BBB seminar: Hrvoje Miletic

Hrvoje Miletic
Department of Biomedicine, University of Bergen

Glioblastoma (GBM) is the most common and most aggressive primary brain tumor. The complex biology, intratumoral heterogeneity and invasive growth pattern are major obstacles preventing successful treatment. The epidermal growth factor receptor (EGFR) is expressed/mutated in many different cancer types and within primary GBM, amplification of wild-type EGFR is the most common genetic alteration (40-50% of tumors). Of the GBMs that have an amplification of EGFR, 63-75% also show rearrangements/mutations of the gene. The most common mutation, EGFRvIII, is an exon 2-7 deletion corresponding to the ligand binding domain of the protein. This mutation results in a constitutive activation of the receptor.

The aim of our work is to determine the in vivo functions of wild-type EGFR and mutated EGFRvIII, respectively, in clinically relevant glioblastoma animal models. We show that wild-type EGFR promotes invasion of glioblastoma cells which is independent of angiogenesis. The invasive process can be blocked by Cetuximab and a dominant-negative EGFR. Moreover, long-term expression of the dominant-negative EGFR leads to transition from invasive to angiogenic tumor growth. In contrast to wild-type EGFR, the mutant EGFRvIII promotes more aggressive and angiogenic tumor growth as verified by contrast enhancement on magnetic resonance imaging (MRI), induction of vascular proliferation as well as HIF1A and VEGF upregulation. In conclusion, our results demonstrate contrasting roles of wild-type EGFR and its mutant EGFRvIII in invasion and angiogenesis and suggest a concerted action of both molecules to promote the aggressive phenotype of human GBM in vivo.

Chairperson: Jaakko Saraste, Department of Biomedicine