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Dysregulation of p53 Gene Expression in Human Prostate Carcinogenesis and Its Relationship to Angiogenesis

Spees, Colleen K.
http://rave.ohiolink.edu/etdc/view?acc_num=osu1313523656

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Allied Medical Professions.
Prostate cancer is a common malignancy in affluent nations. Indeed, it is the most common visceral malignancy in American men impacting over 200,000 annually. The disease is heterogeneous in biology and the molecular biomarkers that define the various subtypes of prostate cancer have not been clearly defined. The host genetic factors and the acquired mutations that drive prostate cancer progression are only beginning to be elucidated. TP53 is a tumor suppressor gene that is known as the "guardian of the genome" due to its central role in the inhibition of the cell cycle and promotion of DNA repair, among many other anticancer activities. Recently our laboratory studies have implicated p53 dysfunction in the early stages of rodent carcinogenesis. Coincidentally, a patient with Li-Fraumeni Syndrome (LFS) presented to The Ohio State University Clinic with prostate cancer at a young age. LFS is an inherited cancer syndrome, with an autosomal dominant Germline mutation in the TP53 gene. Our review of the literature revealed that guidelines for prostate cancer screening and treatment for men with LFS have not been established. Indeed, we proposed that men with LFS should consider earlier screening in hope of diagnosing disease at an early stage where therapy can be provided with curative intent. We recommend that LFS men avoid external beam irradiation and chemotherapy that is associated with DNA damage and risk of secondary cancers. We then pursued the frequency of p53 dysfunction in a set of prostatectomy cases using immunohistochemical techniques. We examined samples from the Health Professionals Follow-up Study (HPFS) initiated in 1986 at the Harvard School of Public Health with over 50,000 men participating in this prospective cohort. Over 500 cases with prostatectomy samples and associated data were available for our studies. The rate of intense nuclear p53 staining indicating a dysfunctional protein that cannot be degraded in noncancerous tissue is 0%, but is 20% in cancer. We further showed that p53 staining is associated with more aggressive disease. Our rodent studies also suggest that the early overexpression of p53 occurs in parallel with establishment of tumor vascularity. Thus, we hypothesized that prostate tumor vascularity may be related to p53 expression. In order to address this relationship, we first needed to fully characterize objective biomarkers of tumor angiogenesis. We utilized digital image analysis to provide quantifiable endpoints defining blood vessels identified by immunohistochemical detection of the clotting factor VIII, known as von Willebrand's factor in areas of normal and cancerous prostate. We report a dramatic increase in microvascular density in cancer samples (p<.0001). In addition, irregularity of the vessels is much greater in cancer (p<.0001). Finally, vessels of smaller diameter and perimeter are found in cancer compared to noncancer (p<.0001). We chose immunohistochemical staining with anti-CD34, another vascular marker associated with more immature vessels, to evaluate vascularity in prostate cancer relative to p53 status and tumor grade. Our analysis shows a significant correlation with grade (p<.0001). Future studies will assess the mechanisms of their interaction and how these two biomarkers predict prognosis.
Kay Wolf, PhD (Advisor)
Steven Clinton, MD, PhD (Advisor)
Anne Smith, PhD (Committee Member)
Sally Rudmann, PhD (Committee Member)
146 p.
Cellular Biology; Epidemiology; Genetics; Health Sciences; Oncology
p53; TP53; prostate cancer; angiogenesis; Li Fraumeni Syndrome; LFS

Recommended Citations

Citations

  • Spees, C. K. (2011). Dysregulation of p53 Gene Expression in Human Prostate Carcinogenesis and Its Relationship to Angiogenesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313523656

    APA Style (7th edition)

  • Spees, Colleen. Dysregulation of p53 Gene Expression in Human Prostate Carcinogenesis and Its Relationship to Angiogenesis. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1313523656.

    MLA Style (8th edition)

  • Spees, Colleen. "Dysregulation of p53 Gene Expression in Human Prostate Carcinogenesis and Its Relationship to Angiogenesis." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1313523656

    Chicago Manual of Style (17th edition)

osu1313523656
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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.