Servizio Comunitario di Informazione in materia di Ricerca e Sviluppo - CORDIS

  • Commissione europea
  • Progetti e risultati
  • Final Activity and Management Report Summary- ELSAQUINTANA-NCSCS (Endothelin-3/Endothelin receptor b signalling in the regulation of neural crest stem cells migration: Therapeutic potential ...)

Final Activity and Management Report Summary- ELSAQUINTANA-NCSCS (Endothelin-3/Endothelin receptor b signalling in the regulation of neural crest stem cells migration: Therapeutic potential ...)

Neural crest stem cells (NCSCs) are a multipotent, migratory cell population that generates an astonishingly diverse array of cell types during vertebrate development including neurons (I) and melanocytes (II). In this project we aimed to study the biology of neural crest stem cells during diverse physiological (I: Neurogenesis in the adult peripheral nervous system) and pathological circumstances such as cancer (II: Characterisation of melanoma stem cells) since tumour cells shared many characteristics with stem cells.

These studies were carried out in both the University of Michigan, United States of America, and the University of Valencia, Spain. We addressed our research in part in Sean Morrison's stem cell laboratory, University of Michigan, given its extensive experience in the identification, characterisation and prospective isolation of adult stem cells; particularly NCSCs.

Regarding the first study, the adult nervous system was once thought unable to generate new neurons, however recent work established that brain stem cells persist throughout adult life. Since then, much was learned about the regulation and function of adult neurogenesis in the brain. Newly formed neurons might participate in some types of learning, repair and odour discrimination. The finding by the Morrison laboratory that NCSCs persisted in the postnatal enteric nervous system raised the important question of why NCSCs would be required postnatally. Our results showed that stem and progenitor cells capable of undergoing neurogenesis existed in the adult gut; however neurogenesis did not occur under normal conditions, raising the question of what physiological role these cells had. Preliminary studies suggested that NCSCs might play an important role in the generation of new glial cells throughout adult life. In addition, these cells might secrete growth factors that regulated gliogenesis, or played a specialised role in the regulation of enteric nervous system automaticity. Future work would continue to provide insight into these important questions.

Regarding the second study, the cancer stem cell model proposed that some tumours, like normal tissues, were organised as a hierarchy so that the formation, growth and progression of cancer would be driven by rare populations of 'cancer stem cells'. This hypothesis was presented as one of the most promising new ideas in cancer biology. Based on this model it was suggested that the most effective way to cure cancer would be to develop therapeutics that specifically targeted the rare cancer stem cell population rather than attempting to eliminate all cancer cells. Melanoma is the deadliest form of skin cancer that originates in the melanocyte. Some supporters of the cancer stem cell model have suggested that melanoma might be more effectively treated by taking aim specifically at these rare cancer stems cells. One of the main goals of this project was to carefully test this hypothesis. In a series of experiments involving human melanoma cell transplanted into mice, we surprisingly found that the tumour forming cells were not rare at all. They were quite common in fact, but standard laboratory tests failed to detect most of them. In addition, we found that melanoma tumour cells could change their appearance by switching various genes on and off, making the malignant cells a stealthy, shape-shifting target for researchers seeking new treatments. The ability for transition between various states might render melanoma more difficult to treat and explained why there was currently no effective therapy to cure this cancer. Our results therefore suggested that the deadliest form of skin cancer did not conform to the increasingly popular cancer stem cell model and that it would not be possible to cure patients by targeting rare sub-populations of cells. This work was presented in several scientific meetings as keynote talks and results were published in high profile journals such as Nature (Nature 2008;456:593; highlighted in the cover of the journal), Cell (Cell 2009; 138:822) and Cancer Cell (Cancer Cell 2010; 18:510). These important publications drew a lot of attention in the scientific community, were cited by the time of the project completion for a total of 326 times and were covered extensively in several media.

Reported by

See on map