, and 56 belong to the high-oncogenic-risk group.
- Type 16 (HPV 16) — is detected with equal frequency in invasive cancer and dysplasias.
- Types 18, 45, 56 (HPV 18, 45, 56) — are detected more frequently in invasive cancer than in precancerous conditions.
- Types 31, 33 (HPV 31, 33) — along with types 16 and 18, are the leading etiological factor for anogenital squamous cell carcinoma.
Infection with these strains causes the majority of precancerous diseases and cancers of the cervix, penis, vulva, vagina, anus, and oropharynx.
Which enzymes are encoded by the pol gene in retroviruses?
The pol gene in retroviruses encodes replication enzymes necessary for the viral life cycle. This enzyme complex includes:
- Reverse transcriptase (reveretase) — synthesizes viral DNA on an RNA template for subsequent integration into the host genome.
- Integrase (integrase) — ensures the integration of viral DNA into the cellular genome.
- Protease (protease) — cleaves precursor polyproteins into functionally active mature proteins.
- RNase (RNase) — participates in the replication processes of the viral genome.
All these enzymes are localized inside the virion nucleocapsid.
What mechanisms for activating cellular proto-oncogenes exist in viral carcinogenesis?
There are four main mechanisms for activating cellular proto-oncogenes in viral carcinogenesis.
- Insertional mutagenesis (insertional mutagenesis) — the integration of a DNA provirus into the cellular genome activates a nearby proto-oncogene.
- Oncogene transduction (transduction) — when a provirus excises from the chromosome, it captures a cellular onc gene, incorporates it into its genome, and transfers it to a new cell in an active state.
- Trans-activation (trans-activation) — enhancement of cellular gene transcription under the action of promoters or enhancers located in the long terminal repeats (LTRs) of the virus.
- Genetic rearrangement (genetic rearrangement) — structural DNA changes resulting from viral integration.
Which malignant tumor develops during chronic infection with hepatitis B and C viruses?
Chronic infection with hepatitis B and C viruses can lead to the development of hepatocellular carcinoma (HCC), which is primary liver cancer. The integration of a fragment or the entire hepatitis B virus genome into the hepatocyte genome is associated with the development of persistent HBV forms and primary HCC. Hepatitis C virus also plays a significant role in the development of liver cirrhosis and the emergence of HCC.
What specific oncoproteins are synthesized by DNA-containing oncoviruses for malignant cell transformation?
High-oncogenic-risk human papillomaviruses synthesize E6 and E7 oncoproteins. They inactivate the tumor suppressor genes p53 and Rb, leading to the loss of cell cycle control, uncontrolled proliferation, and genomic instability.
Which genes are part of the Rous sarcoma virus genome?
The Rous sarcoma virus genome includes the viral oncogene src. As a retrovirus, it also contains the structural genes gag, pol, and env:
- gag encodes internal structural proteins of the virus;
- pol encodes replication enzymes, including reverse transcriptase, integrase, RNase, and protease;
- env encodes envelope proteins.
The src oncogene is associated with malignant transformation and the development of sarcoma in chickens.
To remember the cellular outcome upon infection with different oncoviruses: DNA viruses = Destruction (the cell typically dies from lysis), RNA viruses = Replication (the cell survives and undergoes malignant transformation).
Class and exam questions
Do all oncogenic viruses cause cancer in humans?
No, initially viral carcinogenesis was considered exclusive to animals. However, in recent decades, the role of a number of viruses (EBV, HPV, HTLV-1) in the development of tumors in humans has been proven.
Why do RNA viruses induce tumors more efficiently than DNA viruses?
Upon infection with DNA viruses, the cell most commonly dies due to membrane disruption when viral particles exit. RNA viruses leave the cell without lysis, allowing it to survive and undergo transformation.
How can bacteria cause cancer?
Chronic bacterial infection (e.g., Helicobacter pylori) causes an influx of T lymphocytes. They secrete cytokines that stimulate the proliferation of B cells, which subsequently accumulate oncogenic mutations.
What else to study on this topic
- Mechanisms of reverse transcriptase function in retroviruses
- Pathogenesis of endemic Burkitt lymphoma
- The role of human papillomavirus in the development of carcinomas
- Evidence base of the polyetiological theory of carcinogenesis
- Stages of monoclonal growth in malignant lymphocyte transformation
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