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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA098912-09
Application #
8305770
Study Section
Special Emphasis Panel (ZCA1-GRB-S (O1))
Program Officer
Mohla, Suresh
Project Start
2002-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
9
Fiscal Year
2012
Total Cost
$1,549,929
Indirect Cost
$254,354
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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Torres, Mylin A; Yang, Xiaofeng; Noreen, Samantha et al. (2016) The Impact of Axillary Lymph Node Surgery on Breast Skin Thickening During and After Radiation Therapy for Breast Cancer. Int J Radiat Oncol Biol Phys 95:590-6
Farach, Andrew; Ding, Yi; Lee, MinJae et al. (2016) Neuronal Trans-Differentiation in Prostate Cancer Cells. Prostate 76:1312-25
Masko, Elizabeth M; Alfaqih, Mahmoud A; Solomon, Keith R et al. (2016) Evidence for Feedback Regulation Following Cholesterol Lowering Therapy in a Prostate Cancer Xenograft Model. Prostate :
Li, Qinlong; Yin, Lijuan; Jones, Lawrence W et al. (2016) Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells. Oncotarget :
Miyahira, Andrea K; Lang, Joshua M; Den, Robert B et al. (2016) Multidisciplinary intervention of early, lethal metastatic prostate cancer: Report from the 2015 Coffey-Holden Prostate Cancer Academy Meeting. Prostate 76:125-39
Grigore, Alexandru Dan; Jolly, Mohit Kumar; Jia, Dongya et al. (2016) Tumor Budding: The Name is EMT. Partial EMT. J Clin Med 5:
Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72
Liu, Sandy; Cadaneanu, Radu M; Zhang, Baohui et al. (2016) Keratin 13 Is Enriched in Prostate Tubule-Initiating Cells and May Identify Primary Prostate Tumors that Metastasize to the Bone. PLoS One 11:e0163232
You, Sungyong; Knudsen, Beatrice S; Erho, Nicholas et al. (2016) Integrated Classification of Prostate Cancer Reveals a Novel Luminal Subtype with Poor Outcome. Cancer Res 76:4948-58

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