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REPORT DATE
PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBERFred Hutchinson Cancer Research Center Seattle, WA 98109
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
ABSTRACTThe greatest factor for the development of prostate adenocarcinoma is advanced age. Emerging evidence suggests that molecular alterations in the aged prostate microenvironment mediated by stromal aging and senescence are key factors regulating carcinogenesis and neoplastic progression. We used normal mouse prostate epithelial and adjacent stromal cells from young and old animals, microdissected in situ, to identify factors altered by the aged stroma that may place the prostate gland at risk for developing prostate cancer. Expression profiling demonstrated clear differences in gene expression between old and young prostate stroma, with 219 genes exhibiting significant transcript abundance levels (p<0.005). Transcripts for Type I and III collagen were among the genes most substantially altered with aging. qRT-PCR confirmed the lower expression of Col1a2 and Col3a1 in the aged prostate stroma and immunofluorescence detection for Type-I collagen revealed a disorganized collagen matrix in the aged prostate. The alterations in the collagen network affect the structural and signaling properties of the extracellular matrix and in turn could plausibly facilitate carcinogenesis and neoplastic progression. The aged-expression profiling also demonstrated the up-regulation of several chemokines (Ccl8, Ccl7), and factors that respond to pro-inflammatory agonist and senescent inducers, such as ApoD in the aged stroma. In summary, the transcriptional profile of the aged prostate microenvironment provides novel data regarding senescence-associated candidate genes important in prostate carcinogenesis. Further studies are necessary in order to provide a functiona...