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The function of normal and mutated epidermal growth factor receptors in Glioblastoma Multiforme

– Establishment of an in vivo and in vitro model

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Abstract:

GBM is the most common and most aggressive type of brain tumor in adults. Primary GBM is characterized by amplification and over expression of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase involved in cellular processes such as proliferation, migration and survival. In addition, about one third of the primary GBM express the tumor specific deletion variant EGFRvIII that has been implicated in in vitro experiments and animal models to enhance tumorigenicity.

GBM cells grown in vitro lose the over expression of EGFR and expression of EGFRvIII commonly observed in vivo. This indicates that EGFR and EGFRvIII are exclusively important for tumor growth in vivo or that the cells change their phenotype and/or genotype when grown in vitro. It was recently shown that GBM cell lines established during so-called stem cell conditions more closely mirror the phenotype and genotype of the original GBM tumor, than cell lines established in the presence of serum(1). Interestingly, brain tumor initiation and growth have been suggested to depend on brain tumor stem-like cells (BTSLC) that share characteristics with normal neural stem cells(2;3).

In order to create a representative in vivo and in vitro model for GBM, maintaining the EGFR and EGFRvIII expression, we have subcutaneously xenografted tumor tissue from patients diagnosed with GBM onto the flanks of nude mice. All xenografts are verifed as GBM and analyzed for their expression of EGFR and EGFRvIII after each in vivo passage. Importantly, these xenografts maintain the EGFR and EGFRvIII expression observed in the original tumor, even after several passages in vivo. To establish cell lines that express EGFR and EGFRvIII,

we have set up in vitro cultures from the GBM xenografts in stem cell media. These cells grow as neurospheres and have the ability to clonally expand, both which are characteristics of stem cells, and also BTSLC. We are currently investigating whether these cells express EGFR and EGFRvIII.

1. Lee J, Kotliarova S, Kotliarov Y, Li A, Su Q, Donin NM et al. Cancer Cell 2006;9:391–403.

2. Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S et al. Cancer Res. 2004;64:7011–21.

3. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Nature 2004;432:396–401.

Document Type: Abstract

DOI: http://dx.doi.org/10.1111/j.1600-0463.2008.001165_45.x

Affiliations: 1: Strålebiologisk Laboratorium, Finsencentret Afsnit 6321, Rigshospitalet, Blegdamsvej 9, 2100 København Ø 2: Det Sundhedsvidenskabelige Fakultet, Biomedicinsk Institut, Panum Instituttet, Blegdamsvej 3, 2200 København N 3: Neuropatologisk Laboratorium, Diagnostisk Center Afsnit 6301, Rigshospitalet, Blegdamsvej 9, 2100 København Ø 4: Neurokirurgisk Afdeling, Neurocentret Afsnit 2092, Rigshospitalet, Blegdamsvej 9, 2100 København Ø

Publication date: May 1, 2008

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