Some human cancers are linked with viruses.

Mechanism of viral carcinogenesis

Retroviral model

There are viruses with RNA which are integrated in the genome of the host after opposite copy (reverse transcriptase) in double helix DNA.

Presence of genes of the gag, pol, env and LTR types.

Retrovirus without oncogene sequence (HTLV1 model)

In HTLV1, the expression of one protein of tat-1 type can be observed. This protein is able to activate the transcription of the virus but can also act on cellular genes. Thus, tat-1 induces an over-expression of FIL2 genes and its receiver (CD25). This could constitute the support of the in vitro T lymphocytes  immortalization.

Retrovirus with an oncogene sequence or v-onc (virus model of Rous' sarcoma or RSV). Virus with fast transformation ability (2 to 3 weeks).

The majority of these viruses are non replicative (except RSV) because the oncogene insertion has generally deleted an essential gene of the replication. These viruses thus need a replication auxiliary.

They contain an oncogene sequence probably of human origin because all the retroviral oncogenes have their cellular counterpart (human or animal). The virus of the Rous' sarcoma contains the src oncogene sequence (Tyrosin Kinase). This virus induces sarcomes to chicken.

Several other oncogenes are in question : v-onc (v-myb, N-ras, K-ras…) for example: virus of the avian myelomatose (AMV) includes the v-myb oncogene.

Virus with slow transformation ability (several months).

Example: avian sarcosma leucosis virus (ASLV).

Rearranged sequences LTR in the vicinity of a cellular oncogene (c-myc) induce its over-expression of a factor 100 to 300 compared to the basic level (B lymphocytes of chicken).

Virus of the human immunodeficiency (HIV)

No oncogene direct action. Sequence LTR of HIV could activate certain cellular genes or activate certain viral sequences (EBV) but it is not its main action mechanism.

The cancers increase for HIV+ is related to the immunodeficiency. However, some viral proteins could play a part in the appearance of the Kaposi' sarcoma. It is about the protein tat which increases answer of growth of the endothelial cells and the expression of the type IV collagenase in response of bFGF stimulation.

Virus with DNA

Virus of human papillomas or papillomavirus (PVs)

  • More than 60 different progenitor virus
  • Episomal virus (replicative) integrated during carcinogenesis.
  • Expression of some E1, E2, E6 and E7 genes (progenitor 16-18) which act by activating the cellular expression of close-cropped oncogene. Other proteins act by inhibiting the p53protein.

Epstein-Barr Virus

It acts as an immortalizing and transforming virus

Immortalizing genes : EBNA2: the protein is nuclear and acts like a transcription factor while being fixed on the viral and cellular AND.

Viral genes with oncogenic action: LMP1 is a membrane and cytoplasmic protein which acts by activating cellular factors of transcription and growth promoters (dimerisation): Receiver with THF (TNFR), NF KB> bc! 2, action on the cell multiplication or the apoptose.

Genes with the functions close to genes cellular: BHRFl/bcl2, BCRF1/EL10

Others: transactivateurs who fix themselves on API sites: ZEBRA/fos, BMLFl/c-Myc

Hepatitis B Virus

Virus DNA doubles bit to % and simple bit on 1/4. Need for a pregenomist ARN for his replication then of a transcriptase reverse.

The mechanism of the oncogenesis is little known. There exists of the cofactors of the type aflatoxine Bl or luteoskryne. It does not contain any gene likely to be able transforming. The integration of the virus could act by un-regulating the expression of certain cellular genes. It could be a question of a mechanism of activation of cellular genes in cis. That remains discussed because integration remains random.

The human cancers associated with viruses

Solid tumors

nasopharynx carcinoma

This tumor is very frequent in the endemic zones (southern is Asian, the Maghreb, eskimos) because of the particular living conditions. infection by the EBV is carried out precociously during childhood. The oncogene role of the EBV would be amplified by the presence of the nitrosamines in the food. Moreover, several products of pharmacopeia Chinese comprise viral inductors derived from esters of phorbol.

This tumor is very lymphophilic, and revealed sometimes by cervical metastatic adenopathies. In the areas of endemic, it diagnosis of carcinoma of the nasopharynx can be evoked on a rise in antibody of IgG type but mainly anti-VCA IgA (capsid antigen).

Gastric adenocarcinomas

The association of the EBV with these tumors is of recent description, in particular in Japan. The incidence is approximately 8 to 10% of the cases. The morphological aspect is comparable with that of carcinomas of the nasopahrynx (important lymphoid reaction T). It does not seem to exist of evolutionary characteristic of tumors EBV+ compared to tumors EBV-.

