Defining novel functions for the oncogenic variant EGFRvIII in tumor initiation
- Catherine Amalia Del Vecchio.
- Apr. 2012.
- Physical description
- online resource (xii, 132 pages) : illustrations (some color)
- Del Vecchio, Catherine Amalia.
- Clarke, Michael F. thesis advisor.
- Cleary, Michael L. thesis advisor.
- Palmer, Theo thesis advisor.
- Wernig, Marius. thesis advisor.
- Wong, Albert J. thesis advisor (primary).
- Stanford University. Program in Cancer Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 121-132). 172 refs.
- Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor. Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in GBM, and the most common variant is EGFRvIII. Here we report that EGFRvIII is a novel cancer stem cell (CSC) or tumor initiating cell marker in GBM. EGFRvIII expression is restricted to sub-regions and sporadic cells within the tumor and EGFRvIII is frequently co-expressed in the putative CSC CD133+ population. EGFRvIII gene and protein expression can be maintained when primary GBM are cultured as tumor derived neurospheres and is lost when spheres are exposed to differentiating conditions. Furthermore, cells that express both EGFRvIII and CD133 display the greatest self-renewal and tumor initiating abilities when compared to the single positive or double negative populations. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved across the tumor despite focal expression. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII expression. EGFRvIII defined a hierarchy and epigenetic mechanisms played a role in maintaining heterogeneous EGFRvIII expression, suggesting that drugs which modulate the epigenome might be used successfully in glioblastoma tumors. To assess a broad applicability of our findings to other tumor types, we investigated EGFRvIII expression and amplification in primary breast carcinoma. Our analyses confirmed the presence of EGFRvIII, but in the absence of amplification or rearrangement of the EGFR locus. Interestingly, EGFRvIII was often expressed in a subset of tumor cells and was co-expressed in the putative CSC CD44+/CD24-/low population. EGFRvIII-expressing cells had increased expression of stem cell and epithelial-mesenchymal transition (EMT) associated genes and increased in vitro sphere formation and in vivo tumor formation compared to non-expressing cells. Mechanistically, EGFRvIII mediated its effects through the Wnt/[beta]-catenin pathway. Collectively, this data suggests a novel function for EGFRvIII in tumorigenesis and further supports the use of EGFRvIII-targeted therapy in these tumor types.
- Cell Transformation, Neoplastic > genetics
- ErbB Receptors
- Gene Expression Regulation, Neoplastic
- Glioblastoma > genetics
- Brain Neoplasms
- Epigenesis, Genetic
- Gene Rearrangement
- Publication date
- Submitted to the Program in Cancer Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2012.