All ETDs from UAB

Advisory Committee Chair

Harald Sontheimer

Advisory Committee Members

Mark Bevensee

Michelle Olsen

J David Sweatt

Jacques Wadiche

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Gliomas are the most common and most deadly primary brain cancer. Patient outcome for the most malignant variety, the World Health Organization (WHO) Type IV glioblastoma multiforme (GBM), has stagnated over the last several decades - the best combination treatment of surgical resection, radiation, and chemotherapy results in median survival of just over a year. To escape treatment, GBM must multiply and migrate in a confined brain environment. Both of these aspects of tumor cell invasion rely on the cell's ability to volume regulate; cell division involves a stage called "pre-mitotic condensation" in which the cells shrink immediately prior to splitting, and migration in the tight brain space necessitates cell shrinkage and expansion to accommodate. This volume regulation is in turn dependent on the osmotic flux of ions through dedicated channels across the lipid bilayer - most commonly K+ and Cl-. These channels themselves are regulated by a host of factors including ion concentration, membrane potential (Vm), phosphorylation, and as shown in this thesis, pH. This last component is especially relevant to glioma cells, as they produce copious amounts of protons due to a largely glycolytic metabolism even in the presence of ample oxygen. Here, I demonstrate that glioma tumor spheroids create steep external pH (pHe) gradients. These affect glioma ion channels that are tightly regulated by pHe. By altering the conductance of these pHe-sensitive K+ channels, glioma cells set their Vm based on their location within the tumor mass, and this in turn affects their proliferation state by gating their G1-to-S transition through the cell cycle. Thus, the glioma controls its growth through autocrine proton signaling. Additionally, I found that protons directly permeate the cell membrane through the Cl-/H+ antiporter ClC-3, movement which depends on extracellular Cl- and protons and is uncoupled at acidic pHe. This is a novel finding that adds to the cohort of pH regulators expressed on glioma cells and provides an additional function to a well-described glioma Cl- channel.

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