Scientists in Switzerland are uncovering new clues about how cancer cells grow - and how they can be killed - by studying stem cells, 'blank' cells that have the potential to develop into fully mature or 'differentiated' cells and other scientists in UK have made a breakthrough in understanding the cause of the most common form of childhood cancer, acute lymphoblastic leukaemia (ALL).
The research should lead to less aggressive treatment for the disease and could result in the development of new and more effective drugs, an international conference on stem cell biology was told last month.
The conference, organised by the European Science Foundation's EuroSTELLS programme and held in Barcelona on January 10-13, heard that stem cells and cancer cells share many similar features. For example the cellular machinery that sends signals between stem cells to tell them when and how to develop is in many cases similar to the signalling mechanisms that operate between cancer cells.
On one hand, Professor Ariel Ruiz i Altaba of the University of Geneva in Switzerland is studying key proteins in stem cells and cancer stem cells – cancer cells that are later responsible for tumour growth, the recurrence of tumours and the spread of the cancer to other parts of the body[1]. Four such proteins, called Sonic Hedgehog (Shh) and Gli-1, Gli-2 and Gli-3 act through a biochemical pathway to send important signals between cells. “We have shown that interfering with Shh signalling decreases the size of tumours, which is proof of principle that the tumours require the pathway,” Professor Ruiz i Altaba told the conference participants.
Professor Ruiz i Altaba's team has been experimenting with samples of brain and other tumours from patients, treating tumour cells and their cancer stem cells – the cells that continuously replenish the growing cancer – in the laboratory with chemicals that inhibit the activity of the Shh pathway and lead to the inhibition of Gli-1. “We take tumour samples and grow them in a variety of ways,” said Professor Ruiz i Altaba. “When we treat them with inhibitors that block the Shh-Gli pathway, they all respond, demonstrating that every tumour we have tested requires this signalling pathway.”
Professor Ruiz i Altaba added, “Hedgehog signalling appears to be involved in many kinds of stem cells and many kinds of cancers. Specifically, Gli-1 seems to be important for the proliferation of tumour cells and especially for the proliferation and perpetuation of cancer stem cells. We think the Gli code, the sum of all Gli activities, is locked in a ‘hyperactivating' state in cancer, and if we can revert it to a repressive state, this could provide a possible therapeutic approach.”
Meanwhile Dr Manel Esteller of the Spanish National Cancer Research Centre (CNIO) in Madrid has been investigating the way that genes in cancer cells and stem cells are modified by a process called methylation[2].
In a cell not all of the genes are active. Some are rendered ‘silent' by the attachment of chemical entities called methyl groups. This is one of the mechanisms by which a cell can switch genes on and off. It has become clear that the pattern of DNA methylation is one key difference between a cell that has become specialised – that is differentiated – and one that remains undifferentiated.
“We have studied plant DNA and have seen that in undifferentiated tissue one particular region of the DNA is always unmethylated,” Dr Esteller told the meeting. “In differentiated tissue this same region is methylated. If we take the undifferentiated cell and add the methylated gene we get differentiation.”