New clues about how cancer cells grow

Feb 14 2008

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.”

A similar system appears to operate in human cells. And in some cancer cells there are particular patterns of DNA methylation. “We have seen that in some leukaemias there is a gene involved in differentiation that is methylated,” Dr Esteller said. “In cultured cells we see that if we put the unmethylated gene back into the cell, we stop the growth of the cells in culture, and also in mouse models. This gene is acting as a tumour suppressor.”

The hope is that further investigation of factors such as DNA methylation could lead to potential new treatments for cancer.

On the other hand, Professor Tariq Enver of the Weatherall Institute for Molecular Medicine at the University of Oxford presented findings of his research on acute lymphoblastic leukaemia (ALL), which has now been published in the journal Science[3].

Professor Enver, who is a EuroSTELLS collaborator and his co-workers, demonstrated for the first time the existence of cancer stem cells in ALL. The researchers compared the blood of three-year-old identical twins, one of whom has the disease while the other is healthy.

The researchers found that both twins had genetically abnormal blood cells – ‘pre-leukaemic' stem cells that reside in the bone marrow. It appears that these cells can either lay dormant or can somehow be triggered to develop into full-blown leukaemia stem cells.

The researchers showed that these cells arise from an abnormal fusion of two genes during the mother's pregnancy. Professor Enver said, “This research means that we can now test whether the treatment of acute lymphoblastic leukaemia in children can be correlated with either the disappearance or persistence of the leukaemia stem cell. Our next goal is to target both the pre-leukaemic stem cell and the cancer stem cell itself with new or existing drugs to cure leukaemia while avoiding the debilitating and often harmful side effects of current treatments.”

EuroSTELLS is a EUROCORES programme, managed by the European Medical Research Councils (EMRC) at the European Science Foundation.

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