Glioblastomas are the most common and deadly form of primary brain cancer in adults. Current treatment strategies are aggressive, including a combination of surgical resection, radiotherapy, and chemotherapy. However, median patient survival has remained stagnant at 12 to 15 months for the last several decades. This dismal patient outcome has prompted efforts to understand the unique characteristics of these tumors, since traditional therapeutics have not been efficacious. Extensive invasion is a salient feature of glioblastomas that significantly diminishes the effectiveness of current treatment strategies and is ultimately the cause of tumor recurrence within 2 years in approximately 80% of patients. While progress has been made with regard to defining the niches in which invasion occurs, there are still large gaps in our understanding of the molecules within the brain environment that stimulate glioblastoma cell invasion. Around 90% of all glioblastomas grow in the cerebral cortex, an area of the brain that is densely innervated by neurotransmitter projections. Surprisingly, there have been limited efforts to determine if these neurotransmitters influence glioblastoma invasion.
Here, I demonstrate that glioblastoma cells express functional acetylcholine receptors (AChRs). Activation of these receptors causes a Ca2+ influx and mediates an increase in matrix metalloproteinase-9 (MMP-9) release that led to enhanced invasive potential. Additionally, I found that glioblastoma cells express other components of ACh signaling, suggesting the presence of an autocrine/paracrine ACh signaling loop in glioblastomas.
Secondly, I found that tumor-derived choline is a potential contributor to pyramidal neuron hyperexcitability in peritumoral cortex via upregulation and over-activation of alpha 7 nicotinic acetylcholine receptors (α7nAChRs). This is a novel finding that adds to our understanding of the etiology of tumor-associated seizures, which are a common co-morbidity in glioblastoma.
I was also involved in the development of an improved in vitro migration device that affords rapid customization and chronic, stable gradients of multiple chemoattractants simultaneously. In comparison to traditional migration assays, this device more closely resembles the complex environments that glioblastoma cells encounter in vivo, while providing the easy-of-use and manipulability of in vitro assays. The advantages of this novel device could allow for a better approach to therapeutic development, not only in glioblastoma but also in the field of biomedical research as a whole.
|Commitee:||Gillespie, George Y., Hjelmeland, Anita B., McMahon, Lori L., Olsen, Michelle L.|
|School:||The University of Alabama at Birmingham|
|School Location:||United States -- Alabama|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Keywords:||3D printing, Acetylcholine, Alpha-7 acetylcholine receptor, Glioblastoma, Hyperexcitabilty, Invasion|
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