Recently it has become evident that although it is the prostate epithelial cell that is transformed into prostate? adenocarcinoma, the stromal components of the prostate strongly influence the transformation process and? ultimate fate of the transformed cell. This program will define the components of the human prostate stromal? microenvironment, the contribution of stromal and epithelial cells to this environment and effects of factors? associated with induction of prostate cancer e.g. age, oxidative stress, inflammation product, on the stromal? components, and mechanisms of action of selected components. Products arising from this program that will? be available to the research community will include but are not limited to: functional blocking human? monoclonal antibodies to matrix components, microarray and proteomic databases, preclinical models for? evaluation of stromal factors on human tissue. This program will consist of three projects that include:? 1. The Aged Microenvironment as a Contributor to Carcinogenesis :
Aim 1 : Identify molecular changes in the? major cellular and matrix constituents of stroma that occur in association with aging.
Aim 2 : Determine the? influence of specific age-associated stromal-derived paracrine factors toward tumor growth/ invasion/? differentiation.
Aim 3 : Determine if deficiencies in DMA repair mechanisms contribute to molecular aging in? the tumor microenvironment.
Aim 4. Evaluate hypothesis that aging/senescence of prostate stroma? increases characteristics of wound/stress response (co-Aim with Plymate Project).? 2. Paracrine and Juxtacrine Mediation of Prostate Cancer Progression :
Aim 1. Use of tissue recombination? to model cancer progression, Aim 2. Identification and characterization of mesenchymal regulators of? prostate development.
Aim 3. Juxtacrine signaling models involving tumor and senescent fibroblasts.? 3. Laminin Dysregulation in Prostate Cancer:
Aim1. Define the laminin chains and integrin subunits in normal? and malignant prostate tissue.
Aim 2. Determine function of laminin changes in prostate cancer.
Aim 3. ? Determine age-induced changes in laminin, signaling and transcription on proteolytic remodeling of ECM? with increased invasion of the mesenchyme.? The purpose of this proposal is to define the effects of the prostate environment on development and? progression of prostate cancer. Also we will determine how inhibition of these microenvironmental factors? can be used as potential therapy for prostate cancer prevention and progression. ? ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRRB-3 (O1))
Program Officer
Mohla, Suresh
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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
Long, Thomas J; Sprenger, Cynthia C; Plymate, Stephen R et al. (2014) Prostate cancer xenografts engineered from 3D precision-porous poly(2-hydroxyethyl methacrylate) hydrogels as models for tumorigenesis and dormancy escape. Biomaterials 35:8164-74
Long, Thomas J; Takeno, Marc; Sprenger, Cynthia C et al. (2013) Capillary force seeding of sphere-templated hydrogels for tissue-engineered prostate cancer xenografts. Tissue Eng Part C Methods 19:738-44
Bentov, Itay; Damodarasamy, Mamatha; Plymate, Stephen et al. (2013) B16/F10 tumors in aged 3D collagen in vitro simulate tumor growth and gene expression in aged mice in vivo. In Vitro Cell Dev Biol Anim 49:395-9
Zou, Ying; Zhang, Ningzhe; Ellerby, Lisa M et al. (2012) Responses of human embryonic stem cells and their differentiated progeny to ionizing radiation. Biochem Biophys Res Commun 426:100-5
Gordon, Ryan R; Nelson, Peter S (2012) Cellular senescence and cancer chemotherapy resistance. Drug Resist Updat 15:123-31
Sun, Yu; Nelson, Peter S (2012) Molecular pathways: involving microenvironment damage responses in cancer therapy resistance. Clin Cancer Res 18:4019-25
Sun, Yu; Campisi, Judith; Higano, Celestia et al. (2012) Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat Med 18:1359-68
Coppé, Jean-Philippe; Rodier, Francis; Patil, Christopher K et al. (2011) Tumor suppressor and aging biomarker p16(INK4a) induces cellular senescence without the associated inflammatory secretory phenotype. J Biol Chem 286:36396-403
Meng, Jing; Mostaghel, Elahe A; Vakar-Lopez, Funda et al. (2011) Testosterone regulates tight junction proteins and influences prostatic autoimmune responses. Horm Cancer 2:145-56

Showing the most recent 10 out of 27 publications