It is proposed to characterize an invasive androgen-repressed and flutamide-stimulated phenotype in an ARCaP model of human prostate cancer metastasis. The PI hypothesizes that androgen repression is a central pathway for prostate cancer progression, and its acquisition is often accompanied by the development of androgenindependent, invasive and lethal disease. The metastatic profile of ARCaP cells in athymic mice resembles that of men who die of this disease. ARCaP's unique profile of metastasis and its ability to produce marked osteoblastic reactions provide an opportunity to define the biology and molecular mechanism associated with androgen repression and invasiveness in this tumor model. It is proposed that an imbalance of androgen receptor (AR) and its co-factors may be the molecular basis of aberrant androgen regulation of prostate cancer cell growth and gene expression. Such interaction may impact on the interaction between prostate cancer cells and bone stromal cells and/or bone matrix proteins, which could contribute to tumor invasion, metastasis and osteoblastic reaction. The following specific aims will be studied:
Specific Aim 1 : To characterize the molecular mechanism of AR regulation in growth, gene expression, and metastasis of ARCaP cells and tumors. We propose to identify, clone, and characterize genes encoding cofactors that may interact with AR. The effects of varying levels of AR and its co-factors on growth, gene expression, and the attachment, migration, and invasion of ARCaP cells in vitro and tumor metastasis in vivo will be evaluated.
Specific Aim 2 : To characterize the interaction between ARCaP cells and the bone matrix proteins osteopontin and vitronectin, based on an in vitro cell coculture model and an in vivo animal model. The roles of AR and its co-factors in mediating androgen and flutamide effects on cell attachment, migration, and invasion onto bone matrix proteins will be evaluated in vitro. The efficacy of drugs and antibodies that may block AMP cell interaction with bone matrix proteins and bone stromal cells will be tested both in vitro and in vivo with biomarker assessment. The ARCaP model may allow definition of the molecular basis of prostate cancer progression to androgen independence and expression of invasive and bone-homing phenotypes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082739-05
Application #
6796320
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Mohla, Suresh
Project Start
2000-09-30
Project End
2006-08-31
Budget Start
2004-09-03
Budget End
2006-08-31
Support Year
5
Fiscal Year
2004
Total Cost
$273,600
Indirect Cost
Name
Emory University
Department
Urology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Thalmann, George N; Rhee, Hong; Sikes, Robert A et al. (2010) Human prostate fibroblasts induce growth and confer castration resistance and metastatic potential in LNCaP Cells. Eur Urol 58:162-71
Zhau, Haiyen E; Odero-Marah, Valerie; Lue, Hui-Wen et al. (2008) Epithelial to mesenchymal transition (EMT) in human prostate cancer: lessons learned from ARCaP model. Clin Exp Metastasis 25:601-10
Odero-Marah, Valerie A; Wang, Ruoxiang; Chu, Gina et al. (2008) Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. Cell Res 18:858-70
Wang, Ruoxiang; Xu, Jianchun; Mabjeesh, Nicola et al. (2007) PrLZ is expressed in normal prostate development and in human prostate cancer progression. Clin Cancer Res 13:6040-8
Sung, Shian-Ying; Kubo, Hiroyuki; Shigemura, Katsumi et al. (2006) Oxidative stress induces ADAM9 protein expression in human prostate cancer cells. Cancer Res 66:9519-26
Xu, Jianchun; Wang, Ruoxiang; Xie, Zhi Hui et al. (2006) Prostate cancer metastasis: role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis. Prostate 66:1664-73
Savore, Cristiana; Zhang, Chu; Muir, Caroline et al. (2005) Perlecan knockdown in metastatic prostate cancer cells reduces heparin-binding growth factor responses in vitro and tumor growth in vivo. Clin Exp Metastasis 22:377-90
Wang, Ruoxiang; Xu, Jianchun; Juliette, Lisa et al. (2005) Three-dimensional co-culture models to study prostate cancer growth, progression, and metastasis to bone. Semin Cancer Biol 15:353-64
Wang, Ruoxiang; Xu, Jianchun; Saramaki, Outi et al. (2004) PrLZ, a novel prostate-specific and androgen-responsive gene of the TPD52 family, amplified in chromosome 8q21.1 and overexpressed in human prostate cancer. Cancer Res 64:1589-94
Cinar, Bekir; Yeung, Fan; Konaka, Hiroyuki et al. (2004) Identification of a negative regulatory cis-element in the enhancer core region of the prostate-specific antigen promoter: implications for intersection of androgen receptor and nuclear factor-kappaB signalling in prostate cancer cells. Biochem J 379:421-31

Showing the most recent 10 out of 14 publications