Document Type
Thesis
Date of Award
2022
Degree Name
Master of Science (MS)
Department
Basic Biomedical Science
First Advisor
Khosrow Rezvani
Abstract
Colorectal cancer (CRC) is one of the most globally diagnosed cancers and a leading cause of cancer-related mortality. Metastatic CRC (mCRC) significantly impacts patient outcome and diminishes overall survival outcomes. Despite advances in therapeutic treatment, the 5-year survival rate for mCRC is < 20% and several patients fail to have a beneficial response to available treatments. This could be attributed to alternative routes of mCRC in which current treatments are unable to block these routes of cancer spread. One such alternative route involves the spread of cancer along the nerve termed perineural invasion (PNI) which is an independent prognostic factor in CRC. The tumor microenvironment (TME) is comprised of several different cell types that have been investigated for their role in cancer pathogenesis. Several studies have shown that cells of the TME can provide a supportive environment that allows for the growth and spread of cancer. Primary focus has been placed on cancer, stromal, and immune cells in the TME, but the role of neuronal cells in cancer pathogenesis is still unknown. Since cells of the TME can communicate through the secretion of exosomes, cancer-derived exosomes have gained widespread interest for their role in cancer pathogenesis. This study investigated how CRC-derived exosomes prime neuronal cells and contribute to PNI. By utilizing transwell co-culture systems and conditioned media experiments, we were able to determine that CRC cells secrete extracellular vesicles (EVs) that induce neuronal cell differentiation and growth, and inhibit apoptosis. Furthermore, utilization of an exosome inhibitor revealed that blocking exosome production in CRC cells could attenuate these affects. CRC- derived exosomes were collected utilizing a modified-iodixanol gradient technique and further characterization revealed an enriched pool of exosomes in fractions. Furthermore, proteomic analysis showed several proteins contained in CRC-derived exosomes that were involved in neuronal cell differentiation and growth. Lastly, treatment of CRC cells with the pharmacological tool Veratridine (VTD) was able to attenuate neuronal cell differentiation and growth and alter the proteomic profiles found in CRC-derived exosomes. In addition, VTD treatment slowed the spread of CRC along the sciatic nerve of an NIH-III nude mouse model of PNI.
Keywords
Colorectal cancer, Exosomes, Perineural invasion, Proteomics, Veratridine
Number of Pages
85
Publisher
University of South Dakota
Recommended Citation
Knoblich, Cole, "Exosomes derived from metastatic colorectal cancer mediate perineural invasion: implications for therapeutic intervention" (2022). Dissertations and Theses. 311.
https://red.library.usd.edu/diss-thesis/311
