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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Rohena-Rivera, Krizia; Bhowmick, Neil A (2018) Notch inhibitor screening reveals an unexpected HES1 heterodimer. J Biol Chem 293:8295-8296
Tighiouart, Mourad; Cook-Wiens, Galen; Rogatko, André (2018) A Bayesian adaptive design for cancer phase I trials using a flexible range of doses. J Biopharm Stat 28:562-574
Madhav, Anisha; Andres, Allen; Duong, Frank et al. (2018) Antagonizing CD105 enhances radiation sensitivity in prostate cancer. Oncogene 37:4385-4397
Jan, Yu Jen; Chen, Jie-Fu; Zhu, Yazhen et al. (2018) NanoVelcro rare-cell assays for detection and characterization of circulating tumor cells. Adv Drug Deliv Rev 125:78-93
Grindel, Brian J; Martinez, Jerahme R; Tellman, Tristen V et al. (2018) Matrilysin/MMP-7 Cleavage of Perlecan/HSPG2 Complexed with Semaphorin 3A Supports FAK-Mediated Stromal Invasion by Prostate Cancer Cells. Sci Rep 8:7262
Jimenez, Jose L; Tighiouart, Mourad; Gasparini, Mauro (2018) Cancer phase I trial design using drug combinations when a fraction of dose limiting toxicities is attributable to one or more agents. Biom J :
Martinez, Jerahme R; Grindel, Brian J; Hubka, Kelsea M et al. (2018) Perlecan/HSPG2: Signaling role of domain IV in chondrocyte clustering with implications for Schwartz-Jampel Syndrome. J Cell Biochem :
Farach-Carson, Mary C; Lin, Sue-Hwa; Nalty, Theresa et al. (2017) Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow? Front Oncol 7:163
Stewart, Paul A; Khamis, Zahraa I; Zhau, Haiyen E et al. (2017) Upregulation of minichromosome maintenance complex component 3 during epithelial-to-mesenchymal transition in human prostate cancer. Oncotarget 8:39209-39217
Nandana, Srinivas; Tripathi, Manisha; Duan, Peng et al. (2017) Bone Metastasis of Prostate Cancer Can Be Therapeutically Targeted at the TBX2-WNT Signaling Axis. Cancer Res 77:1331-1344

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