They are said to be rather like knights on white chargers. Medical researchers envisage a major potential in the regeneration of tissue. But these knights also have a dark side, some of them are delinquent and get itchy feet. We are referring to the migrating stem cells that have been the focus of attention for some years now, opening up potential new strategies for cancer research and therapy. Professor Dr. Thomas Brabletz and his team at the University Medical Centre in Freiburg are working on these stem cells that have an ability to generate new tumours anywhere in the body.
It is like in a spy film where the hero can eliminate an informant with apparent ease. But what happens if the enemy manages to send off his information just in time? As a result, new dangers may appear from elsewhere. In the body, the metastases are the items that are 'mailed' by tumours and that might turn into new sources of danger. A cancerous tumour might disappear from the colon wall or from the pancreas following chemo- or radiotherapy, but might nevertheless later recur in the liver, lungs or the brain. “We have known for about ten years that the spread of a tumour is most likely the result of stem cells that have gone astray,” said Professor Dr. Thomas Brabletz from the Department of Visceral Surgery at the University Medical Centre in Freiburg. “We are trying to find out why they lose their way and why they start to migrate.”
A controlled number of stem cells normally slumber in every organ where they consistently replenish the store of cells, as the cells die. The tissue of the outer layer of the colon completely renews itself every four days. Mutations of certain genes might however confuse the stem cells' signalling pathways, which could have an effect on the stem cell character. Mutated stem cells divide incessantly and form shapeless heaps of tissue with partially differentiated body cells. These polyps or adenomas are benign as the cells are still assembled in an organised way and do not set off to establish new cancer colonies. "This only happens when the cells receive certain signals from the surrounding tissue," said Brabletz. These signals induce a process that is referred to as epithelial to mesenchymal transition (EMT).
The colon wall, and indeed the wall of any other organ, consists - roughly speaking - of two types of cells, the epithelial and the mesenchymal cells. Epithelial cells are located in the outer layer and determine the limits of the organ. The mesenchymal cells are located below this layer and are rather loosely organised. During EMT, the epithelial cells abandon their own character and become mesenchymal cells. They also lose contact with each other. This is an important process during embryonic development. However, it can have fatal consequences when it is reactivated in cancer cells. Brabletz and his team have been able to show that degenerated cells of this kind stop to transcribe epithelial genes such as those of the protein E-cadherin. E-cadherins are found on the walls between two epithelial cells where they reduce the gap between the cells.
Epithelial genes such as those found in the E-cadherins are switched off by so-called EMT activators (molecules like ZEB1 or snail). These molecules, which are activated by external, pro-cancer signals, mediate the transformation from epithelial cells to mesenchymal cells. "Metastases are formed when the epithelial genes are no longer transcribed correctly," said Brabletz highlighting the fact that his team was able to show that this is the case. The tumour cells in the outer layer of a tumour, in which the epithelial genes were switched off, detached from the cell assembly and entered the surrounding tissue or the blood. They migrated away from the original tumour in order to colonise new organs. This process reverts when the metastases arrive at foreign tissue and mesenchymal cells retransform into cells of an epithelial nature. These cells assemble and resume their stem cell activity. A new tumour is developing.
"The concept of migrating tumour stem cells helps us to gain further insights into how metastases develop and form daughter tumours," said Brabletz. "In addition, this also opens up new strategies for cancer therapy." Will it one day be possible to block EMT activators? This would prevent the stem cells of a primary tumour from detaching from their neighbours and setting off towards new organs. Brabletz and his team are experimenting with substances that may be able to inhibit ZEB1 or Snail. They are not only cooperating with pharmaceutical companies, but also with other research groups. They are part of the Migrating Cancer Stem Cell Consortium (MCSC), a consortium of five teams that is funded through the 6th EU Framework Programme and which is looking into migrating tumour stem cells. In Freiburg, Brabletz and his team are working closely with the Comprehensive Cancer Centre in Freiburg (CCCF), which helps them transfer their experimental cell culture findings and mouse models into clinical settings.
Further information:Prof. Dr. Thomas BrabletzUniversity of FreiburgDepartment of Visceral SurgeryHugstetter Str. 5579106 FreiburgTel.: +49 (0)761/270-2577Fax: +49 (0)761/270-2579Email: thomas.brabletz(at)uniklinik-freiburg.de