The importance of stromal-epithelial interactions in prostate gland development and tumorigenesis is well established. These interactions likely involve autocrine and paracrine action of multiple growth factors, including members of the transforming growth factor-beta (TGFbeta) family. There is a coincident rise in TGFbeta expression following androgen ablation associated with regression of normal prostates. We used conditional knockout mice having a specific loss of the TGFbeta receptor type II in fibroblasts (FbetaKO) and prostate epithelia (EbetaKO) to identify the cellular component responding to TGFbeta signaling during prostate regression. The FbetaKO mice do not exhibit prostate regression upon androgen ablation. In contrast, EbetaKO mice displayed similar androgen responsiveness compared to non-transgenic mice. Interestingly, the TGFbeta signaling pathway, known to regulate androgen receptor action when activated in epithelial cells, can indirectly inhibit epithelial proliferation when activated in adjacent stromal fibroblasts. These findings are specifically relevant to our understanding of current androgen signaling antagonist treatments used in treating patients with malignant prostate cancer, benign prostate hyperplasia, and as a chemoprevention of prostate cancer in clinical trials. The central hypothesis of this application is that stromal TGFbeta signaling plays an important role in stromal-epithelial interactions responsible for prostate androgen responsiveness. The goal of this project is to specifically identify the TGFbeta-mediated signals in the stroma that mediate prostate androgen responsiveness. The EbetaKO and FbetaKO transgenic mouse models, tissue recombination xenograft models, and cell co-culture models will be used to determine the mechanism of TGFbeta regulation in prostate regression through the following specific aims: 1. Define the role of prostatic TGFbeta signaling as a result of androgen ablation. 2. Identify stromal TGFbeta downstream signaling pathway components for involvement in prostate regression. 3. Define TGFbeta signaling pathway components involved in prostate cancer regression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA108646-01
Application #
6808122
Study Section
Special Emphasis Panel (ZRG1-TME (01))
Program Officer
Sathyamoorthy, Neeraja
Project Start
2004-08-01
Project End
2009-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$278,595
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Surgery
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Madhav, Anisha; Andres, Allen; Duong, Frank et al. (2018) Antagonizing CD105 enhances radiation sensitivity in prostate cancer. Oncogene 37:4385-4397
Smith, Bethany; Agarwal, Priyanka; Bhowmick, Neil A (2017) MicroRNA applications for prostate, ovarian and breast cancer in the era of precision medicine. Endocr Relat Cancer 24:R157-R172
Cheng, Ran; Liu, Wen; Zhang, Rui et al. (2017) Porphyromonas gingivalis-Derived Lipopolysaccharide Combines Hypoxia to Induce Caspase-1 Activation in Periodontitis. Front Cell Infect Microbiol 7:474
Haldar, Subhash; Dru, Christopher; Mishra, Rajeev et al. (2016) Histone deacetylase inhibitors mediate DNA damage repair in ameliorating hemorrhagic cystitis. Sci Rep 6:39257
Bianchi-Frias, Daniella; Basom, Ryan; Delrow, Jeffrey J et al. (2016) Cells Comprising the Prostate Cancer Microenvironment Lack Recurrent Clonal Somatic Genomic Aberrations. Mol Cancer Res 14:374-84
Rogatko, André; Cook-Wiens, Galen; Tighiouart, Mourad et al. (2015) Escalation with Overdose Control is More Efficient and Safer than Accelerated Titration for Dose Finding. Entropy (Basel) 17:5288-5303
Haldar, Subhash; Dru, Christopher; Choudhury, Diptiman et al. (2015) Inflammation and pyroptosis mediate muscle expansion in an interleukin-1? (IL-1?)-dependent manner. J Biol Chem 290:6574-83
Tighiouart, Mourad; Piantadosi, Steven; Rogatko, André (2014) Dose finding with drug combinations in cancer phase I clinical trials using conditional escalation with overdose control. Stat Med 33:3815-29
Tighiouart, Mourad; Liu, Yuan; Rogatko, André (2014) Escalation with overdose control using time to toxicity for cancer phase I clinical trials. PLoS One 9:e93070
Banerjee, J; Mishra, R; Li, X et al. (2014) A reciprocal role of prostate cancer on stromal DNA damage. Oncogene 33:4924-31

Showing the most recent 10 out of 29 publications