Document Detail

A local paracrine and endocrine network involving TGFβ, Cox-2, ROS, and estrogen receptor β influences reactive stromal cell regulation of prostate cancer cell motility.
MedLine Citation:
PMID:  22593181     Owner:  NLM     Status:  MEDLINE    
The tumor microenvironment plays a critical role in supporting cancer cells particularly as they disengage from limitations on their growth and motility imposed by surrounding nonreactive stromal cells. We show here that stromal-derived androgenic precursors are metabolized by DU145 human prostate cancer (PCa) cells to generate ligands for estrogen receptor-β, which act to limit their motility through transcriptional regulation of E-cadherin. Although primary human PCa-associated fibroblasts and the human WPMY-1-reactive prostate stromal cell line maintain this inherent estrogen receptor (ER)β-dependent motility inhibitor activity, they are subverted by TGF-β1 pro-oxidant signals derived from cocultured DU145 PCa cells. Specifically, stromal-produced H(2)O(2), which requires Cox-2, acts as a second paracrine factor to inhibit ERβ activity in adjacent DU145 cells. Chromatin immunoprecipitation analysis reveals that ERβ recruitment to the E-cadherin promoter is inhibited when H(2)O(2) is present. Both neutralization of H(2)O(2) with catalase and prevention of its production by silencing Cox-2 expression in stromal cells restore the motility-suppression activity of stromal-derived ERβ ligand precursors. These data suggest that reactive stromal cells may still have a capacity to limit cancer cell motility through a local endocrine network but must be protected from pro-oxidant signals triggered by cancer cell-derived TGF-β1 to exhibit this cancer-suppressive function.
Melanie J Grubisha; M E Cifuentes; Stephen R Hammes; Donald B Defranco
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-05-16
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  26     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-21     Completed Date:  2012-09-20     Revised Date:  2014-06-23    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  940-54     Citation Subset:  IM    
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MeSH Terms
Androgens / metabolism
Cadherins / genetics,  metabolism
Cell Line, Tumor
Cell Movement*
Coculture Techniques
Cyclooxygenase 2 / genetics,  metabolism*
Estrogen Receptor beta / metabolism*
Gene Expression Regulation, Neoplastic
Hydrogen Peroxide / metabolism*
Intracellular Signaling Peptides and Proteins / metabolism
Paracrine Communication
Promoter Regions, Genetic
Prostatic Neoplasms
Reactive Oxygen Species / metabolism
Signal Transduction
Stromal Cells / metabolism,  physiology*
Transforming Growth Factor beta1 / metabolism,  physiology*
Tumor Microenvironment
Grant Support
Reg. No./Substance:
0/Androgens; 0/Cadherins; 0/Estrogen Receptor beta; 0/Intracellular Signaling Peptides and Proteins; 0/Reactive Oxygen Species; 0/Transforming Growth Factor beta1; BBX060AN9V/Hydrogen Peroxide; EC 2; EC protein, human
Erratum In:
Mol Endocrinol. 2014 Feb;28(2):275

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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