Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 4; pp. 1238 - 1249
• Main Authors: Emlet, David R., Gupta, Puja, Holgado-Madruga, Marina, Del Vecchio, Catherine A., Mitra, Siddhartha S., Han, Shuang-Yin, Li, Gordon, Jensen, Kristin C., Vogel, Hannes, Xu, Linda Wei, Skirboll, Stephen S., Wong, Albert J.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2014
• Subjects: AC133 Antigen; Animals; Antibodies, Bispecific - therapeutic use; Antigens, CD - immunology; Antineoplastic Agents; Biological and medical sciences; Biomarkers, Tumor - metabolism; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Cell Separation; ErbB Receptors - immunology; ErbB Receptors - metabolism; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma - therapy; Glycoproteins - immunology; Humans; Immunoconjugates - therapeutic use; Medical sciences; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy - methods; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Neurology; Peptides - immunology; Pharmacology. Drug treatments; Spheroids, Cellular - metabolism; Spheroids, Cellular - pathology; Tumor Cells, Cultured; Tumors; Tumors of the nervous system. Phacomatoses; Nervous system diseases; Genetic variability; Targeting; Stem cell; Glioblastoma; Genotype; Malignant tumor; Epidermal growth factor receptor; Variant; Malignant glioma; Target; Cell population; Central nervous system disease; Tumor cell; Cancer
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-1407

The relationship between mutated proteins and the cancer stem-cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGF receptor (EGFR) variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here, we show that EGFRvIII is highly coexpressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells (CSC) with the highest degree of self-renewal and tumor-initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers, whereas markers of differentiation are found in EGFRvIII− cells. EGFRvIII expression is lost in standard cell culture, but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ coexpression, self-renewal, and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC-specific expression and be used to specifically target this population. Cancer Res; 74(4); 1238–49. ©2013 AACR.