Many DNA and some RNA viruses, especially the retroviruses, can transform normal cells into abnormal cells called tumors (benign or malignant). This process is called viral transformation, and these viruses are oncogenic viruses. Viruses that can either cause tumors in their natural hosts or other species or can transform cells in vitro are considered to have oncogenic potential. Specifically, a tumor is an abnormal growth of cells and is classified as benign or malignant—depending on whether it remains localized or has a tendency to invade or spread by metastasis. Therefore, malignant cells have at least two defects. They fail to respond to controlling signals that normally limit the growth of nonmalignant cells, and they fail to recognize their neighbors and remain in their proper location.
Many DNA, and some RNA, viruses can transform normal cells into tumors
When grown in tissue culture in the laboratory, these tumor cells exhibit a series of properties that correlate with the uncontrolled growth potential associated with the tumor in the organism. They have altered cell morphology and fail to grow in the organized patterns found for normal cells. In addition, they grow to a much higher cell density than do normal cells under conditions of unlimited nutrients and can lose contact inhibition and the requirement for growth on a solid substrate; therefore, they appear unable to enter the resting G0 state. Furthermore, they have lower nutritional and serum requirements than normal cells and can grow indefinitely in cell culture. These transformed or tumor cells often are used as cell lines for the culture or propagation of viruses in the laboratory.
Malignant cells fail to respond to signals controlling the growth and location of normal cells
In addition to the listed properties, viral transformation usually, but not always, endows the cells with the capacity to form a tumor when introduced into the appropriate animal. Although the original use of the term transformation referred to the changes occurring in cells grown in the laboratory, current usage often includes the initial events in the animal that lead to the development of a tumor. In recent years, it has become increasingly clear that some, but not all, of these viruses cause cancers in the host species from which they were isolated.
Some DNA viruses and some retroviruses can accomplish malignant transformation of cells in culture
Transformation by DNA Human Viruses
The oncogenic potential of human DNA viruses is summarized in Table 7–4. With the exception of parvoviruses, most DNA virus families have some members capable of causing aberrant cell proliferation under some conditions. For some viruses, transformation or tumor formation has been observed only in species other than their natural host. Apparently, infections of cells from the natural host are so cytocidal that no survivor cells remain to be transformed. In addition, some viruses have been implicated in human tumors without any indication that they can transform cells in culture.
Some oncogenic viruses cause tumors in species other than their natural hosts
TABLE 7–4Oncogenicity of DNA and RNA Human Viruses ||Download (.pdf) TABLE 7–4 Oncogenicity of DNA and RNA Human Viruses
|VIRUS OR VIRUS GROUP ||TUMORS IN NATURAL HOSTa ||TUMORS IN OTHER SPECIESb ||TRANSFORM CELLS IN TISSUE CULTURE |
|DNA viruses || || || |
|Parvoviruses ||No ||No ||No |
|Polyomaviruses ||No ||Yes ||Yes |
|Papillomaviruses ||Yes, often benign ||? ||Yes |
|Human hepatitis B virus ||Yes ||? ||No |
|Human adenoviruses ||No ||Yes ||Yes |
|Human herpesviruses (EBV, HHV-8 or KSHV) ||Yes ||Yes ||Yes |
|Poxviruses (Molluscum contagiosum) ||Occasionally, usually benign ||Yes ||No |
|RNA viruses || || || |
|Retroviruses ||Yes ||Yes ||Yes |
|Human T-lymphotropic viruses I and II (HTLV-I and II) || || || |
|Hepatitis C virus ||Yes ||Yes ||Yes |
In nearly all cases that have been characterized, viral transformation is the result of the continual expression of one or more viral genes that are directly responsible for the loss of cell growth control. Two targets have been identified that appear to be critical for the transforming potential of these viruses. Adenoviruses, papillomaviruses, and polyomaviruses (simian virus 40) all code for either one or two proteins that interact with the tumor suppressor proteins such as p53 and pRb (for retinoblastoma protein) to block their normal function, which is to exert a tight control over cell-cycle progression. The end result is endless cell cycling and uncontrolled cell growth.
Many DNA viruses encode proteins that interfere with cell cycle causing uncontrolled growth and transformation
Some viruses integrate into the host chromosome at random sites (with a high efficiency for retroviruses and a very low efficiency for adeno-, polyo-, papilloma- viruses), although the DNAs of papillomaviruses and herpesviruses are found in transformed cells as extrachromosomal DNA. Unlike retroviruses that code for the enzymes necessary for integration, papillomaviruses, polyomaviruses, and adenoviruses may integrate by nonhomologous recombination using enzymes present in the host cell. In summary, two events appear to be necessary for viral transformation: a persistent association of viral genes with the cell, and the expression of certain viral “transforming” proteins.
In human viruses, viral transforming proteins (oncoproteins) and not integration events are responsible for transformation
Transformation by Retroviruses
Two features of the replicative cycle of retroviruses are related to the oncogenic potential of this class of viruses known as oncoretroviruses. First, most retroviruses (exception human immunodeficiency virus, HIV) do not kill the host cell, but rather set up a permanent infection with continual virus production. Second, a DNA copy of the RNA genome is maintained in cell via integration into the host cell DNA by a virally encoded integrase (IN).
