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REPORT DATE
02-02-2008
REPORT TYPE
5d. PROJECT NUMBER 5e. TASK NUMBEREmail: alice.levine@mssm.edu 5f. WORK UNIT NUMBER
PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERMount Sinai School of Medicine New York, NY 10029
SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)
U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012
SPONSOR/MONITOR'S REPORT NUMBER(S)
DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited
SUPPLEMENTARY NOTES
ABSTRACTWe hypothesized that (1) prostate cancer cells that express high levels of cyclooxygenase-2 (COX-2) and prostaglandin E2(PGE2) display enhanced bone targeting and (2) the level of expression of COX-2 and PGE2 in established bone metastases determines the overall bone response, with lower vs. higher levels inducing osteoblastic vs. osteolytic responses, respectively. We utilized two human prostate cancer cell lines (MDA-PCa-2B that expresses low levels of COX-2 and PGE2 and produces osteoblastic lesions vs. PC-3 that expresses high levels COX-2/PGE2 and induces osteolytic mets). We demonstrated that (1) low levels of PGE2 stimulate preosteoblast cell growth, differentiation and Wnt signaling (2) Forced overexpression of COX-2 in MDA-PCa-2b cells induces the Wnt antagonist DKK-1 (3) PGE2 addition to PC-3 cells stimulates Dkk-1 (4) Forced overexpression of COX-2 in MDA-PCa-2B cells inhibits preosteoblastic cell growth in co-culture and, finally, (5) Treatment with a COX-2 inhibitor reduced PC-3 metastatic lesons in vivo after intracardiac inoculation. Over the next several weeks we will analyze bone metastatic lesions to determine overall bone response in vivo from the PC-3 experiments and from tibia of mice inoculated with wild-type vs. COX-2 overexpressing MDA-PCa-2b cells. These studies confirmed our hypothesis that levels of COX-2/PGE2 expression in prostate cancer cells modulates both bone targeting and bone response.
SUBJECT TERMS
INTRODUCTIONThe overall purpose of these studies was to investigate our hypothesis that dose-dependent expressio...