Prostate cancer is the most commonly diagnosed cancer and increasing with the expanding aging population. Epithelial transformation is predicated on its phenotypic, epigenetic, and genomic changes. The reciprocating phenotypic changes in the adjacent stromal microenvironment, or stromal co-evolution, are supportive of the adjacent epithelia by the differential production of extracellular matrix and growth factors. However, the classic demonstration of isolated carcinoma associated fibroblasts, grown ex vivo for a period of time, to subsequently induce tumorigenesis on non-tumorigenic epithelia in vivo is suggestive of epigenetic """"""""imprinting"""""""". We have characterized the PCa associated stroma in mouse models and human disease to have TGF-?-dependent epigenetic changes not observed in stromal fibroblasts associated with benign prostate epithelia. Two independent conditional stromal knockout mouse models of the TGF-? type II receptor (Tgfbr2) models develop prostate adenocarcinoma that support castrate resistance. In the last funding cycle we also identified that the knockout of Tgfbr2 up regulates Stat3 signaling. We find that there is elevated epigenetic silencing of DNA damage repair genes associated with a disproportionate amount of DNA double stranded breaks in the stromal fibroblastic cells. We will test the hypothesis that, TGF-? signaling regulation of tumor suppressors in stromal fibroblasts mediates prostate cancer progression. The mechanism of the epigenetic changes in the tumor microenvironment and its role in prostate cancer progression is the focus of Aim 1. It is still poorly understood how in prostate cancer androgen receptor function is abnormally switched from a pro-differentiation role in development and normal adult prostate homeostasis, to one pro-proliferation in cancer. Since prostate epithelial androgen responsiveness is mediated through the stromal androgen signaling, the role of stromal epigenetic signaling will be a focus of Aim 2. The role of Stat3 in tumor progression and stromal androgen signaling will be determined in terms of its role on DNA methyl transferase and androgen receptor activity. The clinical relevance of the co-evolving stromal changes observed we be tested in a retrospective case control trial for patient outcome following radiation therapy for localized prostate cancer. We are uniquely positioned to address the role of cancer associated stromal changes that occurs in tumorigenesis and castrate resistant growth, based on TGF-?'s role in tumor suppressor silencing and defining stromal heterogeneity through cell culture, tissue recombination xenograft, and transgenic mouse models. .

Public Health Relevance

Prostate cancer is the second leading cause of cancer-related death in men. Mortality from the disease results from those cancers that escape the primary site and become androgen ablation therapy-resistant. These studies will direct future therapeutic intervention and patient selection by taking into account the impact of prostatic stromal fibroblastic cells on outcome.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA108646-09
Application #
8681376
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Mohla, Suresh
Project Start
2004-08-01
Project End
2017-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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-1β (IL-1β)-dependent manner. J Biol Chem 290:6574-83
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
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
Banerjee, J; Mishra, R; Li, X et al. (2014) A reciprocal role of prostate cancer on stromal DNA damage. Oncogene 33:4924-31
Jackson 2nd, Roger S; Placzek, William; Fernandez, Ana et al. (2012) Sabutoclax, a Mcl-1 antagonist, inhibits tumorigenesis in transgenic mouse and human xenograft models of prostate cancer. Neoplasia 14:656-65
Bhowmick, Neil A (2012) Metastatic ability: adapting to a tissue site unseen. Cancer Cell 22:563-4
Di Vizio, Dolores; Morello, Matteo; Dudley, Andrew C et al. (2012) Large oncosomes in human prostate cancer tissues and in the circulation of mice with metastatic disease. Am J Pathol 181:1573-84
Franco, Omar E; Jiang, Ming; Strand, Douglas W et al. (2011) Altered TGF-β signaling in a subpopulation of human stromal cells promotes prostatic carcinogenesis. Cancer Res 71:1272-81
Stabler, Sally; Koyama, Tatsuki; Zhao, Zhiguo et al. (2011) Serum methionine metabolites are risk factors for metastatic prostate cancer progression. PLoS One 6:e22486

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