Most animal retroviruses produce virions without causing host cell death
A DNA copy of the retroviral genome is integrated, but not at a specific site
Retroviruses are known to transform cells by three different mechanisms; the first and second mechanisms for animal retrovirus and the third mechanism for human retrovirus (HTLV). First, many animal retroviruses have acquired transforming genes called oncogenes. These retroviruses require a helper virus as the insertion of the oncogene replaces a viral gene. More than 30 such oncogenes have now been found since the original oncogene was identified in animal Rous sarcoma virus (called v-src, where the v stands for viral). Because normal cells possess homologs of these genes called protooncogenes (eg, c-src, where c stands for cellular), it is generally thought that viral oncogenes originated from host DNA. It is possible they were picked up by “copy choice” recombination involving packaged cellular mRNAs, as previously described. Because these transforming viruses carry cellular genes, they are sometimes referred to as transducing retroviruses. Most of the viral oncogenes have undergone mutations that make them different from the cellular proto-oncogenes. These changes presumably alter the protein products such that they cause transformation. Although the mechanisms of oncogenesis are not completely understood, it appears that transformation results from inappropriate production of an abnormal protein that interferes with normal signaling processes within the cell, causing uncontrolled cell proliferation. Because tumor formation in vitro by retroviruses carrying an oncogene is efficient and rapid, these viruses are often referred to as acute transforming viruses. Although common in some animal species, this mechanism has not yet been recognized as a cause of any human cancers.
Animal retroviruses may carry transforming oncogenes
Oncogenes encode a protein that interferes with cell signaling causing transformation in some animal species
The second mechanism is called insertional mutagenesis and is not dependent on continued production of a viral gene product. Instead, the presence of the viral promoter or enhancer is sufficient to cause the inappropriate expression of a cellular gene residing in the immediate vicinity of the integrated provirus. This mechanism was first recognized in avian B-cell lymphomas caused by an avian leukosis virus, a disease characterized by a very long latent period in birds. Tumor cells from different hosts were found to have a copy of the provirus integrated at the same place in the cellular DNA. The site of the provirus insertion was found to be next to a cellular proto-oncogene called c-myc. The myc gene had previously been identified as a viral oncogene called v-myc. In this case, transformation occurs not because the c-myc gene is altered by mutation, but because the viral promoter adjacent to the gene turns on its expression continuously and the gene product is overproduced. The disease has a long latent period because, although the birds are viremic from early life, the probability of an integration occurring next to the c-myc gene is very low. After such an integration event does occur, however, cell proliferation is rapid and a tumor develops. No human tumors are known to be caused from insertional mutagenesis caused by a retrovirus. However, some human cancers such as Burkitt lymphoma and chronic myelogenous leukemia (CML) are known to occur in which a chromosome translocation has placed an active cellular promoter next to a cellular proto-oncogene. In addition, a few retroviral gene therapy trials were stopped because of the induction of leukemia likely due to retroviral insertion near a proto-oncogene.
Insertional mutagenesis causes inappropriate expression of a proto-oncogene adjacent to integrated retroviral genome in animal retroviruses
The third mechanism was revealed by the discovery of the first human retrovirus, human T lymphotropic virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia and lymphoma (ATLL). HTLV-I sequences are found integrated in the DNA of the leukemic cells, and all tumor cells from a particular individual have the proviral DNA in the same location. This observation indicates that the tumor is a clone derived from a single cell; however, the sites of integration in tumors from different individuals are different. Thus, HTLV-I does not cause malignancy by promoter insertion near a particular cellular gene. Instead, HTLV has a regulatory gene called tax that encodes for Tax protein that transactivates or upregulate not only the transcription of its own proviral DNA, but also the transcription of many cellular genes, including proto-oncogenes. The resulting cellular proteins cooperate to cause uncontrolled cell proliferation. HTLV-I is commonly described as a transactivating retrovirus. The same mechanism is also observed in the second human retrovirus, HTLV-II that causes hairy T cell leukemia.
Human T-cell leukemia is caused by transactivating factor (Tax) encoded in integrated HTLV
Tax turns on cellular proto-oncogenes, causing cell proliferation
Transformation by Other RNA Viruses
Hepatitis C virus (HCV) causes chronic infection in more than 80% of infected people. The chronicity in HCV infection increases the risk of cirrhosis of liver and hepatocellular carcinoma (HCC). HCC occurs on average approximately 20 to 30 years after chronic infection but alcohol and drug abuse can accelerate this process. It is thought that the constant inflammation and regeneration of hepatocytes leads to the eventual induction of the tumor and is, therefore, considered indirect oncogenesis. However, several studies suggest that HCV nonstructural proteins, NS3 and NS5A, NS5B, and the HCV core protein may be involved in transformation. These HCV proteins interfere with cellular proteins that are responsible for the regulation of cell cycle control.