Viruses And Oncogenesis

In Chapter 1, we pointed out the role that viruses have historically played in our understanding of the molecular bases of cancer. Viruses have been defined as the Rosetta Stone for unlocking the mysteries of cell growth control. They have also revealed the functional foundations of the genetic bases of cancer and provided a conceptual framework applicable to all can-cers.34 The concept that viruses cause cancer dates back to the first decade of the twentieth century, when Francis Peyton Rous demonstrated that tumors can be induced in particular breeds of chickens by inoculating tumor derived cell-free filtrates, containing a transmissible agent, most probably a virus.35

Viruses are a type of infectious agent that must invade living cells in order to reproduce. According to the type of nucleic acid that represents the virus genome, a distinction is usually made between DNA and RNA oncogenic viruses, the latter also being referred to as retroviruses. This basic distinction is not only qualitative; it also reflects a substantial difference in the way viruses attack and are assumed to transform a normal cell into a cancerous one. All RNA oncogenic viruses (or retroviruses) show the unusual characteristics of reverse transcription. After infecting the host cell, the viral RNA genome is transcribed into double-stranded DNA by the viral enzyme reverse transcriptase—typical of this kind of viruses. The double-stranded DNA is then integrated into the chromosomal DNA of the host cell with the help of the enzyme integrase. The integrated copy, termed a provirus, is similar to a cellular gene, but its expression is regulated by the virus rather than by the cell. Also, cellular genes, particularly cellular oncogenes, are usually copied together with the integrated proviral DNA in such a way that the viral genome carries cellular oncogenes after infection. Once incorporated into the viral genome, an oncogene is freed from normal cellular constraints and is expressed constitu-tively in infected cells under the direct control of the virus, leading to cell transformation and cancer development. Alternatively, a retrovirus containing a cellular oncogene may infect a cell type that does not express that oncogene and thus lacks controls to regulate it. Therefore, in the case of retroviruses, a combination of overexpression or inappropriate expression of a modified oncogene leads to malignant transformation of the target cell.

Unlike retroviruses, the oncogenes of small DNA tumor viruses are of viral, not cellular origin, and are essential for both viral replication and cell transformation. Small DNA tumor viruses are dependent on the host cell machinery to replicate the viral DNA. Viral DNA encodes nonstructural proteins that stimulate resting cells to enter the S phase of the cell cycle, to provide an environment that enhances DNA replication. One such protein, the large-T antigen of the simian virus 40 (SV-40), is required both for initiation of viral DNA synthesis and for stimulation of cell entry into the S phase. The large-T antigen of SV-40 was found to form a complex with a host cell protein (p53) in SV-40 transformed cells,36 and this led to the conclusion that the gene synthesizing this protein (the p53 gene) could be included in the growing list of oncogenes. However, a decade later it was definitely demonstrated that the p53 gene is in fact a tumor suppressor gene,37 that is, a gene that inhibits instead of stimulating cell growth. A second tumor suppressor protein, the retinoblastoma gene product (pRb) was also identified as one of several host cell proteins com-plexed with the E1A oncoprotein in adenovirus transformed cells.38 The SV-40 T antigen also forms complexes with pRb and, by binding to and abolishing the normal function of both p53 and pRb inhibitory proteins, disrupts cell growth control mechanisms (Figure 2.3).39 Once again it is clear from the previous outline that the study of both RNA and DNA oncogenic viruses and their close relationship with oncogenes and tumor suppressor genes, respectively, has played an outstanding role in the elucidation of the mechanisms of control of cell proliferation in normal cells and cancer. It may therefore sound rather paradoxical to question whether there is a role for viruses in cancer development, and the great majority of scientists working with tumor viruses would have no doubt at all. However, it is clear that even in cancers with proven viral etiology, the virus appears to be necessary but not sufficient, for tumor development. The interpretation is that viruses do not behave as complete carcinogens, but rather act as initiating or promoting factors. Additional changes must necessarily accumulate to complement those produced by the virus, to disable the multiple regulatory pathways and checkpoints that control proliferation in normal cells. Different data support this interpretation:

1. It is well known that the majority of individuals infected with a tumor virus do not develop cancer. As demonstrated by epidemiologic data, more than 90% of humans are infected with Epstein-Barr virus, but cancer due to EBV is rare, unless an individual becomes immuno-compromised.

