Viruses and Human Cancer
An estimated 15 percent of all human cancers worldwide may be caused by viruses (Viruses and Human Cancer. Yale J Biol Med. 2006 79: 115 122). Both DNA and RNA viruses are capable of causing cancer in humans. Although it is convenient to consider human tumor viruses as a discrete group of viruses, the six viruses which cause human cancers have very different genomes, replication cycles, and come from five different virus families. The path from virus infection to tumour formation is slow and inefficient. Only a minority of infected individuals progress to cancer, usually years or even decades after primary infection. Virus infection alone is generally not sufficient for cancer, and additional events and host factors, such as immunosuppression, somatic mutations, genetic predisposition, and exposure to carcinogens must also play a role.
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Hepatitis B and C viruses
Hepatitis C virus (HCV) is an enveloped RNA virus of the Flavivirus family. It is capable of causing both acute and chronic hepatitis in humans by infecting liver cells. It is estimated that approximately 3 percent of the world s population are hepatitis C carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to primary hepatocellular carcinoma. Between 1 and 2 percent of infected patients with cirrhosis of the liver will develop primary hepatocellular carcinoma per year of infection. Transmission of HCV occurs through the blood, by shared needles in intravenous drug abuse, sexual activity, and birth being the primary routes.
The hepatitis B virus (HBV) of the family Hepadnaviridae is a DNA virus, but uses reverse transcription as part of its replication cycle. Hepatitis B virus also is a blood-borne pathogen that can result in acute and chronic hepatitis. Chronic hepatitis (infections lasting more than three months) can lead to cirrhosis and liver failure, and to the development of hepatocellular carcinoma. Hepatitis B infections is a significant global health problem with an estimated 2 billion people infected and 1.2 million deaths per year attributed to subsequent hepatitis, cirrhosis and hepatocellular carcinoma.
Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8)
EBV and HHV-8 (also known as Kaposi sarcoma herpesvirus) are both herpesviruses that possess large double-stranded DNA genomes. As with all herpesviruses, they encode enzymes involved in DNA replication and repair and nucleotide biosynthesis. They also both possess the ability to establish latency in B lymphocytes and reactivate into the lytic cycle. Both also are associated with naturally occurring tumors in humans.
EBV is a ubiquitous virus that is most commonly known for being the primary agent for infectious mononucleosis (glandular fever). Up to 95 percent of all adults are estimated to be seropositive for EBV, and most infections are subclinical. EBV is associated with a number of malignancies: B and T cell lymphomas, Hodgkin s disease, post-transplant lymphoproliferative disease and nasopharyngeal carcinoma. Burkitt’s lymphoma, post-transplant lymphoproliferative disease show an increased frequency in patients with immunodeficiency, suggesting a role for immunosurveillance in the suppression of malignant transformation.
In 1994, HHV-8 DNA was identified in biopsies from tumors of a patient with Kaposi sarcoma, a relatively rare malignancy prior to the AIDS epidemic. In addition to it likely being an essential cofactor for the development of Kaposi sarcoma, HHV-8 also is believed to have a role in Castleman’s disease and primary effusion lymphoma. The HHV-8 genome is expressed in these tumors and encodes transforming proteins and anti-apoptotic factors. As with EBV, the predominant cell type infected is the B lymphocyte, although in these cells the lytic cycle occurs rather than being repressed. This may play a crucial role in the pathogenesis of Kaposi sarcoma by elaboration of virus and host cytokines promoting cell proliferation, angiogenesis, and enhancement of virus spread.
Human Papillomavirus (HPV)
Human papillomaviruses are small non-enveloped DNA tumour viruses that commonly cause benign papillomas or warts in humans. Persistent infection with high-risk subtypes of HPV is associated with the development of cervical cancer. HPV infects epithelial cells, and, after integration in host DNA, the production of oncoproteins, mainly E6 and E7, disrupts natural tumor suppressor pathways and is required for proliferation of cervical carcinoma cells. HPV is also believed to play a role in other human cancers, such as head and neck tumors, skin cancers in immunosuppressed patients, and other anogenital cancers.
Cervical cancer is the second leading cause of cancer mortality in women worldwide, causing 240,000 deaths annually. Of approximately 490,000 cases reported each year, more than 80 percent occur in the developing world, where effective but costly Pap smear screening programs are not in place. Early precancerous changes and early cancers detected by Pap smears are effectively treated and cured with surgical therapy or ablation. In the absence of effective screening, the disease is detected late.
The immune system plays an important role in the prevention of persistent HPV infection and progression of precancerous lesions. Human papillomavirus is a poor natural immunogen. As a double stranded DNA virus, there is no RNA intermediate, nor does infection cause cytolysis, allowing initiation of innate immune responses. HPV mainly encodes non-secreted nucleoproteins, which are poorly cross-presented and compared to other viruses its non-structural proteins are expressed at low levels. However, genital infection with HPV is usually transient. Additionally, inadequate T cell responses may lead to failure to clear HPV-infected cells. AIDS patients, renal transplant patients receiving immunosuppressive therapy, and individuals with T cell deficiencies have increased rates of HPV persistence, anogenital lesions, and cervical cancer.
Human T lymphotropic virus type I (HTLV-1)
HTLV-1 is a retrovirus and is associated with adult T-cell leukemia. This virus has a worldwide distribution, with an estimated 12 to 25 million people infected. However, disease is only observed in less than 5 percent of infected individuals. It is transmitted through blood transfusions, sexual contact, and during birth. HTLV-1 displays a special tropism for CD4 cells, which clonally proliferate in adult T cell leukemia, though how this is caused is not known.
HTLV-1 infection has a very long latency period of 20 to 30 years, but once tumor formation begins, progression is rapid. Standard chemotherapy often can bring about an initial response with a partial or complete remission; however, relapse is common, and median survival is eight months. The HTLV-1 Tax gene has been postulated to play an important role in tumour formation through the activation of virus transcription and the hijacking of cellular growth and cell division machinery, but the mechanisms leading to adult T cell leukemia are not well understood.
These six viruses illustrate the diverse biological pathways to malignancy and the challenges of treating the resulting diseases. The study of viruses and human cancer has led to optimism about the development of new strategies for the prevention of the infections that can lead to carcinogenesis. Antiviral drugs such as lamuvidine used against heptatitis B and ganciclovir for Kaposi sarcoma specifically target the virus replication machinery. The presence of virus gene products in tumour cells can provide important targets for directed therapies that specifically can distinguish tumour cells from normal cells. The inability of traditional cancer therapy, such as chemotherapy and radiation, to distinguish cancer cells from normal cells is a significant drawback and leads to toxicities for patients undergoing treatment. Targeted therapies directed against virus proteins or generate immune responses in order to either prevent infection or kill infected cells or cancer cells hold much promise for more effective and tolerable treatment strategies for virus-related tumours.
Tags: Biology, HIV/AIDS, Immunology, Medicine, Microbiology, Podcast, Science, Virology
