Viruses - One of the agents that cause cancer

The article was written by Master, Doctor Bui Thi Hong Khang - Pathologist - Laboratory Department - Vinmec Central Park International General Hospital.

Carcinogenic agents are classified into three main groups: chemicals, radiation, and viruses. They can act separately or synergistically. In this article, we will talk about tumorigenous viruses.

All tumorigenic RNA viruses belong to the Retrovirus family, meaning that they contain the enzyme reverse transcriptase, which allows viral RNA to be copied into DNA. The genetic makeup of the Retrovirus is a single-stranded RNA, containing the pol gene encoding for reverse transcriptase, the gag gene encoding the capsid protein, and the env gene encoding the envelope protein. In addition, on the 3' and 5' ends, there are 2 LTR (long terminal repeats) segments about 250 - 1200 nucleotides long, containing regulatory elements necessary for retroviral activity such as gene integration into the genome. host cell, protein synthesis.
Depending on their ability to induce transformation of cultured animal cells quickly or slowly (after several weeks or months), tumorigenic RNA viruses are classified into two types as follows.
1.1. Acute transforming oncogenic RNA virus The ability of these viruses to cause rapid transformation is due to the fact that their genomes contain transformation genes, called oncogenes, or oncogene-viruses. (viral oncogene), abbreviated as v-onc. For example, v- sis is the oncogene of the retrovirus that causes monkey sarcoma (si mian s arcoma virus), and v-fes is the oncogene of the retrovirus that causes feline sarcoma (fe line s arcoma virus). The structure of the genomes of these retroviruses includes env, v-onc, gag genes and two LTR segments at both ends. Non-transforming retroviruses do not contain oncogenes in their genomes.
Protein molecules encoded by the synthesized oncogene, called oncoproteins, have the ability to transform cultured cells into cancer cells; is therefore also known as a transformation factor.
By molecular hybridization, it was surprising to discover that the DNA of normal human cells also contains genes similar to viral oncogenes; these genes are called pre-oncogenes (proto-oncogenes); eg: The pro-oncogene similar to v- sis called sis , is found on chromosome 22, the pro-oncogene similar to v-fes is fes located on chromosome 15.
The pro-oncogene is also found. found in almost all living things, from lower organisms to humans. The conservation of these genes throughout evolution suggests that pro-oncogenes are essential for normal cell growth and differentiation. When the pre-oncogene structure is altered or when its expression is aberrant, the pre-oncogene is activated into a cellular oncogene, abbreviated as c-onc (cellular oncogene), which can cause cell proliferation disorders. cells, leading to tumor formation.
Based on the above findings, it is assumed that the oncogenic retroviruses causing rapid transformation initially have the same genome structure as other non-transforming retroviruses, that is, do not contain v-oncs. These v-oncs are the result of random recombination between the viral genome and normal host cell DNA, whereby pro-oncogenes in the host cell genome are transferred to the viral genome and turn into v-oncs.
1.2. Slow transforming oncogenic RNA virus

This virus does not contain v- oncs ; After entering the cell culture, the entire viral genome is reverse transcribed into DNA, called a provirus, and randomly incorporated into the host cell's genome. If a random proviral is bound to a pro-oncogene, then, under the influence of a regulatory factor located in the LTR sequence of the proviral, the host cell pre-oncogene can be activated into a cellular oncogene, causing to cell transformation. Due to this random nature, it can take several months to have a transformative effect.
Although many types of retroviruses have been detected in experimental animals, but in humans, only one retrovirus has the ability to cause cancer, which is human T-cell leukemia virus (HTLV-1). virus type 1) , which causes type 1 T-cell leukemia. This is a common disease in some parts of Japan and the Caribbean. The HTLV-1 virus, after entering humans, will attack and transform CD4+ T lymphocytes; 1% of people infected with the virus will develop T-cell monoclonal leukemia after a latent period of 20-30 years.
The genome structure of HTLV-1 also contains gag, pol, env and LTR genes like other retroviruses. In addition, there is an additional tax gene at the 3' end. The oncogenic mechanism of HTLV-1 is not the same as that of the two above-mentioned tumorigenic RNA viruses; because it contains no v-oncs and is not randomly assigned to a host cell's pre-oncogene edge.
The oncogenic potential of HTLV-1 is due to the activity of the tax gene: The tax protein is capable of activating a number of host cell genes, such as the gene encoding for IL-2 and the corresponding receptor, the gene encoding for GM-CSF. Once in the body, the HTLV-1 virus enters and stimulates the proliferation of multiple T-cell lines in an autocrine (through production of IL-2 and the corresponding receptor) or parasecretory (through production of GM). -CSF stimulates macrophages to produce IL-1. The proliferation of T-cell polyclonals favors the occurrence of new mutations, leading to the emergence of a dominant proliferative T-cell line, leading to cancer.

To date, only three DNA viruses have been identified as having the potential to cause cancer in humans. When entering a cell, the viral DNA is usually stably combined with the host cell's DNA. As a result, it is possible to detect their presence by molecular hybridization.
2.1. Human papillomavirus (HPV) The human papillomavirus (HPV) is a DNA virus with an affinity for epithelial cells that can cause papillomas of the skin and mucous membranes. Papillomavirus has a spherical shape with a diameter of 55 nm, composed of a 20-sided protein coat (capsid), inside containing a double-stranded DNA molecule about 8000 base pairs long, including 2 regions: The gene carrier region consists of 6 expressed genes. early are E1, E2, E4, E5, E6, E7 and 2 late expressed genes, L1, L2; The remaining region does not carry the gene but contains regulatory factors necessary for HPV activity in the host cell.

