Grubisha, Melanie
(2011)
TGFβ-Dependent ROS Regulates a Local Endocrine Communication Network Between Stromal and Epithelial Cells in the Prostate.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The development of prostate cancer (PCa) can be considered a co-evolution of both the epithelial and stromal cells; indeed, the latter develop their own unique gene signature during cancer progression that has potential predictive value in determining a patient’s outcome. Cancer-associated “reactive” stroma is characterized by heterogeneity in Transforming Growth Factor β (TGFβ) signaling, transdifferentiation into a myofibroblast phenotype by stromal fibroblasts, and an increased production of reactive oxygen species (ROS). In this study, we sought to examine the basis for PCa cell response to reactive prostate stromal cells (i.e. myofibroblasts) in vitro. Specifically, we have shown that human prostate derived fibroblastic (i.e. PS30) and myofibroblastic (i.e. WPMY-1) cell lines and primary stromal cells have the capacity to inhibit DU145 PCa cell motility in co-culture through the production of a precursor ligand for estrogen receptor β (ERβ). Activating the ERβ pathway in adjacent DU145 cells leads to induction of the cell adhesion molecule E-cadherin and a subsequent reduction in cell motility. However, an increased responsiveness to TGF-β1 in WPMY-1 cells triggers induction of COX-2 expression and elevated ROS production, which ultimately raises extracellular H2O2. H2O2 derived from WPMY-1 cells acts in a paracrine manner to decrease the recruitment of ERβ to the E-cadherin promoter in co-cultured DU145 cells, as revealed by chromatin immunoprecipitation assays. shRNA knockdown of COX-2 in WPMY-1 cells abolishes the TGF-β1-induced ROS production and restores the inhibitory effects of myofibroblasts on DU145 cell motility in co-culture. Therefore, despite their “reactive” stroma phenotype, limiting the TGFβ-driven ROS production in WPMY-1 cells restores their inherent capacity to limit tumor progression through a local endocrine network targeting ERβ in adjacent PCa cells. Our results imply that controlling the redox status of the local milieu may offer a route for utilizing inherent regulatory mechanisms to limit cancer cell motility, ultimately acting to reduce its spread and dissemination.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 December 2011 |
| Date Type: |
Publication |
| Defense Date: |
1 November 2011 |
| Approval Date: |
16 December 2011 |
| Submission Date: |
14 November 2011 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
120 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Molecular Pharmacology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
TGF-beta, prostate, COX-2, ROS, ER-beta |
| Date Deposited: |
16 Dec 2011 20:34 |
| Last Modified: |
19 Dec 2016 14:38 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/10470 |
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