A Brief History of Cancer Virology“Diseases desperate grown/By desperate appliance are relieved/Or not at all” - Hamlet, Act 4, scene 3, lines 9–11
Cancer Virology: OriginsThe concept of cancer was first described around 3000 BC, but the role infectious disease plays in different cancers has been appreciated for only a century. Scientists now recognize that there are both environmental and biological factors that influence the development of cancer:
- Environmental factors: exposure to DNA-damaging chemicals such as cigarette smoke, formaldehyde and asbestos play roles in cancer development.
- Genetic factors: risk for inherited diseases, such as breast, colon, endometrial, and ovarian cancers, can be passed down in families.
- Infectious diseases: microbial infections can lead to cancers such as lymphoma, carcinoma and leukemia. Tumor virology has also helped us develop prophylactic vaccines (such as those for hepatitis B virus and human papillomavirus).
The virus Rous discovered was Rous sarcoma virus (RSV), named after its discoverer, and this virus incorporates its genetic material into the host genome. This viral genome contains a v-src gene that triggers uncontrolled growth in infected cells, a process that promotes tumorigenesis and cancer. The v-src gene codes for a protein tyrosine kinase that has pleiotropic effects in cells; for example, it can activate transcription factors and upregulate mitogenesis. Discovery of the v-src gene helped lay the groundwork for studies of proto-oncogenes (genes that cause normal cells to become cancerous when they are mutated). “It is not an exaggeration,” write Chang et al., “to say that tumor virology formed the bedrock for all areas of modern cancer molecular biology.”
How Can Viruses Influence Cancer?Together, microbes are estimated to underlie between 10% and 20% of all cancers worldwide. Unknown microbes may also play an additional role in tumorigenesis. In 2002, HPV accounted for the largest global cancer burden, making up 5.2% of infection-associated cancers. While it is clear that cancer is not contagious, virus-associated cancers continue to afflict populations throughout the world. Viruses aren’t the only microbial culprits; Helicobacter pylori, a type of bacteria, plays a role in stomach cancers, while helminths are often causal in bladder and gall bladder cancers. Microbes are thought to promote development of cancer through two routes: expression of an oncogene or induction of chronic inflammation.
Chronic inflammation leading to tissue damage is one mechanism of carcinogenesis. For example, liver cancer caused by the hepatitis C virus (HCV) is a multi-step process that begins with HCV infection. Once the virus has infected the liver, inflammatory agents such as reactive oxygen species (ROS) and cell death signals promote higher mutation rate and liver scarring. As illustrated in Figure 1, low-level inflammation increases ROS and other mutagenic compound production, genetic instability leads to unchecked cell growth, and increased immune evasion result from HCV infection. Additionally, initiation of neoplastic clones, cancer cells capable of indefinite proliferation, leads to additional tumor progression. This process can take over 20-40 years. In other studies, HCV viral proteins appear to affect the innate immune pathway, which is normally responsible for the body’s first-line defense against pathogens. While HCV activates a beneficial immune response known as the interferon pathway, recent studies have shown that robust induction of the interferon pathway actually predicts treatment failure and viral persistence.
Another mechanism of carcinogenesis is the expression of an oncogene, such as during RSV infection. The “provirus hypothesis,” proposed by Howard Temin of the University of Wisconsin in 1964, reversed the flow of the central dogma of biology in which genes provide the instructions for creating proteins (namely, transcription and translation). His hypothesis stated that human cancer viruses were caused by the conversion of RNA to DNA. While this idea may not have been accepted into the scientific mainstream, some have argued that it laid the groundwork for retrovirology. The role of retrovirology in the study of cancer biology remains a topic of research.
How Viruses Advance Cancer ResearchMore recently, scientists have begun to turn to viruses to learn more about the development of human cancers. There are many reasons that viruses improve our understanding of cancer. Viruses have very small genomes in comparison to mammals, and several viruses contain at least one gene that is associated with cancer. Some human genes and their roles in cell cycle maintenance or DNA damage repair have been discovered based on their interaction with viral genes. For instance, the p53 tumor suppressor gene, appropriately nicknamed “the guardian of the genome,” was identified by its association with tumor virus proteins.
Additionally, the study of host-virus interactions and viral evasion of the immune system has allowed viruses to become engineering platforms for combination immunotherapy. Human cancer viruses have several mechanisms of immune evasion, and viral cancers are more common in patients with longstanding immunological deficiency. For example, by inducing preferential cytotoxicity, scientists can exploit viruses to develop therapies for cancer patients.
Because immune evasion by viruses and tumors targets analogous human immune pathways, the intersection between virology and immunology creates a rich landscape for future research. Researchers and physician-scientists may be better able to tailor effective therapies by studying tumor virology and gaining a better understanding of the role of viruses in human cancers. Furthermore, study of virally-induced human cancers may help quell the fears surrounding cancer development and the “contagious” nature of these diseases. Stay tuned for a deeper dive into the viruses associated with cancer, or as I like to call them, the seven deadly oncoviruses.
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