A turning point in cancer research: capturing the human genome
One of the goals of cancer research is to ascertain the mechanisms of cancer. Efforts in this direction have been made by using model systems of limited complexity, such as cancer cells in vitriol and oncogene viruses. The use of cell cultures avoided the complexity of the whole animal but not the complexity of the animal genome. The use of oncogene viruses seemed to replace the extraordinary simplicity of the viral genome. This simplicity made the study of viruses very productive. The persistence of the transformed state in a cell clone could be explained by the persistence of the viral genome in cells (1); genetic and molecular results showed that transformation is the consequence of the expression of one or a few viral genes.
Finally, viral transforming genes, or “oncogenes”, and their designated proteins were identified. The crowning development was the demonstration that in retroviruses the oncogenes are picked up from the cellular genome during the viruses most recent history
(2). As a result of these studies, cancer appeared to be linked to the expression of some viral gene. Possibility of “hit and run” mechanism, in which the virus changes the cell and then disappears. Two types of oncogenes were identified: some which immortalize cells, and others which make them primogeniture
(3). In most cases oncogenes of both types are needed to cause a continuously growing tumor. Subsequent work, however, blurred the distinction between immortalizing and transforming oncogenes by showing that their effects differ in primary cultures or permanent lines and in cells of different species (4). These findings suggested that the state of the cellular genes is important for the effect of oncogenes, in agreement with the great differences in cancer incidence and in the effects of chemical or viral carcinogens in different species.
These studies dealt with the initial cancer events. But natural cancers evolve slowly toward malignancy through many definable Stages in a process called “progression” (5), which is the least understood but probably the most crucial phase in the generation of malignancy. Progression generates the marked heterogeneity of cancers (6) and their many chromosomal abnormalities (7); it must be differentiated from the initial action of oncogenes (8). Progression is observed in cells transformed by viruses. This is the case, for instance, of bursa lymphomas induced by avian leukocytes viruses (9). of viral T-cell lymphomas in mice (10), and of iatrogenesis by Friend leukemia virus in cultures of mouse bone marrow cells (11). Step wise transformation is observed also with DNA viruses (12). Fibrillation cells from a variety of organs of a transgenic mouse containing mys and simian virus 40 (SV40) sequences, although expressing SV40 T antigen, were normal but became gradually transformed upon cultivation (13). In all these cases cellular changes occurring during culture growth determined full transformation. The “hit-and-run hypothesis of viral transformation must be reconsidered.
A clue on what these changes are is obtained by examining the heterogeneity of chemically induced rat mammary carcinomas with reference to several well-characterized markers. The expression of the markers is altered in different ways in different parts of the same cancer; the alterations seem to be clonal, being uniform in small parts of a rumor but different in adjacent parts (14). The closeness of the parts makes it unlikely that the differences are due to the environment; it is more likely that they are caused by structural changes of the genes, as is also suggested by the chromosomal rearrangements observed in cancers (15) and by the finding that cache chemically or radiation-induced mouse sarcoma expresses a different class I major incompatibility antigen, probably produced through gene rearrangement (16). A major gap in our understanding of cancer is how the activity of an oncogene is related to the events of progression. But the first task is to ascertain whether the DNA of an advanced cancer is as heterogeneous as the phenotype of its cells. If it is so, a new field of cancer research opens up, possibly leading to the discovery of the genes whose activity or inactivity is responsible for infiltration and metastasis.
We are at a turning point in the study of tumor virology and cancer in general. If we wish to find out more about cancer, we must now consider the cellular genome. We are back to where cancer research started, but circumstances are drastically different because we’ve new knowledge and crucial tools, like DNA cloning. We have two options: either to try to discover the genes important in malignancy by a piecemeal approach, or to sequence the whole genome of a selected animal species. The former approach seems less formidable, but it’ll still require a huge investment of research, especially if the important genes differ in cancers of various organs and if they encode regulatory proteins. A major difficulty for conventional approaches is the heterogeneity of tumors and the lack of cultures representative of the various cell types present in a cancer. I think that it will be far more useful to begin by sequencing the cellular genome. The sequence will make it possible to prepare probes for all the genes and to classify them for their expression in various cell types at the level of individual cells by means of scatological hybridization. The classification of the genes will facilitate the identification of those involved in progression.
In which species should this effort be made? If we wish to know human cancer, it should be made in humans because the genetic control of cancer seems to vary in several species. Research on human cancer would receive a major boost from the detailed knowledge of DNA. Humans would become the well-liked experimental species for cancer research with cells in culture or in immunodeficient mice. Because cancer might be defined in mole-cu liar terms, the agents capable of inducing cancer in humans might be identified by the mixture of in vitriol and epidemiological studies. Knowledge of the genes involved in progression would open new therapeutic approaches, which could cause a general cancer cure if progression has common features in all cancers.
Knowledge of the genome and availability of probes for any gene would even be crucial for progress in human physiology and pathology outside cancer; as an example, for learning about the regulation of individual genes in various cells types.