Benign prostatic hyperplasia (BPH) is typified by epithelial and stromal hyperplasia and progressive enlargement of the prostate gland. BPH is associated with chronic inflammation, however specific mechanisms are unknown. We have reported that hyperplastic BPH epithelium overexpresses interleukin-8 (IL-8) and that this correlated significantly with a myofibroblast reactive stroma phenotype with altered expression patterns of tenascin. IL-8 is a potent chemokine that induces chemotaxis of marrow-derived cells and stimulates reactive stroma / wound repair mechanisms. We have generated a human xenograft model that overexpresses IL-8 and transgenic mouse lines expressing KC (a murine homolog of IL-8) and observe a hyperplastic epithelial and reactive stroma phenotype induced by IL-8(KC) with elevated tenascin-C and pro- collagen I. Our preliminary data suggests that reactive stroma may be recruited from circulating marrow- derived progenitor fibrocyte (CD14+) cells. It is our hypothesis that elevated IL-8 functions to activate and/or recruit reactive stroma progenitor cells at foci of glandular BPH and that this hyperplastic reactive stroma further drives BPH glandular and stromal hyperplasia. To address this hypothesis three Specific Aims are proposed: 1. To characterize the role of IL-8(KC) / CXCR2 signaling and tenascin-C, as a downstream effector, in the induction of prostate hyperplasia. 2. To determine the role of IL-8 / CXCR2 receptor signaling in the recruitment of reactive stroma progenitor cells. 3. To target IL-8(KC) / CXCR2 signaling in reactive stroma cells using drug-inducible gene expression to uncouple signaling and therefore attenuate the genesis of reactive stroma and epithelial hyperplasia in BPH. The purpose of this project is to determine basic mechanisms of IL-8 action in recruiting reactive stroma and establish proof-of-concept that reactive stroma progenitor cells and subsequent reactive stroma can be targeted to uncouple key pathways in order to attenuate the hyperplastic phenotype.

Public Health Relevance

This objective of this study is to determine how interleukin-8 (IL-8) regulates the biology of benign prostatic hyperplasia. This project will provide data on key mechanisms and pathways using several model systems. These mechanisms and pathways may evolve as therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083293-04
Application #
8543714
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Mullins, Christopher V
Project Start
2010-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
4
Fiscal Year
2013
Total Cost
$310,238
Indirect Cost
$112,003
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ressler, Steven J; Dang, Truong D; Wu, Samuel M et al. (2014) WFDC1 is a key modulator of inflammatory and wound repair responses. Am J Pathol 184:2951-64
San Martin, Rebeca; Barron, David A; Tuxhorn, Jennifer A et al. (2014) Recruitment of CD34(+) fibroblasts in tumor-associated reactive stroma: the reactive microvasculature hypothesis. Am J Pathol 184:1860-70
Kim, Woosook; Barron, David A; San Martin, Rebeca et al. (2014) RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation. Proc Natl Acad Sci U S A 111:16389-94
Yang, Feng; Zhang, Yongyou; Ressler, Steven J et al. (2013) FGFR1 is essential for prostate cancer progression and metastasis. Cancer Res 73:3716-24
Rogers, Erin; Wang, Ben X; Cui, Zhu et al. (2012) WFDC1/ps20: a host factor that influences the neutrophil response to murine hepatitis virus (MHV) 1 infection. Antiviral Res 96:158-68
Ressler, Steven J; Rowley, David R (2011) The WFDC1 gene: role in wound response and tissue homoeostasis. Biochem Soc Trans 39:1455-9
Schauer, Isaiah G; Rowley, David R (2011) The functional role of reactive stroma in benign prostatic hyperplasia. Differentiation 82:200-10
Barron, David A; Strand, Douglas W; Ressler, Steven J et al. (2010) TGF-ýý1 induces an age-dependent inflammation of nerve ganglia and fibroplasia in the prostate gland stroma of a novel transgenic mouse. PLoS One 5:e13751