Lessons from Viral Carcinogenesis

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Transforming retroviruses carry oncogenes derived from cellular genes that are involved in mitogenic signalling and growth control. DNA tumor viruses encode oncogenes of viral origin that are essential for viral replication and cell transformation; viral oncoproteins complex with cellular proteins to stimulate cell cycle progression and led to the discovery of tumor suppressors. Viral systems support the concept that cancer development occurs by the accumulation of multiple cooperating events. Viruses are now accepted as bona fide etiologic factors of human cancer; these include hepatitis B virus, Epstein–Barr virus, human papillomaviruses, human T-cell leukemia virus type I and hepatitis C virus, plus several candidate human cancer viruses.

It is estimated that 15% of all human tumors worldwide are caused by viruses. The infectious nature of viruses distinguishes them from all other cancer-causing factors; tumor viruses establish long-term persistent infections in humans, with cancer an accidental side effect of viral replication strategies. Viruses are usually not complete carcinogens, and the known human cancer viruses display different roles in transformation. Many years may pass between initial infection and tumor appearance and most infected individuals do not develop cancer, although immunocompromised individuals are at elevated risk of viral-associated cancers.

Variable factors that influence viral carcinogenesis are reviewed, including possible synergy between viruses and environmental cofactors. The difficulties in establishing an etiologic role for a virus in human cancer are discussed, as well as the different approaches that proved viral links to cancer. Future directions for tumor virus studies are considered.

Viruses have been key instruments in the revolution in cancer biology that has occurred over the last 20 years. Without the contributions of viral carcinogenesis, it is difficult to conceive that the molecular basis of cancer would stand revealed so clearly today. Although viewed originally as unusual agents that caused cancer in animals but were of no particular relevance to humans, viruses have turned out to be the Rosetta stone for unlocking the mysteries of cell growth control. They have revealed the functional foundations of the genetic basis of cancer and have provided a conceptual framework applicable not only to cancer induced by viruses but to all neoplasia.

The tumor viruses have played two major roles in cancer research over the last 2 decades: first, as tools for the discovery and dissection of cell signalling and growth control pathways and, second, as newly appreciated causative agents of human neoplasia. The RNA tumor viruses have figured prominently in the first field of endeavor, whereas the DNA tumor viruses have been principals in both areas.

This article will be an interpretation of major developments and conceptual changes that have been shaped by viral carcinogenesis over the past 20 years. Due to space constraints, it is not possible to present the fascinating details of specific virus-cancer systems, but recent publications may be consulted for in-depth descriptions of the characteristics of individual viruses, properties of different tumor virus systems and mechanisms of action of viral transforming genes (1–5). The biochemical and molecular details of cellular processes that may be affected by tumor viruses are covered in other articles in this issue (6).

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Conceptual advances
Viral carcinogenesis provided the breakthroughs that crystallized current concepts of cancer development (Table I) and revealed mechanisms responsible for the orchestration of normal cell growth control. Both the RNA tumor viruses and the DNA tumor viruses played pivotal roles in the establishment of paradigms that extend far beyond virology to form the foundation of contemporary cancer biology.

Oncogenes
Transforming retroviruses carry cellular genes.
retroviruses share the unusual characteristic of reverse transcription in their life cycle. Soon after infection, the viral RNA genome is transcribed by a virion-associated enzyme, the reverse transcriptase, into a double-stranded DNA copy which is then integrated into the chromosomal DNA of the cell with the help of the viral integrase enzyme. There are many possible sites for proviral integration in the cellular genome. The integrated copy, termed the provirus, is similar to a cellular gene except that transcription is usually controlled by sequences in the viral long terminal repeat. Retroviral infection of a cell is permanent, as proviruses are almost never lost from the chromosome.

Rous sarcoma virus (RSV), the transmissible cause of a chicken sarcoma isolated by Rous in 1911 (7), together with basic virology studies in the 1960s provided the tools that led to the discovery of oncogenes (8). The development of a quantitative in vitro focus assay for RSV (9) permitted genetic studies that showed that replication and transformation represented separate viral gene functions and that the transforming gene (src) was dispensable for viral growth. Following the revolutionary discovery of reverse transcriptase (10,11), a probe specific for the src gene was prepared and, most unexpectedly, was found to be able to hybridize to normal cell DNA (12). The implications of this observation, that a tumor virus contained a gene related to a cellular gene, were enormous.

Numerous animal retroviruses with oncogenic capabilities had been isolated in the 1950s and 1960s, primarily from chickens and mice (8) (Figure 1). All the oncogenes carried by those transforming retroviruses were subsequently shown to be derived from the cell. The progenitor cellular genes, referred to as proto-oncogenes, have been identified as classes of genes involved in mitogenic signalling and growth control, including protein kinases, growth factor receptors, growth factors, G proteins, transcription factors and adapter proteins (Table II) (13). The observation that first linked an oncogene from a chicken sarcoma virus with a cellular transcription factor was quite unanticipated (14). More than 30 transduced oncogenes in transforming retroviruses have been identified (15).

http://carcin.oxfordjournals.org/content/21/3/405.full