Oncogenes and human cancer

Abstract

The first demonstrations that cancer could have an infectious nature was by Ellerman and Bang (1) ~ who showed that leukemia in chickens was transmissible with cell-free extracts and by Rous (2), who found in a similar fashion that naturally occurring chicken sarcomas were transmissible. Although they were able to show that these cell-free extracts contained a transmissible agent~ the idea that this induced cancer was received by the scientific world at that time with great skepticism. The interest in oncogenic viruses was strongly enhanced in the early 60's by the isolation of mammalian tumor viruses and the general acceptance that at least some of these viruses were tumorigenic. The discovery of the reverse transcriptase enzyme in RNA tumor viruses (3,4), gave a logical explanation for how these viruses became integrated in the chromosomes of eukaryotic cells. Taxonomically, oncogenic viruses are members of diverse families. DNA viruses (herpes-, adeno- and papovaviruses) as well as many members of the retrovirus family (containing RNA such as the type C RNA viruses) are capable of inducing tumors. For the retroviruses two different routes to become transforming (oncogenic) have become clear. The majority of these viruses (the acute type C RNA transforming viruses) 11 acquire11 certain genetic sequences (oncogenes) from their host, which are necessary to initiate and maintain the malignant transformation of the cell by the virus. Other retroviruses integrate their genome nearby oncogenic sequences in the chromosome of their host. Independent of the exact mechanism, these viruses share the capability of inducing tumorigenesis by triggering the transcription of certain sequences, and it is the proteins encoded by these sequences which are necessary to maintain the neoplastic phenotype of the infected cell The accumulating number of independent isolates of tumorigenic retroviruses induced in the mid-70's a worldwide search for these viruses in humans. Only very recently the isolation of a human tumor T-cell leukemia retrovirus (HTLV) was reported (5,6). Another approach was initiated in the beginning of the 80's, with the finding that the acquired sequences of retroviruses are strongly conserved among species. In general, the cellular homologs of these sequences were easily detectable and could be studied in more detail by molecular cloning, using the oncogenic acquired sequences of retroviruses as probes. This approach seems to be very fruitful and will be discussed in more detail below. Although the oncogenic potential of the acquired sequences in a number of these viruses in vertebrates is well estabished, the involvement of their human cellular homologs in human tumorigenesis has been and will be a rich source for discussion. However, at the moment they provide us the best available model for the induction of human cancer at the molecular leve