Although there have been great medical advances in fighting cancer over the past few years, we are often rather powerless in the face of this disease. A better understanding of how different types of cancer de velop and spread throughout the body could pave the way towards new forms of therapy. Up to now, it has been assumed that tumours are composed of a group of cells that multiply malignantly and thus contribute to tumour growth. According to a new hypothesis, however, cancer could also arise from individual cancer stem cells, which have a different growth and spreading potential than most of the tumour cells. Efficient treatment of tumours must therefore deal mainly with these cancer stem cells.
During embryonic development, normal stem cells are responsible for building organs, and in the adult body they contribute towards maintenance and re generation of tissues and organs. They can perform these functions thanks to their ability to multiply al most indefinitely and to develop into different cell types in the body. There are many indications that cells having stem cell characteristics are present in almost all tumours and that they are considerably involved in tumour growth and spread through me tastases. Like normal stem cells, cancer stem cells can make unlimited copies of themselves and to a certain extent can develop into other, less malignant cell types. For this reason, it is believed that the tis sue heterogeneity observed in most cancer types is caused by cancer stem cells, similar to the way that normal stem cells can produce organs with complex structures. In technical terminology we refer to the
Prof. Lukas Sommer, PhD
Head of the Division of Cell and Developmental Biology at the Institute of Anatomy at the University of Zurich
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“hierarchical structure” of a tumour, which had its origins in one cancer stem cell from which all other tumour cells derived.
Cancer stem cells – a new perspective in research and therapy
With the discovery and experimental investigation of cancer stem cells, the way of looking at how cancer could be treated must be reconsidered. Namely, tra ditional therapy strategies cannot or can only insuf ficiently reach cancer stem cells. For example, chemo therapies aim to stop the growth and survival of the cancer as a whole. But cancer stem cells appear to possess a specific protective mechanism that allows them to send toxic chemical substances out of the cell. And so, chemotherapies seem to destroy a large part of the tumour cells – but without being able to get to the root of the actual cause of the carcinogen esis. Cancer recurrence following chemotherapy could therefore be due to just a few cancer stem cells surviving in the patient’s body.
For this reason, cancer stem cell research must find new ways to fight cancer. Here the focus is on tar geted destruction of the cancer stem cells producing the tumour. But methods are also being tested that specifically block the cell division of cancer stem cells or that accelerate their differentiation into less malig nant cells. To be able to implement these new types of strategies of cancer therapy, research is needed on the molecular and cellular characteristics and growth conditions of cancer stem cells in different tumour types. As for normal stem cells, it can also be as sumed for cancer stem cells that their characteristics,
their growth conditions, and their potential for spreading are dependent upon the tissue of origin and thus on the type of cancer.
Cancer stem cells have already been demonstrated in various types of cancer in different organs, such as breast cancer, colon cancer, brain tumours, different forms of blood cancer (leukaemias) and some other cancers. Depending on the cancer type and on the patient, cancer stem cells in the tumour tissue appear to differ in number. In our research, we are mainly studying malignant skin cancer (melanoma). This type of cancer is extremely aggressive, and the inci dence rate of melanoma is rising. Melanoma devel ops from a malignant change in melanocytes, which are pigment cells and, in developmental biology, de velop from what is called the neural crest. The neu ral crest is a structure in the embryo with great de velopment potential. Not only pigment cells but also nerve cells in the peripheral nervous system, for ex ample, and facial cartilage and bones derive from the neural crest. To be able to build these structures, neural crest stem cells must divide substantially and move across long distances in the embryo.
Since pigment cells in the skin also derive from neu ral crest stem cells, we raised the question as to whether these normal stem cells could have some thing to do with the cause of skin cancer. We sup posed that possible cancer stem cells in the mela noma could show the characteristics of normal neural crest stem cells. That kind of connection could also explain why melanoma cells are so aggressive – why they can multiply so strongly and spread through tissue to form metastases. And in fact, in numerous melanoma biopsies we found cells that clearly showed the features of neural crest stem cells. In
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University Hospital Zurich, we made the important discovery that the number of these cells in the pa tient’s tumour was connected with the course of the disease: The higher the number of cells with charac teristics of neural crest stem cells that are found in a biopsy, the greater the probability of metastasis and of the patient dying of cancer.
Inhibition of melanoma stem cells
Thanks to our experience in the area of neural crest development, we were able to more precisely char acterize these tumour cells and test their cancerpro ducing effect in animal models. In these experi ments, the cells prove to be actual melanoma stem cells that can multiply arbitrarily and are responsible for tumour growth in animal models. This finding is not undisputed, as no cells having stem cell charac teristics could be found in melanoma in research work conducted in the United States. This also shows that research in this area is still in its beginnings. In particular, researchers need to develop standard protocols for how cancer cells are removed from the tumour and then cultivated. For example, we were able to demonstrate melanoma stem cells only using refined methods by which the tumour tissue was treated as carefully as possible. In addition, we discovered that melanoma stem cells have a special ability to evade detection by the immune system.
Finally, this research work can create a foundation for the development of new strategies in cancer ther apy. For example, target structures for therapies could be identified by comparing normal stem cells and cancer stem cells. Based on this, genetic charac teristics and cellular properties of cancer stem cells are determined. The knowledge of stem cellspecific biomarkers and growth factors could aid the discov ery of pharmaceutically active substances that in hibit cancer stem cell development. By using this approach, in cooperation with the Institute of Phar maceutical Sciences at ETH Zurich, we have already identified chemical substances that suppress the division of melanoma stem cells and, in animal mod els at least, counteract with tumour formation. How ever, the exact mechanisms of how these substances work must still be investigated, and it will take some time and more research work before their clinical application with patients can be tested. However, it is definitely conceivable that knowledge gained via melanoma stem cells could considerably improve the therapy approaches available today.
To achieve these goals, there are still many questions that must be clarified. Do tumour stem cells derive from normal stem cells? Do they form tumour tissue “hierarchically”, as in the healthy organ? Or is the opposite developmental direction in the tumour also possible, so that tumour cells without stem cell characteristics can again become tumour stem cells under certain conditions? That kind of neoplasm of cancer stem cells could take place in the course of metastasis or under the influence of the immune sys tem, for example. If that were so, the aim of therapy would perhaps not consist so much in eliminating a certain (stem) cell population in the tumour. Instead,
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the attempt should be made to stop the specific mo lecular processes of stem cell multiplication and in this way to block the fatal activity of the cancer stem cells.
Extensive investigations of this kind can only be successful through cooperation among different re search groups that complement each others’ compe tencies. Here, synergies between stem cell biologists, pathologists, clinicians, and pharmaceutical scientists are imperative. This is the only way we can increase our understanding of cancer stem cells and their effect – and that is urgently needed if we want to be able to possibly establish new specific and efficient strategies in cancer therapy.
Prof. Lukas Sommer, PhD
Lukas Sommer has been full pro fessor and head of the Division of Cell and Developmental Biology at the Institute of Anatomy at the University of Zurich since 2007. He completed undergradu ate studies in biology at the Biocenter in Basel, Switzerland, and received his PhD in 1992 at the Swiss Institute for Experimental Cancer Research (ISREC) in Lausanne. After conducting research as a postdoctoral fellow at California Institute of Technology (CALTECH) in the United States, he returned to Switzer land in 1997 to join the Institute of Cell Biology at ETH Zurich, where he worked as a group leader and then as assistant professor.
Phone +41 (0)44 635 54 43 [email protected]
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Basic biomedical research