Glioblastoma cancer stem cell properties and synthetic biomaterials

Craig E Barcus, Purdue University

Abstract

Cancer stem cells serve as the initiating cells of some tumors, with self-renewing and differentiation capacity. Recently, cancer stem cells have been implicated in the aggressiveness and metastatic properties of solid state tumors such as glioblastoma. Current therapies fail to remove cancer stem cells from the tumors, where the cells are able to recapitulate the tumor and prolong the suffering of the patients. Much like cancer itself, cancer stem cells vary in the processes that control their properties, exhibiting degrees of heterogenicity that are often dependent on each line of cancer stem cells examined. The broad variety of signal processes dictates that broad examination techniques must be employed to fully characterize cancer stem cells. In this study, broad spectrum mass spectrometry examination of a line of glioblastoma cancer stem cells reveals four common themes in distinct cell states: DNA damage responses/cell cycle control, cancer and stem cell specific proteins, neural developmental signaling pathways, and stress response mechanisms coupled to metabolic regulation. DNA damage response proteins such as p53 and BRCA1 are hallmarks in cancer progression and were present in the GBAM1 cancer stem cell line examined. Cancer and stem cell proteins such as the transcription factor Sox2 and the cancer related transcription factor MEL1 are present in the cell line after prolonged culture conditions (n = 16), indicative of the self-renewal and cancerous properties of the cells. Neural developmental processes such as Notch and TGF-β signaling appear to control portions of differentiation, as inhibition of these two pathways leads to reduced cell numbers and a change in the differentiation biomarkers when compared with native differentiation. Notch inhibition leads to a more mature astrocytic cell, with an apparent increase in the astrocyte marker glial fibrillary acidic protein (GFAP) and subsequent decrease of the neural stem cell marker nestin. Inhibition of TGF-β signaling resulted in a distinct cell phenotype with flat, rounded cells that do not extend processes, unlike Notch inhibited cells and cells differentiated in normal conditions. Biomarker expression reveals that the astrocyte marker present in the other cell states is not expressed in TGF-β inhibited cells. Oxidative metabolism may be tightly regulated in GBAM1 cells, as glucose uptake increases 37-fold from expansion state cells to differentiated cells. This increase in uptake may potentially be explained by the lactate-shuttle theory, a theory in which cells sensitive to oxidative metabolism utilize other cells in their environment to produce lactate for them, forgoing stresses caused by glycolysis. Finally, atomic force microscopy was utilized to explore peptide modified silica gels, examining distinct characteristics between peptide modified silica gels and the native silica gels.

Degree

M.S.A.B.E.

Advisors

Clase, Purdue University.

Subject Area

Molecular biology|Cellular biology|Biomedical engineering

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