If you were to spread bacteria onto a nutrient agar plate, in a short period of time the bacteria would grow to cover the entire plate surface. The only limiting factor would be the edge of the plate. Imagine if the plate were the size of a football field, would the bacteria still cover the entire surface? If you started with only one type of bacterial cell, all of the cells covering the plate would be the same. Now consider the growth of our own cells. For example, how do our liver cells know when to grow and when to stop? The liver cells receive go and stop signals from neighboring cells and when this process goes wrong, cells can grow uncontrolled resulting in cancer. Our current model of cancer is somewhat more complex than that.
Scientists generally refer to a traffic light analogy as a model for cancer. Cancer may result from or be sustained by mutations at the following signals:
1) Immortality: continuous cell division and limitless replication
2) Production of ‘Go’ signals: growth factors from oncogenes
3) Overriding of ‘Stop’ signals: anti-growth signals from tumour suppressor genes
4) Apoptosis: resistance to cell death
5) Angiogenesis: induction of new blood vessel growth
6) Metastasis: spread to other sites
The diagram above shows that the neighbouring cells may send either a ‘go’ signal or a ‘stop’ signal. These signals on the cell surface lead to transcription of factors that regulate the cell cycle
. Mutations of the ‘go’ signal may lead to the cell dividing even in the absence of the stimulatory signal. On the other hand, mutations of the ‘stop’ signal may lead to the cell dividing because it is not receiving the inhibitory signal. Cumulative mutations of both types of cell receptors considerably increase the chances of that cell growing out of control.
Besides oncogenes (stimulatory) and tumor suppression genes (inhibitory), other genes have been identified which play roles in each of the other signal steps as well. That makes it is possible to design or select drugs which have specific biological actions mitigating mutations at these signal steps. For example, one interesting area for research relates to immortality and continuous cell division. The presence of telomeres on the ends of the chromosomes are involved in cell division. Telomeres are made up of repeating 6-base sequences which seem to protect the genetic information of chromosomes from degradation. Under normal cell growth and division, these telomeres shorten with each cell generation. That means that the cellular lifespan is constrained by the number of cell generations, not by chronological time. Cells gain immortality when the telomerase enzyme becomes abnormally activated and therefore maintains the telomere length. “Telomerase is an attractive target
for diagnosis and therapy since it is expressed in over 90% of breast cancer cells, while it is not expressed in most normal cells.”
A second very promising area for research relates to apoptosis. The oncogene p53 (also called TP53) normally produces a small protein which acts as a regulating mechanism in both cell cycle regulation and in apoptosis. Mutations in p53 are found in more than 50% of all cancers making it a very high priority area for study. Individuals with a germline mutation in TP53 (Li-Fraumeni syndrome
) “have a 73% to 100% lifetime risk of cancer, including colorectal cancer.” Targeting this gene is an important undertaking.
James Watson is well aware
of how much research money is being spent on the various genes involved in cancer. He highly encourages the bulk of the research to move away from ‘genome-based personal cancer therapies’ with a lot more effort being directed ‘towards innovative, anti-metastatic drug development’.
Human genome project pioneer J. Craig Venter cautioned
graduating medical students that “within a decade, new doctors will find it hard to believe they practiced medicine without knowing the genome of their patient first.” He was most certainly aware that genome sequencing research shows that 3% or more of supposedly healthy individuals may have a genetic disorder. One study of 1000 genomes
found 100 individuals had genomic variants predicting that they would have a rare disease. Many of the participants “with harmful mutations and an associated physical change didn’t know they might have a genetic condition.”
Coming full circle to the football field of bacteria, when microorganisms are growing in an environment of mixed species, there are examples of signals between the cells. It has long been known that some microbes produce metabolites with antibiotic properties such as penicillin. High school students and biology undergrads often grow bacteria on petri dishes that have blotter paper soaked with substances to test the antibiotic properties. This is not entirely unlike the experiments carried out by Sir Alexander Fleming, the first scientist to discover penicillin. Very recent research
indicates that microorganisms in our gut cooperate in a positive way under certain conditions. The development of stop and go signals was an important part of the evolution of multi-cellular organisms. These signals seem to play an important role in the way single-celled organisms interact in their natural environments as well.
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