David Turay

Abstract

Touted among the major achievements in the diagnosis and management of Prostate cancer (PCa) in the past few decades has been, the dramatic decline of men with advanced/metastatic PCa at diagnosis coupled with a significant improvement ( >90%) in the five and ten year survival rates of the disease. Non-palpable PCa (potentially clinically treatable disease) now accounts for 70-80% of all newly diagnosed cases of PCa. Preceding these changes by about a decade was the introduction of Prostatic Specific Antigen (PSA) into clinical practice; first as biomarker for monitoring response to therapy and subsequently as a complementary screening tool. It is not surprising then that a cause-effect relationship has been suggested. Like a double-edged sword, the use of PSA as a screening tool has also been blamed for the rise of unnecessary prostate related invasive procedures including biopsies and surgeries. Some of the documented criticisms of PSA include its lack of specificity (elevated in inflammation) for PCa and the difficulty of establishing a cut-off value that is highly sensitive and specific for the disease. It is estimated that perhaps up to half of the PCa diagnosis are patients whose tumors would have been clinically undetectable had PSA not been included in the screening process. The dissatisfaction with PSA has created opportunities to search for novel biomarkers for screening and monitoring of treatment in PCa. Some of the more novel biomarkers that have been examined as potential replacements for PSA are the RNA product prostate cancer antigen-3 (PCA 3), the enzyme alpha methylacyl-CoA, and the gene fusion product TMPRSS2-ERG. More recently Zhang, Casiano and colleagues described an increased predominance of autoantibodies to Cyclin-B1 in the sera of PCa patients compared to controls with Benign Prostatic Hyperplasia (BPH). All these efforts are in different stages of maturity but yet to have ground breaking clinical impact. We hereby examined the role of exosomes in PCa and a qualitative profile of its proteomic composition. The higher levels of circulating exosomes in sera of PCa patients is directly prostate-derived and could be stress-induced as the non-cancer prostate stroma and the immune system interact with neoplastic cells. This could be reflected in some of the similarities in the proteomic profile of serum-derived exosomes and exosomes derived from direct PCa in vitro cell line cultures. Moreover, PCa has a higher incidence and a greater disease severity in non-Hispanic African Americans and this difference in disease biology can be reflected in the difference in the proteomic profile of exosomes across ethnicities/races. Serum exosomes originate from a diverse population of normal, neoplastic or inflammatory cells. Tumors do shed membrane vesicles directly into serum or extracellular space. These vesicles are referred to as tumor derived exosomes (TEX). Our overall objective was to use a seroproteomics approach focused on profiling serum exosomes in PCa patients. This profile would then be compared with that of non-cancer patients in an effort to identify proteins unique to cancer patients. A comparative study across racial groups will help us begin to identify possible protein markers/players involved in determining disease aggressiveness. The project hopes to one day fill the gap of the lack of biomarker identification in PCa patients and perhaps give us potential therapeutic targets to help lower morbidity in the black and indeed all cohorts of patients. It builds on preliminary data indicating that PCa patient sera have exosomes containing stress survival and cancer related proteins.

LLU Discipline

Anatomy

Department

Pathology and Human Anatomy

School

School of Medicine

First Advisor

Wall, Nathan R.

Second Advisor

Casiano, Carlos A.

Third Advisor

Langridge, William

Fourth Advisor

Nava, Pedro

Fifth Advisor

Mirshahidi, Saied

Sixth Advisor

Reeves, Mark

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2016

Date (Title Page)

6-2016

Language

English

Library of Congress/MESH Subject Headings

Prostatic Neoplasms; Proteomics; Exosomes; Prostatic Hyperplasia; Prostate-Specific Antigen; Biomarkers; Tumor; Lymphocytes

Subject - Local

Serum-derived Exosomes; Prostate cancer; Stress survival proteins

Type

Dissertation

Page Count

145

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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