Author ORCID Identifier
Date Available
11-30-2023
Year of Publication
2022
Degree Name
Doctor of Philosophy (Medical Science)
Document Type
Doctoral Dissertation
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
First Advisor
Dr. Daret K. St. Clair
Abstract
As a result of improvements in cancer detection and treatment methods, a growing population of cancer survivors are living with side effects associated with their cancer therapy. Oxidative stress plays a significant role in the development of cancer and as a mechanism for cancer therapy to exert its therapeutic effects, resulting in off-target tissue damage. Radiation has been long established as a means to utilize the generation of reactive oxygen species to kill cancer cells, and 50% of chemotherapy agents currently used are associated with inducing oxidative stress. One major side effect observed in cancer survivors is a decline in neurocognition, where oxidative stress has been demonstrated to contribute to neuronal injury. Detection of oxidative stress and neuronal injury markers may provide opportunities for intervention to improve the quality of life of cancer survivors. Extracellular vesicles (EVs) are lipid-bound organelles that are excreted from cells and contain the molecular content of their cell of origin. Therefore, the molecular content within EVs may provide insight into biochemical alterations that occur following cancer treatment. Utilizing a mouse model given cranial radiation, we established that EVs are sensitive indicators of oxidative damage by measuring 4-hydroxy-2-nonenal (HNE) and astrocyte activation and glial fibrillary acidic protein (GFAP). These initial findings demonstrate the sensitivity of EVs compared to serum and brain tissue as an indicator of radiation-induced injury.
Pediatric acute lymphoblastic leukemia (ALL) patients are particularly susceptible to neuronal injury as a result of oxidative stress due to their median age of diagnosis between 2 to 5 years, a critical point during development. EVs isolated from these patients were shown to be more sensitive indicators of oxidative damage throughout consolidation treatment compared to patient sera and cerebrospinal fluid (CSF). A decrease in the neurogenesis marker, brain-derived neurotrophic factor (BDNF), was also observed throughout the treatment course, illustrating the sensitivity of EVs as markers of decreased neuronal stability. The relationship between oxidative stress, inflammation, and neuronal injury is well-established. Therefore, we determined whether the EVs generated from the leukemia cells contributed to inflammation, utilizing an in vitro system. We found that EVs produced from leukemia cells increased following treatment with the chemotherapy agent, methotrexate. Our findings reveal that EVs can be used as sensitive indicators of oxidative stress and neuronal injury.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2022.382
Recommended Citation
Ho, Jenni, "EXTRACELLULAR VESICLES AND CANCER THERAPY: AN INSIGHT INTO THE ROLE OF OXIDATIVE STRESS" (2022). Theses and Dissertations--Toxicology and Cancer Biology. 44.
https://uknowledge.uky.edu/toxicology_etds/44