2. The latent period between the initial virus infection and tumor appearance is often too long to establish a clear-cut relationship between infection and tumor development. This is clearly illustrated by epidemiological evidence showing that, for example, Chinese with chronic HBV infections ac

FIGURE 2.3. Mechanisms of cell transformation by RNA and DNA viruses.

quired as newborns usually develop hepatocellular carcinoma (HCC) beyond 50 years of age.

3. Finally, although it could be assumed that the host immune response may play a major role in explaining outcome, evidence from in vitro experiments conducted on isolated cell systems still confirms that additional changes must accumulate within a virus-infected cell for it to be fully transformed and that the transformation potential of a virus, given the necessity of these additional changes, is not instantaneous but requires a long latency period. Note that SV 40 or its cloned antigen alone has been known since 1962 to be a particularly efficient aneuploidogen in human cells. This effect would be produced, particularly by the T antigen, by displacing histone proteins from chromosomal DNA, thus inducing unwinding of nucleosomally organized DNA, with the block of the normal chromosomal binding sites for tubu-lin fibers.5

A list of some of the major viruses and related human cancers is presented in Table 2.1. The recognition of the viral etiology of human cancer provides the rationale to develop preventive strategies to inhibit viral infection, thus reducing cancer risk. Prophylactic vaccines can induce antibodies that can neutralize the virus before it infects the cell. The HBV vaccine has been used for more than 15 years to prevent transmission of the virus to newborns and to prevent the establishment of a lifelong persistent infection. Large-scale immunization programs have been undertaken in some countries to clarify the efficacy of the vaccine in reducing the incidence of HCC.40 Given the worldwide burden of HPV-related diseases, papillomavirus vaccines are under development, recombinant virus-like particles (VLPs) are also under investigation.

Viruses can be also harnessed for novel approaches to cancer treatment. A number of gene-based therapies use viral vectors to deliver tumor suppressor genes (e.g., p53): immune response genes (cytokines), drug resistance genes, drug sensitivity genes, and genes to inhibit activated oncogenes. A further application of viruses to cancer therapy is represented by the so-called viral oncolysis. A prototype of this approach is represented by a mutant form of adenovirus

TABLE 2.1. Major Viruses Implicated in Human Cancer.

Name of virus

Type of cancer

Cofactors

Epstein-Barr virus (EBV)

Burkitt's lymphoma

Malaria

Nasopharyngeal carcinoma

Nitrosamines

B-cell lymphoma

Immunodeficiency

Hodgkin's disease

Unknown

Hepatitis B virus (HBV)

Liver cancer

Aflatoxin, alcohol

Human immune deficiency virus (HIV)

Severe immune deficiency predisposing to

EBV, HPV, herpes virus

Kaposi sarcoma, lymphoma, and cervical cancer

Human papilloma virus (HPV)

Cervical cancer

Smoking

Skin cancer (epidermodysplasia verruciformis,

Sunlight

a rare hereditary condition) and conjunctival cancer

Human T-cell lymphotropic virus type I

Adult T-cell leukemia/lymphoma

Unknown

(HTLV-1)

Human T-cell lymphotropic virus type 2

Hairy cell leukemia

Unknown

(HTLV-2)

Kaposi sarcoma-associated herpesvirus

Kaposi sarcoma

Unknown

(KSHV)

Body-cavity-based lymphoma

EBV and HIV

that fails to express E1B that can replicate and destroy cancer cells that lack p53.41 For updated information on this kind of therapy, see Reference 42.

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