Prostatitis and prostate cancer are extremely common diseases in men, but the relationship between these two diseases is unknown. While acute prostatitis is thought to be infectious in nature, the etiology of chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) and asymptomatic inflammatory prostatitis remains unclear. By studying Aire-deficient mice that have defective immune tolerance and develop spontaneous prostatitis, we have identified a novel prostate autoantigen. Moreover, we have found that CP/CPPS patients with biopsy-proven inflammation in their prostate glands possess immune responses to the analogous human protein, semenogelin (Sg). These results provide new evidence to support autoimmunity as a potential cause for chronic prostatitis. Moreover, by assessing for immune responses to Sg, we may be able to detect prostate inflammation in symptomatic or asymptomatic men. Animal models as well as clinical observations demonstrate that chronic inflammation can enhance the development or certain tumors. We hypothesize that chronic prostatitis contributes to prostate cancer development. The overall objectives of this proposal are to examine: 1) whether there is an association between an immune responses to the prostate autoantigen Sg and prostate cancer in humans;and 2) whether chronic inflammation can enhance the development of prostate cancer in mouse models.
In specific aim 1, we will determine whether immune responses to Sg are associated with the presence of inflammation and/or prostate cancer in men undergoing prostate biopsy. In the specific aim 2, we will determine whether chronic prostatitis can alter the development of tumors in mouse models of prostate cancer. This proposal will provide insight in the role of chronic inflammation and prostate cancer development. Moreover, these results could provide a rationale for prostate cancer prevention by treating chronic prostatitis.

Public Health Relevance

Chronic inflammation is thought to contribute to the development of many different malignancies, but the role of inflammation in prostate cancer is unknown. Prostate cancer is the most common non-skin cancer in men. Chronic prostatitis is also an extremely common problem in men. By using a mouse model with a genetic deficiency that predisposes these mice to autoimmune disease, we have identified a protein target for the immune system that we believe to be important in chronic prostatitis in humans. We propose to assess for immune responses to this protein in men who are undergoing prostate biopsies. We will evaluate whether immune responses to this protein are associated with prostate inflammation and prostate cancer on biopsy. We will also determine whether prostatitis can accelerate the development of tumors in mice that are genetically engineered to develop spontaneous prostate cancer. In doing so, we may understand how autoimmunity can contribute to prostate cancer. Moreover, this work could provide the foundation for developing an approach to prostate cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA163012-02
Application #
8462944
Study Section
Special Emphasis Panel (ZRG1-OTC-C (02))
Program Officer
Mccarthy, Susan A
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
2
Fiscal Year
2013
Total Cost
$389,187
Indirect Cost
$137,186
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lou, David Y; Fong, Lawrence (2014) Neoadjuvant therapy for localized prostate cancer: Examining mechanism of action and efficacy within the tumor. Urol Oncol :
Fong, Lawrence; Carroll, Peter; Weinberg, Vivian et al. (2014) Activated lymphocyte recruitment into the tumor microenvironment following preoperative sipuleucel-T for localized prostate cancer. J Natl Cancer Inst 106:
Cheng, Michael L; Fong, Lawrence (2014) Beyond sipuleucel-T: immune approaches to treating prostate cancer. Curr Treat Options Oncol 15:115-26
Khan, Imran S; Mouchess, Maria L; Zhu, Meng-Lei et al. (2014) Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med 211:761-8
Friedlander, Terence W; Fong, Lawrence (2014) The end of the beginning: circulating tumor cells as a biomarker in castration-resistant prostate cancer. J Clin Oncol 32:1104-6
Cha, Edward; Klinger, Mark; Hou, Yafei et al. (2014) Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med 6:238ra70