When the squamous epithelium is infected with HPV (eg, in the cervix), the virus can only bind to the cell membrane of the basal layer to penetrate inside. So there must be a tear in the epithelium for the virus to get in. Once inside the basal cell nucleus, two situations can occur:
Latent infection: HPV exists "silently" as circular DNA outside the host cell's chromosomes, in the number of 50 - 100 copies. Viral cyclic DNA is replicated only once per basal cell cycle. In the latently infected epithelium, there were no morphological changes indicating HPV infection. Active infection: The E6 and E7 genes of the virus are expressed, causing the basal cells, after morphologically differentiated and migrated to the subbasal layer, to retain the ability to replicate DNA, and at the same time, allow the DNA of virus replication. In cells of the intermediate layer, the genes E1, E2, E4 and E5 promote viral DNA replication strongly. The L1 and L2 genes are expressed later, producing capsid proteins to combine with viral DNA to form new HPVs. The E4 gene destroys cytokeratin superfilaments in the cytoplasm, which helps to release HPV from the cell surface layer. The hollow cell appearance in the medial layer is the result of destruction of the cytoskeleton, creating a bright space in the cytoplasm around the nucleus. Currently, more than 100 different types of HPV have been isolated:
HPV types 1, 2, 4, 7, causing benign skin papillomas. HPV has an genital-anal affinity, including about 40 different types; can cause intraepithelial lesions with the risk of turning into cancer. HPV is spread mainly through sexual contact. HPV infection is very common, 80% of women in their 20s are infected with HPV, there can be many different types at the same time, but by the age of 50, this rate is only 5%. Fortunately, most HPV infections are temporary, disappearing after 1-2 years due to the effects of the immune system; Only persistent HPV infections increase the risk of cancer. Depending on this risk more or less, we can distinguish 2 groups: Low-risk groups such as HPV types 6, 11, 42, 44, 53, 54, 62, 66, causing condylomas or intraepithelial lesions low grade spikes (LSIL); High-risk groups include HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, causing potentially high-grade squamous intraepithelial lesions (HSIL) progression to invasive cancer. The mechanism of HPV's carcinogenicity is because the viral genome has been randomly incorporated into the host cell's DNA, disrupting the activity of genes there; while in precancerous lesions, the viral genome remains isolated outside. The activity of the E6 gene will inactivate the p53 and bax proteins, and at the same time reactivate the telomerase enzyme. The E7 gene inhibits the Rb protein, releases transcriptional regulatory factors, and promotes host cell proliferation. As a result, the host cell is transformed into a cell capable of auto proliferating, disrupting the basement membrane and infiltrating the surrounding tissue. However, HPV infection alone is probably not enough to cause cancer, but also requires some other genetic mutations (such as the pre-oncogene ras mutation), which are now more likely due to the cellular genome The host is no longer stable as before the virus infection.

2.2. Epstein-Barr virus (Epstein-Barr virus - EBV) is a virus belonging to the Herpes family, is considered the cause of two types of cancer, Burkitt lymphoma and undifferentiated carcinoma of the oropharynx.
Burkitt lymphoma is common in some parts of Africa, EBV DNA has been found in the cancer cells of all these patients. EBV has a strong affinity for B lymphocytes, after infiltrating it stimulates B lymphocytes to proliferate. In the normal body, B-lymphocyte proliferation is controlled, but in immunocompromised patients (due to malaria or infection), the control mechanism is no longer effective; B lymphocytes continue to proliferate, facilitating the occurrence of new mutations, giving rise to a dominant proliferative B-cell lineage, leading to Burkitt lymphoma.
Undifferentiated carcinoma of the oropharynx is a common cancer in Southeast Asia and China. EBV DNA has been found in the cancer cells of all patients with this type of cancer. Similar to Burkitt lymphoma, EBV may have interacted with several other factors to cause undifferentiated carcinoma of the oropharynx.
2.3. Hepatitis B Virus (HBV) Epidemiological studies have shown a strong association between chronic HBV infection and liver cancer. The mechanism of HBV carcinogenesis is still unknown despite the association between viral DNA and host cell DNA. The mechanism of HBV tumorigenesis is probably through its ability to cause liver cell death, causing the remaining liver cells to proliferate continuously, facilitating the emergence of new mutations leading to cancer.
In addition to the above viruses, the role of Helicobacter pylori (Hp) bacteria has recently been identified in 2 types of gastric cancer, adenocarcinoma and B-cell lymphoma. The carcinogenic mechanism of Hp is probably through its ability to cause cancer. ability to cause chronic gastritis; leading to intestinal metaplasia, dysplasia and eventually adenocarcinoma. Polyclonal B-lymphocyte proliferation in chronic gastritis favors the occurrence of new mutations, giving rise to a dominant proliferative B-cell lineage, leading to gastric lymphoma.
In summary, the study of tumorigenous viruses has helped us to discover the existence of human pro-oncogenes of which more than 100 different types are known to date. Although most human cancers are not directly caused by viruses, it is the activation of pro-oncogenes, together with the inactivation of many other genes, that induce somatic cell transformation, leading to into tumours.
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