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Autor     Joo-Hee Wälzlein
Titel    Endogenous neural precursor cells suppress glioblastoma
Ort    Berlin
Jahr    2007
Anmerkung    Dissertation Zur Erlangung des akademischen Grades Doctor of Philosophy in Medical Neurosciences (PhD in Medical Neurosciences) vorgelegt der Medizinischen Fakultät Charité – Universitätsmedizin Berlin
URL    http://www.diss.fu-berlin.de/diss/receive/FUDISS_thesis_000000003225?lang=en

Literaturverz.   

nein
Fußnoten    nein
Fragmente    5


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1.1. Brain tumors and their classification

Glia cells are the most common cell type in the brain and make up 90 % of the total cell number (Kettenmann, H et al, 1995) depending on species. They were discovered by Virchow (1856), who described them as Nervenkitt, a kind of glue for neurons (gr. glia: glue). Initially, they were considered as merely supporting cells for neurons, yet recently they were shown to fulfill a range of far more complex functions. The group of glia cells consists of astrocytes, oligodendrocytes and Schwann cells (Kettenmann, H et al, 1995). Historically, brain tumors were thought to consist of transformed glia cells and are therefore called gliomas. Different types of gliomas are astrocytomas, oligodendrogliomas and schwannomas, depending on the preferential type of differentiation of these tumors. Schwannomas often correspond to benign tumors. It is still unknown how these transformations occur and what triggers them. One theory claims that disruptions in the glial cell cycle lead to glioma formation. However, recent research provided more and more evidence that gliomas emerge from neural precursor cells.

Gliomas are the most common group of primary tumors in the brain and make up 30 – 40 % of all brain tumors (Kleihues, P et al, 1993). The World Health Organisation (WHO) introduced a classification in 1993, which divides astrocytomas into four malignancy grades:

1.3. Brain tumours and their classification

Glia cells are the most common cell type in the brain and make up 90 % of the total cell number (37). They were discovered by Virchow (1856), who described them as Nervenkitt, a kind of glue for neurons (gr. glia: glue). Initially, they were considered as merely supporting cells for neurons, yet recently they were shown to fulfill a range of far more complex functions. The group of glia cells consists of astrocytes, oligodendrocytes and Schwann cells (37).

Historically, brain tumours were thought to consist of transformed glia cells and are therefore called gliomas. Different types of gliomas are astrocytomas, oligodendrogliomas and schwannomas, depending on the relevant cell type. Schwannomas often correspond to benign tumours. It is still unknown how these transformations occur and what triggers them. One theory claims that disruptions in the glial cell cycle lead to glioma formation. However, recent research provided more and more evidence that gliomas emerge from neural precursor cells (1.2.).

Gliomas are the most common group of primary tumours in the brain and make up 30 – 40 % of all brain tumours (40). The World Health Organisation (WHO) introduced a classification in 1993, which divides astrocytomas into four malignancy grades:


37. Kettenmann,H. and Ransom,B. 1995. Neuroglia. Oxford University Press.

40. Kleihues,P., Burger,P.C., and Scheithauer,B.W. 1993. The new WHO classification of brain tumours. Brain Pathol. 3:255-268.

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Tab. 1.1. The World Health Organization (WHO) grading system for astrocytomas

Scr 010a diss.png

In the present work research and conclusions will be restricted to cells representing glioblastoma multiforme (GBM) or glioma, i.e. a grade IV brain tumor.

1.2. Epidemiology of gliomas

Gliomas or glioblastomas occur with an incidence of 5 in 100,000 (Friese, M.A.et al, 2004). The peak of onset of glioblastomas is around 50 - 55 years, which makes them a strongly age-related pathology. Men are slightly more prone to these neoplasms. Furthermore, the incidence is 2 - 3 times higher in white than in black people. Prognosis is poor and the median survival has remained at 9 to 12 months for decades (Stupp, R et al, 2005), only few patients survive for three or more years. Main risk factors are high dose radiation, hereditary syndromes and increasing age. Although the last years have revealed some major approaches to develop new surgical and radiation techniques as well as multiple antineoplastic drugs, a cure for glioblastoma remains elusive (DeAngelis, L.M. et al, 2001).

Tab. 1.2. The World Health Organization (WHO) grading system for astrocytomas

Scr 010a source.png

In the present work research and conclusions will be restricted to cells representing glioblastoma multiforme (GBM), i.e. a grade IV brain tumour.

