Oncogenic Viruses.doc

Oncogenic Viruses The association of viruses with malignancy dates from the observation by Ellerman and Bang (1908) that the mode of transmission in leukemia in fowls resembled that of an infectious disease. Rous (1911) showed that a solid malignant tumour, fowl sarcoma, was caused by a virus, a discovery for which he was awarded the Nobel prize belatedly in 1966. Viruses causing tumours in animals were first demonstrated by Shope, who isolated the rabbit fibroma virus in 1932 and the papilloma virus in 1933. Though these are benign tumours, papillomas may turn malignant. Bittner (1936) proposed that breast cancer in mice could be caused by a virus transmitted from mother to offspring through breast milk. During the 19505 many viruses were identified which induced leukemia in rodents. Considerable interest was aroused by the discovery by Stewart and Eddy (1957) of the polyoma virus which could produce a wide variety of neoplasms when injected into newborn rodents. Injection of certain types of human adenovirus into newborn hamsters was shown by Trentin (1962) to cause sarcomas. Burkitt (1963) identified a peculiar geographical distribution of lymphoma in African children and suspected that it may be caused by a virus transmitted by an insect. The Epstein-Barr virus isolated from Burkitt’s lymphoma has been identified as the causative agent. Many viruses have been isolated from human cancer or demonstrated electronmicroscopically in affected cells and tissues but most of them were merely ‘passenger’ viruses present in the lesions and not the causative agents. However, it is now acknowledged that virus infections account for 10 to 20 per cent of human malignancies. These include hepatocellular carcinoma caused by Hepatitis B or C viruses, uterine cervical cancer by certain types of papilloma viruses, anaplastic nasopharyngeal carcinomas by the EB virus and adult cutaneous T cell lymphoma/leukemia by HTLV1. Viruses that produce tumours in their natural hosts or in experimental animals, or induce malignant transformation of cells on culture, are known as oncogenic viruses. Transformation represents the various changes that accompany the conversion of a normal cell into the malignant cell (Table 61.1). Transformation from normal to malignant cell is a multistep process and may be partial or complete. For example, some viral agents can ‘immortalise’ infected cells, so that they become capable of continuous multiplication in culture, without possessing other features of malignancy. Transformation is recognised primarily by a change in morphology of cultured cells. Transformed cells are altered in shape and lose the property of ‘contact inhibition’ so that, instead of growing as monolayer, they grow piled up, one over another, forming ‘microtumours'. Foci of transformation can easily be made out and are used in the assay of oncogcnic viruses, such as the Rous sarcoma virus. About a quarter of the 600 or so animal viruses possess oncogenic potential (Table 61.2). The viruses associated with cancers in human beings are shown in Table 61.3. Both RNA and DNA viruses are oncogenic. While all oncogenic RNA viruses (formerly called oncornaviruses) belong to a single family (retrovirus), oncogenic viruses occur among all major groups of DNA viruses, except parvovirus. Retroviruses are responsible for naturally occurring leukemia and sarcoma in several species of animals. Among DNA viruses, some herpesviruses and hepadnaviruses cause malignant tumours in their natural hosts.

Table 61.1 Properties of cells transformed by viruses I. Altered cell morphology: Fibroblasts become shorter, parallel orientation is lost, chromosomal aberrations appear II. Altered cell metabolism: Increased growth rate, increased production of organic acids and acid mucopolysaccharides III. Altered growth characteristics: Loss of contact inhibition, formation of heaped-up growth (microtumours), capacity to divide indefinitely in serial culture, capacity to grow in suspension or in semisolid agar IV. Antigenic alterations: Appearance of new virus specified antigens (T antigen-TSTA), loss of surface antigens, cells become agglutinable by lectins V. Capacity to induce tumours in susceptible animals Table 61.2 List of oncogenic viruses RNA truses l. Retroviruses R 1. Avian leukosis viruses 2. Murine leukosis viruses 3. Murine mammary tumour virus 4. Leukosis-sarcoma virus of various animals 5. Human T cell leukemia viruses

DNA Viruses I. Papovavirus 1. Papillomaviruses of human beings, rabbits and other animals 2. Polyomavirus 3. Simian virus 40 4. BK and IV viruses

