All ETDs from UAB

Advisory Committee Chair

Harald Sontheimer

Advisory Committee Members

Jeffrey Engler

Kevin Kirk

Burt Nabors

Lucas Pozzo-Miller

Document Type

Dissertation

Date of Award

2013

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Malignant gliomas are highly invasive brain tumors, which lack effective treatment options. To date, the standard therapy includes surgical debulking followed by chemotherapy and radiation. Despite efforts to eradicate the disease, the median patient survival time is only 14 months. In an attempt to discover novel therapies, research has focused on understanding the heterogeneous biological mechanisms employed by these cells. Uniquely, they do not metastasize through the vasculature or lymphatics like other solid cancers but alternatively, glioma cells utilize the abluminal surface of the vasculature to guide invasion and migration throughout the brain. The intimate association between glioma cells and vasculature suggests that there are likely biological advantages exploited by these invading perivascular cells. First, we confirmed that when perivascular glioma cells encounter an invasion barrier, they utilize chloride ion channels and cotransporters to efflux Cl- thereby creating an osmotic gradient for water to follow. The movement of these ions and subsequent water causes cellular volume changes, which facilitate the process of invasion and migration through the brain's limited extracellular space. Additionally, perivascular glioma cells occupy the space normally reserved for astrocytic endfeet. As glioma cells associate with vessels, they displace the astrocytic endfeet which thereby compromises several astrocyte functions. Removal of the astrocytic endfeet leads to extravasation of blood-born molecules in the brain's parenchyma highlighting the important role that astrocytes play in the maintaining this barrier. Additionally, displacement of the astrocytic endfoot prevents astrocyte-mediated alterations of vascular tone, thereby eliminating communication between neurons, astrocytes and blood flow. Lastly, increases in the glioma cell [Ca2+]i activate Ca2+-activated K+ channels which efflux K+ onto vascular smooth muscle cells, causing vasoconstriction. Glioma cells can actively regulate the vessel diameter likely promoting vasoconstriction to increase the perivascular space needed for invasion. We propose that the intimate association between glioma cells and the vasculature aid in invasion and migration mechanisms while actively modulating the existing brain cells for their own benefits. Finally, our data suggests that targeting glioma cell volume changes and glioma cell regulation of vascular tone may be a novel therapeutic strategy for the management of malignant gliomas.

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