Hedgehog Signalling in Embryonic Development and Carcinogenesis
Inside and between our cells, there is a constant signal traffic controlling gene activity in the cell nuclei. Multitudes of different signals are used and all have their set significance to the life, function, and reproduction of cells. If persistent errors arise in this complicated signalling, the consequence can be various cancerous diseases.
Professor Rune Toftgård and his research group are mapping such cancer-causing signal errors and working on the development of drugs to correct them.
At the start of the 1990s, the research group began a new project with colleagues in the USA and Australia. The idea was to exploit one of Nature's own experiments in order to find out more about the genetic background to certain forms of cancer. There is a hereditary syndrome (Gorlin Syndrome) which amongst other things leads to basal cell cancer in the skin of sufferers and an increased risk of a certain type of brain tumour. The syndrome also affects other features, such as the shape of the head and is easy for a specialist to detect. Many families where this syndrome was hereditary were known to the researchers, who now wanted to use the potential of molecular genetics to find the gene which was mutated (altered) in the affected families.
All to increase knowledge of how cancer arises and can be treated.
One evening in February 1996 Rune Toftgård, as on so many other evenings, was sitting in front of his computer screen in the laboratory. But the analysis results on the screen made this evening special. It was clear that after long and patient work, the research group had finally succeeded in identifying the human gene they were looking for.
"Moments like that evening are one of the reasons you carry on with research," says Toftgård.
The gene that was discovered controls a certain signal mechanism in cells. The mechanism is called Hedgehog signalling (see explanatory box).
As a rough illustration, it can be said that the cells in the body signal through molecules being formed and reaching receptors (receivers) within the cell or on other cells. This triggers a new event, such as a molecule being formed or changed and in turn reaching a receiver. Such a signal may contain many steps like this.
during development of the foetus. Hedgehog signalling is one of them. It is activated during the foetal period. Later in the life of the adult on the other hand, this signal should normally be switched off.
But mutations can mean that the signal is switched on when it ought not to be. Ongoing research has shown that erroneous Hedgehog signalling can cause not only the hereditary forms of basal cell cancer and brain tumours but also other forms of cancer such as prostate cancer, pancreatic cancer, gastrointestinal cancer and certain forms of lung cancer.
Rune Toftgård's research group continues to map the stages, one detail at a time, of this signal mechanism and its significance in cancer development. There are situations where it is normal for Hedgehog signalling to be activated in an adult. There is much to indicate, for example, that the mechanism is required when an injury is being healed by the replacement of damaged cells with new ones, and is therefore activated during processes like inflammation. It could be a contributory mechanism behind the well-known fact that chronic inflammation can cause cancer in an affected area.
The research group is also working on turning the new knowledge into what will hopefully be of future practical benefit to cancer patients. This involves finding substances which can block a stage in the signal mechanism and thereby "switch off" the erroneous signalling. Such substances, called inhibitors, can be drug candidates.
The work takes place using cultivated cells, animal models and tissue samples from patients.
A closely-related research trail which Rune Toftgård and his co-workers are also following is to map signal mechanisms involved in the development of squamous cell carcinoma, another form of skin cancer.
Rune Toftgård emphasises how important it is to collaborate with other researchers all over the world and at the same time to dare to go your own way. For example, in the development of novel drug candidates, it may be a case of focussing on your own ideas about which stages in an erroneous cell signal should be blocked, and how. In his opinion, the hunt for quick results risks leading to the majority trying what others have already started to try.
"More innovation is needed in drugs research."
About the hedgehog
In 1980, the researchers Nüsslein-Volhard and Wieschaus published a piece of work for which they received the Nobel Prize in 1995. They had studied the embryo of the fruit fly and the effects of gene mutations. In embryos with a certain mutation, the appearance was changed such that a specific embryonal structure became scattered instead of arranged in bands. The appearance of these embryos was reminiscent of a hedgehog and this mutation was given the name Hedgehog.
The gene which upon mutation leads to this appearance was identified in 1992 and likewise given the name Hedgehog. Hence the term Hedgehog signalling for the signal mechanism which includes the Hedgehog gene's protein.
The same signalling mechanism exists in humans with certain differences.
Text: Helene Wallskär