The overarching theme of this Program Project is that prostate cancer (PCa) bone metastasis is driven by progressive changes acquired through tumor-stroma interaction in the bone and prostate microenvironment. Genes activated in prostate and bone stroma confer growth and survival advantages to cancer cells and encode gene products that serve as novel predictive biomarkers for PCa progression. Our discoveries defining intra- and extra-cellular reactive oxygen species (ROS) show that ROS can mediate increased expression of perlecan (Pln), a key heparin sulfate proteoglycan (HSPG), and ?2-Microglobulin (?2-M) expression by PCa cells. There appears to be a tight signaling relationship among ?2-M, Pln, and ROS by which the expression of these signaling molecules is coordinated and regulated. PCa cells with mitochondrial DNA mutations produced increased levels of ROS, ?2-M and Pln. We investigated the clinical translation of these molecular biomarkers in primary and bone metastatic human PCa tissues. Results showed significant correlation of LIV-1 (p<0.001), a driver of epithelial to mesenchymal transition (EMT), cytoplasmic but not nuclear BDNF (p<0.001), ?2-M (p=0.006), focal adhesion kinase (FAK) (p=0.010), a target gene of ROS in human prostate cancer cells, and heparanase, a Pln degradative enzyme (p<0.001) with the progression of PCa from normal, benign, PIN, and localized cancer to bone metastasis. In the first Program Project funding period, we made remarkable progress with paradigm-shifting discoveries, collaborative publications, and successful mentoring of the next generation of prostate cancer researchers. The Projects successfully accomplished all of the proposed aims, reflected in 82 publications, 37 of which were considered to be high impact. In this competitive renewal, Project 1 focuses on characterization of ?2-M-mediated growth and signaling pathways in prostate cancer bone metastasis. Project 2 focuses on the characterization of multiple Pln domains known to interact with soluble growth factors in extracellular matrices to ultimately affect cancer growth and metastasis. Project 3 focuses on the characterization of ROS-mediated gene expression and signaling in prostate epithelial cells in response to bone stromal interaction. The Projects and Cores will continue to define the biology and targeting potential of tumor-stromal interaction, validate biomarkers in tissue and serum specimens and ultimately translate these discoveries into clinical practice.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S (O1))
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Mohla, Suresh
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Cedars-Sinai Medical Center
Los Angeles
United States
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Li, Xiangyan; Chen, Yi-Ting; Hu, Peizhen et al. (2014) Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP-regulated metabolic pathways and androgen receptor signaling. Mol Cancer Ther 13:855-66
Miles, Fayth L; Sikes, Robert A (2014) Insidious changes in stromal matrix fuel cancer progression. Mol Cancer Res 12:297-312
Warren, Curtis R; Grindel, Brian J; Francis, Lewis et al. (2014) Transcriptional activation by NF?B increases perlecan/HSPG2 expression in the desmoplastic prostate tumor microenvironment. J Cell Biochem 115:1322-33
Shao, Chen; Liao, Chun-Peng; Hu, Peizhen et al. (2014) Detection of live circulating tumor cells by a class of near-infrared heptamethine carbocyanine dyes in patients with localized and metastatic prostate cancer. PLoS One 9:e88967
Pradhan-Bhatt, Swati; Harrington, Daniel A; Duncan, Randall L et al. (2014) A novel in vivo model for evaluating functional restoration of a tissue-engineered salivary gland. Laryngoscope 124:456-61
Shi, Changhong; Wu, Jason Boyang; Chu, Gina C-Y et al. (2014) Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1?/OATPs signaling axis. Oncotarget 5:10114-26
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
Fong, Eliza L S; Martinez, Mariane; Yang, Jun et al. (2014) Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening. Mol Pharm 11:2040-50
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
Josson, Sajni; Gururajan, Murali; Hu, Peizhen et al. (2014) miR-409-3p/-5p promotes tumorigenesis, epithelial-to-mesenchymal transition, and bone metastasis of human prostate cancer. Clin Cancer Res 20:4636-46

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