Leiomyosarcomes and leiomyomes during the AIDS or post transplantation,

Very recently, it was shown that in a immunodeficiency context, these tumors were associated with the EBV. The significance of this association is not known. It is about the demonstration of the infection and of the possible transformation of the muscular cells smoothen by the EBV.

Hepatocellular Carcinoma

It's the most frequent cancer in the world. It prevails in the endemic zones where there are cofactors. In particular, in central Africa, aflatoxine Bl exit of metabolism of a parasitizing mushroom groundnut is one of the most known cofactors. In Asia, the same phenomenon occurs with the rice and the production of luteoskryne. As much, in Europe, hepatocellular carcinoma frequently occurs on cirrhosis (post ethyl), as much in Africa it develops on Liver healthy.

Malpighiens epithelioma of the uterine collar, skin (Lutz Levandowski)

It particularly acts of malpighians carcinomas of the collar occurring more frequently after infections by stocks oncogenes (HPV 16 and 18). The preneoplasic lesion is it condylome plan. The papillomavirus would be associated, in a less significant way to the adenocarcinomists of the uterine collar and with epithelioma malpighiens of the esophagus and the bronchi.

The epidermodysplasy verruciforme is a lesion which has a capacity of malignant transformation high. This lesion is often associated the HPV 5 and 8.

Malignant hemopathies

Burkitts' Lvmphoma (EBVet rearrangement of c-myc)

Burkitt's lymphoma is a lymphoma initially described in equatorial Africa by Denis Burkitt (1958). It is starting from this tumor that the EBV was insulated. It is classically of a tumor of the mandible or a mass rétropéritonéale whose growth is carried out at sight ofeye. The dissemination neuro méningée is frequent. Morphologiquement, it acts of mature lymphoblastic cells, closing again the virus of Epstein-Barr in more than 90% of the cases. This tumor is also a cytogenetic entity with translocation of the gene c-Myc: T (8; 14) and alternatives T (2; 8) and T (8; 22). One does not know the exact mechanism of emergence of this tumor (EBV + paludism??). In Occident, the lymphoma of Burkitt is rare, but is carrying the translocations described in Africa. On the other hand, the EBV is present only in 20% of the cases.

Lymphoma T centrofacial and lymphomas angiocentric

These tumors correspond to old the granulome malignant centrofacial and in old Granulomatose bronchocentric of Liebow. They are lymphomas T aggressive, induced by the virus of Epstein-Barr. Some of these tumors have a natural killer phenotype (NK).

Hodgkins' disease

The Hodgkins' disease is associated to the EBV in nearly 50% of the cases. The virus is monoclonal and the distribution is unequal according to under types. Thus, the disease of Hodgkin of the type 1 is never associated the EBV, the disease of scléro-nodular Hodgkin of the type 2 is associated in 10% of the cases whereas the strongest incidence is observed in the disease of Hodgkin of the type 3 with mixed cellularity (60%). This association does not imply any clinical consequence. The tests serologic do not show profile specific or at least evocative.

Lymphomas of the immunodéprimés patients.

The majority of the lymphomas occurring among patients immunocompétents are of phenotype T. Immunodéprimés patients (hereditary immunodépression related to FX (syndrome of Purtilo), AIDS or post transplantation) develop lymphomas generally associated with the virus with Epstein-Barr.

Among persons receiving a transplant, these lymphomas are polyclonaux or monoclonal. At the stage polyclonal, these tumors can regress on simple reduction in ciclosporine A. At the monoclonal stage, the regression is less easy to obtain. At grafted marrow, the appearance of such tumors can be suppressed while treating grafted by lymphocytes of donor stimulated. The answer cytotoxic will eliminate the cells infected by the virus from Epstein-Barr.

Among patients reached of AIDS having more than 400 T4 lymphocytes (normal), one will observe the development of lymphomas of the Burkitt type with translocations but containing the EBV only in 20% of the cases. Among patients, having less than 400 T4, one will observe rather the development of lymphomas EBV+ of the immunoblastic type.

Leukaemia-lymphoma T (HTLV1)

Tumor attends in Japan and in the Caribbean. It is about a very aggressive lymphoma associated HTLV1. One finds provirus HTLV1 integrated into the genome of the lymphomateuses cells.

leukaemia with tricholeucocytes T and certain syndromes lymphoprolifératifs T

The virus of the type HTL VII could play a part in the genesis of these tumors.

Mycosis fongoide and syndrome of Sézary

Very recent work (February 1995), brings back the association of the cutaneous lymphomas of type mycosis fongoide to stocks virus of the type HTLV. They are probably viral strains different of HTLV I and II. It seems to exist a correlation between detection viral sequences in the blood and the presence of anti-HTLV markers serologic.

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