1.3.1. Epidemiology of gliomas

Gliomas occur with an incidence of 5 in 100,000 (19). They make up 44 % of all primary brain tumours and 52 % of these are represented by the glioblastoma multiforme. The peak of onset of glioblastomas is around 50 - 55 years, which makes them a strongly age-related pathology. Men are slightly more prone to these neoplasms. Furthermore, the incidence is 2 - 3 times higher in white than in black people. Prognosis is poor and the median survival is 14.6 months (67); only few patients survive for three or more years. Main risk factors are high dose radiation, hereditary syndromes and increasing age. Although the last years have revealed some major approaches to develop new surgical and radiation techniques as well as multiple antineoplastic drugs, a cure for glioblastoma remains elusive (11).


11. DeAngelis,L.M. 2001. Brain tumors. N.Engl.J.Med. 344:114-123.

19. Friese,M.A., Steinle,A., and Weller,M. 2004. The innate immune response in the central nervous system and its role in glioma immune surveillance. Onkologie. 27:487-491.

67. Stupp,R., Mason,W.P., van den Bent,M.J., Weller,M., Fisher,B., Taphoorn,M.J., Belanger,K., Brandes,A.A., Marosi,C., Bogdahn,U. et al. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N.Engl.J.Med. 352:987- 996.

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1.3. Diagnosis and treatment of gliomas

Scr 011a diss.png

Fig. 1.3. MRT of a human brain, revealing a glioblastoma multiforme

(rad.usuhs.mil/rad/who/zs224248)

If a neurological examination points to a brain tumor, additional testings will be made. These mainly include scans like magnetic resonance imaging (MRI, Fig. 1.3.), computer tomography (CT) or positron emission tomography (PET). In most cases therapy starts with surgical removal of the tumor. Since for the tumor patient gliomas may be located in brain areas which are of vital importance and the surgical removal of these neoplasms can be much more difficult than removing a tumor in other parts of the body. Even if the surgery is successful it has to be assumed that tumor cells have already spread throughout the brain and may be the source for tumor relapses.

One of the main properties of glioma cells is their invasive behaviour, which also signifies the biggest challenge regarding therapy (Holland, E.C. et al, 2001; Kleihues, P et al, 1995). Therefore combined radiochemotherapy typically follows surgery. Conventional radiation therapy uses X- or gamma-rays but also other types of radiation are available. At present, the standard chemotherapeutic is temozolomide (Temodal®). Its cytotoxicity is due to alcylation of the nucleobase guanine.

1.3.3. Diagnosis and treatment of glioblastoma

Scr 011a source.png

Fig. 1.4. MRT of a human brain, revealing a glioblastoma multiforme

(rad.usuhs.mil/rad/who/zs224248)

If a neurological examination points to a brain tumour, additional tests will be made. These mainly include scans like magnetic resonance imaging (MRI, fig. 1.4.), computer tomography (CT) or positron emission tomography (PET). In most cases therapy starts with surgical removal of the tumour. Due to the limited space in the brain this is much more difficult than removing a tumour in other parts of the body. Even if the surgery is

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successful it has to be assumed that tumour cells have already spread throughout the brain and may be the source for tumour relapses.

One of the main properties of glioma cells is their invasive behaviour, which also signifies the biggest challenge regarding therapy (31;41). Therefore combined radiochemotherapy typically follows surgery. At present, the standard chemotherapeutic is temozolomide (Temodal®); its cytotoxicity is due to alcylation of the nucleobase guanine.


31. Holland,E.C. 2001. Gliomagenesis: genetic alterations and mouse models. Nat.Rev.Genet. 2:120-129.

41. Kleihues,P., Soylemezoglu,F., Schauble,B., Scheithauer,B.W., and Burger,P.C. 1995. Histopathology, classification, and grading of gliomas. Glia 15:211-221.

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[Although many efforts have been made during the last years to improve] the existing therapies, the biggest problem is still the extreme invasive nature of glioblastomas. It is virtually impossible to prevent migration of tumor cells into the adjacent brain tissue, which may be the primary cause for relapses.

1.4. Pathophysiology of gliomas

Glioma or Glioblastoma multiforme (GBM) consist of a heterogenous mixture of poorly differentiated neoplastic astrocytes (Holland, E.C.et al, 2001). They can occur as primary, which means de novo tumors but can also, although less frequent, develop from lower grade astrocytomas and thus are defined as secondary tumors. The latter typically develop in younger patients (< 45 years) whereas de novo tumors arise almost solely in elderly patients (around 65 years). The tumor as such forms a solid mass from which neoplastic cells are disseminating into the adjacent brain tissue. The tumor itself can reach a considerable size and squeeze out larger amounts of brain mass (Fig. 1.4.), which usually leads to diverse neurological defects.