II. Poxvirus . 1. Molluscum contagiosum 2. Yaba virus 3 . Shope fibroma III. Adenovirus Many human and nonhuman types IV. Herpesvirus 1. Marek’s disease virus 2. Lucke’s frog tumourvims 3. Herpes virus pan, papiO. ateles and saimiri 4. Epsteianarr virus 5. Herpes simplex virus types 1 and 2 6 Cytomegalovirus V. Hepatitis B and C viruses ONCOGENIC DNA VIRUSES Papovaviruses Papilloma viruses cause benign tumours in their natural hosts but some of them (for example, condyloma acuminatum in humans, rabbit papilloma) may turn malignant. The association between human papilloma virus (HPV) infection and cancer of cervix uteri, particularly HPV types 16 and 18, has been established. The continuous cell line HeLa, derived many decades ago from a cervical carcinoma and used widely in various laboratories, has been found to contain HPV-l8 DNA. In general, infectious virus particles cannot be demonstrated in tumours induced by DNA viruses but papilloma in the wild cottontail rabbit is an exception. Rabbit papilloma virus, or DNA extracted from it, can produce papilloma in rabbits following subcutaneous injection. The polyoma virus causes natural latent infection in laboratory and domestic mice. However, when injected into infant mice or other rodents, it induces a wide variety of histologically diverse tumours. The virus can be cultivated in mouse embryo fibroblasts or baby hamster kidney cells in which it induces transformation. The polyoma virus produces a hemagglutinin. The papovaviruses BK and IC, which cause widespread asymptomatic human infection, can induce tumours in immunodeficient subjects.

Simian virus 40 (SV 40) was discovered in apparently normal monkey kidney cultures used for the production of the polio vaccine. It causes an inapparent infection in rhesus and cynomolgus monkeys and does not cause cytopathic effects in cell cultures from such monkeys. However, when fluid from such cultures is inoculated into renal cell cultures derived from African green monkeys, cytopathic change with prominent cytoplasmic vacuolation results. Injection into newborn hamsters produces tumours. Transformation is induced in cultured cells from several species, including human cells. Millions of doses of the polio vaccine prepared in monkey kidney cultures that may have harboured the SV 40 virus had been used before the virus was discovered. These individuals have been followed up for over 25 years and no SV 40-related tumours have been reported. T here was considerable apprehension when the oncogenic effect of SV 40 was discovered. However, there is no evidence that the injection of the vaccine containing SV 40 has induced cancer in humans. Poxvirus Three members of the poxvirus group induce benign tumours, rabbit flbroma, molluscum contagiosum and Yaba virus. The last causes naturally occurring benign histiocytomas in monkeys. It is apparently transmitted by insects. Similar tumours can be induced experimentally in many species of primates, including human beings. The tumours regress spontaneously in a few weeks. Nonprimates are unsusceptible. Adenovirus Though some types (12, 19, 21) of human adenovirus may produce sarcomas in newborn rodents after experimental inoculation, they do not appear to have any association with human cancer. Herpesvirus Many herpesviruses have been associated with natural cancers in animals and humans. Marek’s disease: This is a fatal contagious neurolymphomatosis of chickens. No infectious virus particle can be isolated from the lesions or seen under the electron microscope. However, sick birds shed large quantities of virus from their feather follicles. The virus is a typical herpesvirus. Marek’s disease can be induced in young chicken by the injection of the virus. The virus grows well in chick embryo fibroblasts producing cytopathic changes but no evidence of transformation. Marek’s disease can be prevented by a live avirulent vaccine. This is the first instance of a malignant disease being controlled by a viral vaccine. Lucke’s tumour of frogs: A herpesvirus is considered to be the causative agent of a renal adenocarcinoma in frogs. Herpesvirus saimiri: This virus was isolated from a culture of Squirrel monkey kidney cells. It causes fatal lymphoma or reticulum cell sarcoma when injected into owls, monkeys or rabbits. Herpesvirus saimiri infection has been suggested as a primate model for the study of interactions between the EB virus and human beings.

Epstein-Barr virus: A herpesvirus, called the EpsteinBarr virus, is found regularly in cultured lymphocytes from Burkitt’s lymphoma patients. In the body, the tumour cells contain no virus but cell lines established from them contain 5-20 per cent of cells that produce the virus. The virus multiplies only in human lymphoid cell lines. Serological surveys show that infection with the virus is worldwide. Infection is usually asymptomatic. In young adults without pre-existing antibodies, EB virus infection induces infectious mononucleosis. Lymphoma is believed to occur when the infection takes place in children whose immune systems are compromised, as for instance, by chronic malaria. EB virus associated lymphomas have been reported in transplant recipients. EBV has also been linked to nasopharyngeal carcinoma in the Chinese male population in southeast Asia and East Africa. Herpes simplex and cancer cervix: An association has been proposed between herpes simplex type 2 infection and cancer of the uterine cervix, though not proved. It has also been suggested that herpes simplex type 1 infection may be associated with cancer of the lip. Herpesvirus type 8 has been linked to Kaposi’s sarcoma. Cytomegalovirus infection has been associated with carcinoma of the prostate and Kaposi sarcoma. Hepatitis B Virus HBV has been claimed to be directly or indirectly involved in the causation of hepatocellular carcinoma. Studies in many countries have demonstrated an excess prevalence of markers of HBV infection in patients with primary hepatocellular carcinoma as compared with matched controls or with the general population. Hepatitis C virus infection has also been reported to lead to hepatocellular carcinoma.