Figure 1. An extra copy of Ink4/Arf and p53 attenuates NSCs function decline in SVZ with aging (C) Expression of several NSC markers is elevated in SVZ from aged (24-30 months) transgenic mice. (D) Neuroblast and neuronal markers of are also elevated in olfactory bulbs of aged transgenic mice.
Investigating the transformation of neural stem cells Glioma stem cells play a significant role in the initiation, maintenance and development of certain forms of tumour, including glioblastoma multiforme, a highly malignant form of brain cancer. New strategies to directly target these cells could lead to great improvements in treatment, as Dr Ander Matheu of the SOX-BMI1 project explains The body’s population
of neural stem cells plays a central role in generating, maintaining and repairing the central nervous system throughout life. However, as we age the number of neural stem cells declines, a process which has been associated with a decline in cognitive activity and neurodegenerative diseases and the emergence of certain mutations, which can have significant consequences for personal health. “Mutations in these cells induce cell transformation, which can lead to tumour formation and glioblastomas,” says Dr Ander Matheu. Based at the Biodonostia health research institute in the Spanish city of San Sebastian, Dr Matheu is the Principal Investigator of the SOX-BMI1 project, an initiative investigating the transformation of neural stem cells and their role in certain pathologies, including glioblastomas and neurodegenerative disease. “We aim to discover whether a general mechanism affects the different pathologies associated with aging,” he outlines.
Cancer stem cells A key focus in this research is the development of cancer stem cells and the maintenance of their characteristics. Mutations in neural stem cells can lead to their transformation into glioma stem cells,
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a rare subpopulation of tumour cells, which leads to the development of glioblastoma, a highly aggressive form of brain tumour. “It has been established that specific mutations in neural stem cells induce tumours and glioblastoma, in part by affecting the TP53 protein,” says Dr Matheu. Indeed, results generated within the project and published in the journal Aging Cell demonstrates that mice carrying a combined extra copy of p53 and Ink4/Arf display elongated lifespan, delayed neural stem cell
Established therapies like chemotherapy and radiotherapy are not very effective and the location of the tumour often makes surgery complicated, underlining the importance of continued research. Dr Matheu and his colleagues are investigating the underlying mechanisms and factors behind the maintenance and function of both neural stem cells and glioma stem cells; two specific transcriptor factors – SOX9 and BMI1 – are known to play an important role in these terms. “If
Glioblastomas are very aggressive, and they are resistant to commonly used therapies. The prognosis for patients is poor, as established therapies like chemotherapy and radiotherapy are not very effective, and the location of the tumour often makes surgery complicated exhaustion and enhanced resistance to cellular transformation and tumor formation (Carrasco-Garcia et al., 2015). Glioma stem cells are not only involved in the initiation and maintenance of the disease, but also its progression and later resistance to therapy. “Glioblastomas are very aggressive, and they are resistant to commonly used therapies, so the prognosis for patients is poor” continues Dr Matheu.
neural stem cells lack SOX9 or BMI1 then they differentiate. They don’t maintain the characteristics of stem cells and they cannot proliferate,” he explains. Researchers in the project are investigating the significance of both SOX9 and BMI1 in regulating the population of cancer stem cells, using both animal models and cell samples from human patients. “We have been able to isolate and generate cultures of human glioma stem cells. We also have
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