Scr 012a diss.png

Fig. 1.4. Macroscopic view of glioblastoma multiforme in a human brain

(www.neuropat.dote.hu/jpeg/tumor/3gliobl1).

Although primary and secondary tumors differ on the genetic level in many ways, there are some common genetic abnormalities, which are considered as hallmarks of glioblastomas. One of them is the loss of heterozygosity (LOH) on chromosome 10, which seems to be specific for grade IV brain tumors.

1.3.2. The pathophysiology of glioblastoma

Glioblastoma multiforme (GBM) consist of a heterogenous mixture of poorly differentiated neoplastic astrocytes (31). They can occur as primary, which means de novo tumours but can also, although less frequent, develop from lower grade astrocytomas and thus are defined as secondary tumours. The latter typically develop in younger patients


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(< 45 years) whereas de novo tumours arise almost solely in elderly patients (around 65 years).

The tumour as such forms a solid mass from which neoplastic cells are disseminating into the adjacent brain tissue. The tumour itself can reach a considerable size and squeeze out larger amounts of brain mass (fig. 1.3.), which usually leads to diverse neurological defects.

Scr 012a source.png

Fig. 1.3. Macroscopic view of glioblastoma multiforme in a human brain

(www.neuropat.dote.hu/jpeg/tumor/3gliobl1).

Although primary and secondary tumours differ on the genetic level in many ways, there are some common genetic abnormalities, which are considered as hallmarks of glioblastomas. One of them is the loss of heterozygosity (LOH) on chromosome 10, which seems to be specific for grade IV brain tumours.

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Although many efforts have been made during the last years to improve the existing therapies, the biggest problem is still the extreme invasive nature of glioblastomas. It is virtually impossible to prevent migration of tumour cells into the adjacent brain tissue, which is the cause of relapses in most cases.


31. Holland,E.C. 2001. Gliomagenesis: genetic alterations and mouse models. Nat.Rev.Genet. 2:120-129.

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[Very well known are] mutations in the tumor suppressor gene p53 on chromosome 9, which also plays a pivotal role in other types of cancer. In fact, only about a third of glioblastomas carries this mutation, which corresponds to the percentage in lower grade gliomas. [...] This suggests that the p53 gene is involved rather early in neoplastic transformation (Kleihues, P., et al, 1993). In about one third of all GBMs one can find amplification and mutation of the endothelial growth factor receptor gene (EGFR) like EGFRvIII which is the mutant version of EGFR in Glioblastoma multiforme mutation which leads to increased cell proliferation. Furthermore platelet-derived growth factor alpha (PDGF-α) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) are two more genes, of which the expression is altered in GBMs (Knobbe,C.B. et al, 2002; Nakamura, J.L. et al, 2007). PDGF-α belongs to the family of growth factors and is involved in the regulation of cell growth and cell division. It plays a particular role in angiogenesis, which is characteristically increased in cancer to provide sufficient nutrition supply for the tumor. The phosphatase PTEN is a tumor suppressor, which is related to a variety of biological functions like apoptosis, inflammation and immunity. These genetic defects have an effect on other cell proteins and finally result in tumor formation. Very well known are mutations in the tumour suppressor gene p53 on chromosome 9, which also plays a pivotal role in other types of cancer. In fact, only about one third of glioblastomas carries this mutation, which corresponds to the percentage in lower grade gliomas. This suggests that the p53 gene is involved rather early in neoplastic transformation (40). In about one third of all GBMs one can find amplification of the endothelial growth factor receptor gene (EGFR), which leads to increased cell proliferation. Furthermore platelet-derived growth factor alpha (PDGF-α) and phosphatase and tensin homolog (PTEN) are two more genes, of which the expression is altered in GBMs (42;52). PDGF-α belongs to the family of growth factors and is

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involved in the regulation of cell growth and cell division. It plays a particular role in angiogenesis, which is characteristically increased in cancer to provide sufficient nutrition supply for the tumour. The phosphatase PTEN is a tumour suppressor, which is related to a variety of biological functions like apoptosis, inflammation and immunity. These genetic defects have an effect on other cell proteins and finally result in tumour formation.


40. Kleihues,P., Burger,P.C., and Scheithauer,B.W. 1993. The new WHO classification of brain tumours. Brain Pathol. 3:255-268.

42. Knobbe,C.B., Merlo,A., and Reifenberger,G. 2002. Pten signaling in gliomas. Neuro.-oncol. 4:196-211.

52. Nakamura,J.L. 2007. The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications. Expert.Opin.Ther.Targets. 11:463-472.

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