Investigating novel immunomodulatory roles of prostate-specific antigen.

摘要

Prostate-specific antigen (PSA) is a serine protease expressed almost exclusively by normal and malignant prostate epithelial cells. Remarkably high levels of enzymatically active PSA are present in the extracellular fluid surrounding the normal prostate. This high level expression of PSA continues in prostate cancer (PCa) cells even as they become increasingly less differentiated and lose the morphological characteristics of the normal prostate gland. On this basis PSA is best known for its use as a biomarker for the screening of PCa, or to detect recurrence after therapy.;The continued high-level expression of PSA throughout the stages of PCa suggests it may have a role in the pathogenesis and/or progression of disease, but surprisingly there has been relatively little interest in understanding the role of PSA in the pathobiology of PCa. The studies described herein suggest a previously uncharacterized function of PSA as an immunoregulatory protease that may help to create an environment hospitable to malignancy through the inactivation of the complement system. I also propose the hypothesis that PCa cells have assimilated this immunoregulatory role from healthy cells as this activity may exist under normal circumstances to aid in fertility.;The American Cancer Society estimates that in 2012 in the United States alone there will be 241,740 new diagnoses of PCa and 28,170 men will die from the disease. This places prostate cancer at ;A therapeutic approach championed by our laboratory yet not fully exploited is the use of PSA-activated prodrugs and protoxins for the targeted therapy of PCa. In this thesis I describe two attempts at applying PSA-activation technology to create new therapeutic options for PCa patients. The first therapeutic is an innovative humanized pore-forming immunotoxin while the second utilizes cell penetrating peptides to deliver cytotoxins in a controlled manner.