Stem cells signal the way to better treatment

Uncontrolled cell growth is closely associated with the development of paediatric brain tumours. Research into the signalling mechanisms in cancer stem cells could lead to more targeted treatments for tumours in both children and adults, says Professor Monica Nistér of Karolinska Institutet..

Composed of heterogeneous cell subpopulations, glioblastomas are the most common form of brain tumour found in adults, and are known to be highly malignant. Detailed analysis of cellular behaviour is central to understanding how such tumours develop and progress, an area which forms the primary focus of Professor Monica Nistér’s research group. “We are researching the molecular signatures and the biological features of tumours. The most interesting components to study are called cancer stem cells,” she says.

Based at Karolinska Institutet in Stockholm, Sweden, Professor Nistér is also part of a project looking at the molecular characterisation of idiomatic brain tumour stem cells. “We are trying to identify the actual cancer stem cells within the tumour tissue – both in adults and in children – and we are also trying to culture them,” she continues. “This means taking the fresh human tumour, putting cells in culture, and culturing them under the same conditions as the developmental biologists and those dealing with regenerative medicine. So we are actually using the same culture conditions as they do for normal neural stem cells.”

Uncontrolled cell growth

This work is central to understanding the uncontrolled cell growth associated with paediatric tumours, and to designing experimental treatments. The group is looking at brain tumours in both children and adults in this work. “In adults we concentrate on glioblastomas, while in children we concentrate on medulloblastomas, and also glial tumours. It’s important to know more about the often less malignant glial tumours in children and see how they are different from tumours in adults,” says Professor Nistér. The group is using both animal models and human tissue to analyse key signaling mechanisms in cancer stem cells.

“The ultimate definition of a cancer stem cell is that it can be injected into the brain of a mouse and there lead to the development of a brain tumour similar to the original human one. From a few cancer stem cells you can theoretically generate a whole tumour,” explains Professor Nistér. “We have worked for several years to generate our own mice models for brain tumours, and then we can look at these transgenic mice expressing PDGF (platelet-derived growth factor). This is an important growth factor, which regulates normal brain development and is present in human brain tumors.”

These models can be used to study the effects of the over-expression of PDGF and to isolate cancer stem cells from the tumour. However, Professor Nistér says they hold particular importance in terms of studying the initial stages of tumour development.

“We are trying to find out what the precursor state of cancer is, how the growth actually starts changing the pattern of cells in the brain,” she outlines. “Analysis of the earliest features of a tumour can be an accurate indicator of its future development, and with the difficulty to gain biopsy material from the initial stages of tumour development in humans, the mice models take on even greater importance. “We study the tumour itself, and the stem cells of the tumour in the human. What is available is usually material from advanced, fully developed tumours,” explains Professor Nistér. “We can also look at fully developed tumours in mice and see what characterises that compared to the early stages, but it’s really difficult to study these very early developments in humans. One of the ways you can do that is to study the different grades of glial tumours in adults.” These tumours include low-grade astrocytomas, anaplastic astrocytomas and glioblastomas, graded 2, 3 and 4 respectively by the World Health Organisation in ascending order of malignancy. However, in some cases grade 2 type tumours can be the forerunner of grade 4 tumours, further reinforcing the importance of Professor Nistér’s research.

“We work in collaboration with Associate Professor Anja Smits, a neurologist in Uppsala who is responsible for the lowgrade glioma patients in central Sweden. She has very well-characterised material that we can use for our research, that’s very valuable,” she stresses. This allows researchers to relate molecular findings to clinical data, and gain valuable insights into disease progression; glial tumours present particular challenges in this respect. “These glial tumours grow very diffusely into the brain and disseminate widely,” says Professor Nistér. “At the border of the tumour mouth you can see that there are still malignant cells disseminated within the seemingly normal brain.”

Cancer recurrence

Even if a surgeon operates on such a tumour then some cells are always likely to be left in the seemingly normal brain and the surrounding tissue. It is likely there will also be stem cells among those left behind, the precursor-type of cells that then have the ability to regenerate new cancer cells, and are responsible for the recurrence of the disease.

“Possibly these cells hide in the perivascular space around the small vessels in the brain – that has been reported by several research groups,” says Professor Nistér. It has also been suggested that stem cells can come from the bone marrow and the surrounding brain and contribute to cancers. “There have been reports that the normal neural stem cells in the brain, especially in medulloblastomas, are attracted to the tumour and mix with the tumour cells. It’s not clear what the effect of these additional stem cells is – maybe they interact with the abnormal stem cells and combine to form a tumour, or maybe they are inhibitory,” outlines Professor Nistér. “The goal of our project is to understand how the cancer stem cells differ from normal neural stem cells and develop treatments targeting the cancer-specific signals.”

Further inter-disciplinary collaboration is crucial to translating this potential into reality. The group has already been involved in a project on the inhibition of growth factor receptors, and Professor Nistér says establishing even stronger links with both the pharmaceutical sector and other researchers is an important part of her agenda.

“We have managed to inhibit neural tumour cell growth in two ways. One is by combining two different growth factor receptor inhibitors and the other is by knocking down a transcription factor specific for the precursor stage of brain cells. Colleagues in neurosurgery also identified the differences between normal neural stem cells and glioblastoma stem cells in terms of how they grow and differentiate,” she outlines.

“We work in collaboration with stem cell researchers, neurooncologists and neurosurgeons at Karolinska Institutet and the Universities of Uppsala and Lund. Researchers who specialise in stem cell biology can apply their knowledge to tumour biology. It’s important to have professionals from different areas involved in the project.”

For further information, please contact Monica Nister: monica.nister@ki.se

Published: Wednesday, 4th May 2011