Caims of cancer cures abound in the corridors of human genomics research. But a sober look at the scientific findings forces a rethink. Brian Goodwin reports on an important new perspective.
David Rasnick and his colleagues in the Department of Molecular and Cell Biology in University of California Berkeley first proposed that genetic instability is linked to cancer three years ago . In a more recent publication, a more complete theory is presented on how cancer is caused by the large-scale disturbance in genomic organisation that results from the genetic instability .
Rasnick starts by showing why the current theory that cancer is caused by genetic mutation in a few oncogenes (genes associated with cancer) is implausible.
He uses Metabolic Control Analysis invented by the late Henry Kacser, geneticist and biochemist of Edinburgh University, to demonstrate that mutations in a few primary control genes will either kill a cell or produce only a small disturbance in its metabolic activities. Furthermore, the conventional theory predicts that all cancers will have mutations in some of the key oncogenes (genes purported to be involved in cancer), which is not the case. In fact, all cancers differ from each other in their molecular signatures, and are distinct from normal cells. Changes are typically found in hundreds, or thousands of genes, not just a few.
It has been known for nearly 100 years that cancer cells have a large imbalance in their genomes compared with normal cells: technically, they are aneuploid, ie, irregular genomes, with large changes in chromosomal organisation. The most familiar example of aneuploidy is Down's Syndrome, in which three copies of chromosome 21 are present instead of the usual two. This genomic imbalance results in a disturbance of embryonic development so that tissues and organs are altered, though the cells of a Down's Syndrome individual are not cancerous. It takes a more severe imbalance to turn cells cancerous. Cancer cells have many copies of some chromosomes, additional fragments of others, and loss of whole chromosomes so that some have only one copy, resulting in imbalance in thousands of genes. How could this come about?
Cell division is a complex process, involving not just precise copying of the genes but also their exact distribution to the two new cells so that each has two copies of every chromosome. Anything that disturbs these processes can result in genomic imbalance. Damage to the genes that monitor the intricate copy and delivery procedure, the so-called guardians of the genome, can result in an altered chromosome balance in the daughter cells. Mutations in those key genes can therefore initiate aneuploidy, so that there is indeed a role for mutation in cancer production. However, there are many other disturbances that can start the process going wrong, such as chemicals from the environment, radiation or any form of stress, (or indeed, stray foreign DNA jumping into the genome*). It doesn't have to be mutation.
Once genomic imbalance (aneuploidy) starts, it will tend to get worse: the imbalance in chromo-somes will result in further disturbances to cell division, so that there is a positive feedback effect. However, this is counteracted by the reduced survival of aneuploid cells and the body will tend to get rid of them.
Rasnick puts all the above observations together to produce a simple and elegant mathematical description of the development of aneuploidy, and to test this against data on the age distribution of different types of cancer in humans. His theory fits those observations considerably better than the mutation theory. Furthermore, he explains a number of other classical experimental obser-vations on human cells grown in cell culture, such as the limited number of cell divisions that primary cultures can achieve (the Hayflick limit), and the rates of transformation of different types of human cell to the cancerous condition. He also proposes a very useful experimental test of chemicals for their capacity to disturb cell division and produce aneuploidy.
This new/old approach to cancer shifts the emphasis from cure to prevention. First, the recognition that every cancer is different means that it will be very difficult to target cancer cells specifically with new drugs. This has been known for many years, but the hope remained that there would be a primary, common molecular signature of cancer because of its attractiveness for drug-based cures. Current treatment is based on the use of toxic chemicals that kill all dividing cells, normal as well as cancerous, with the hope that the treatment will destroy the cancer before it kills the patient.
Second, the emphasis on the diverse factors that disturb cell division means that the mutiple chemicals that pollute our environment need to be screened for their capacity to produce aneuploidy. Most of these don't cause mutation, but may well disturb chromosome separation. And finally, the phen-omenon of cancer remission, in which the individual gets rid of the cancer spontaneously, needs to be much more thoroughly explored. Remissions can occur after various types of stimulus to the whole body, such as change of diet, change of life-style, and many other non-specific influences.
A new, holistic approach based on many different levels - the molecular, the cellular, tissue, whole body, person and environment- needs to be developed. What we have learned about cancer in recent years is useful, but the theory described by Rasnick provides a much more comprehensive approach with important implications for prevention as well as cure.