TISSUE ENGINEERING STRATEGIES FOR MODELING THE PERIVASCULAR NICHE IN GLIOBLASTOMA MULTIFORME
McCoy, Michael Gene
Glioblastoma Multiforme (GBM) is the most common and lethal primary brain tumor in adults, with a median survival time of 12-15 months. Current therapies rely on surgical resection and extensive chemotherapy and radiotherapy, however the lack of progress in overall patient survival has spurred research into the tumor microenvironment as an alternative target. As a result, studies have focused on gaining a better understanding of the cellular and molecular mechanisms that may underlie interactions between tumor cells and the surrounding tissues. In GBM, matrix remodeling and hypervascularization of the tumor are well-documented, yet the underlying interactions between endothelial cells (ECs), the extracellular matrix (ECM) and tumor cells is poorly understood. Elucidation of these interactions may yield potential therapeutic avenues. During tumor formation, biologically aberrant signaling and changes in support cell behavior often result in tumor-induced mechanical and compositional changes in the ECM. In GBM, the most aggressive subtypes are correlated with increased ECM remodeling and high neovascularization. Biochemical and biomechanical changes in the ECM such as changes in matrix fiber structure, composition, and alignment, can alter EC mechanosignaling and promote recruitment of ECs towards tumors; this promotes subsequent tumor neovascularization. However, isolating the effects of specific mechanical properties of the ECM and the ensuing changes in EC behavior and EC-mediated signaling has remained problematic due to relevant cell culture models. Within the population of GBM tumor cells, a subpopulation of cancer stem-like cells (CSCs) has been attributed to being partially responsible for GBM tumor growth. CSCs exhibit stem cell-like properties such as expression of putative stem cell markers, self-renewal, and stimulated multi-lineage differentiation. However, they also exhibit tumorigenic properties such as mutated oncogene and tumor suppressor gene profiles, unregulated proliferation, and full tumor recapitulation in xenografts. CSCs are typically found in close proximity to microvasculature at the tumor front where they appear to be involved in angiogenesis; this perivascular space appears to support their survival and stem cell status. Due to the high vascularity and invasive properties of GBM, CSCs have come under increased scrutiny as a possible mechanism of GBM progression and thus a potential therapeutic target. Despite this, interactions between CSCs and the perivascular niche and how they contribute to tumorigenesis remain largely unknown. To resolve some of the unanswered questions listed above, the studies presented here utilize a tissue-engineering approach towards modeling the perivascular niche in GBM in the following contexts: 1) dissecting the role of the ECM in regulating EC behavior and 2) the influence that ECs have on CSCs through cell-cell interactions and biomolecule signaling. By modifying the collagen fiber size and orientation as well as the compositional properties of 3D collagen hydrogels, the role of these cues in regulating EC behavior, signaling, and vascular network formation were assessed. Then, the role of ECs in modifying CSC invasion was investigated through heterotypic cultures of CSC tumor spheroids and ECs in the context of interleukin-8 crosstalk. These findings highlight that while aspects of the microenvironment are certainly physiologically linked, each has a contributory effect in overall tumor progression. The conclusions of this work provide new insight for the development of physiologically relevant model platforms and potential therapeutic approaches for GBM.
Collagen; Cancer Stem Cell; Biomedical engineering; Glioblastoma Multiforme; Interleukin-8; Extracellular Matrix; Endothelial Cell
Schaffer, Chris; Stokol, Tracy
Ph. D., Biomedical Engineering
Doctor of Philosophy
dissertation or thesis