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SUPPLEMENTARY NOTES14. ABSTRACT The 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 microdissected in situ from young and old animals, 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 63 genes exhibiting significant transcript abundance levels given a moderate estimate of false positive differences of 10%. Genes associated with inflammation, oxidative stress, and structural proteins were among the genes most substantially altered with aging. Factors identified in this study, such as ApoD and Ccl8, were selectively expressed and up-regulated only in the aged prostate stroma and not in the prostatic epithelium or inflammatory cells. The aged prostate microenvironment was characterized by a pro-inflammatory gene expression profile and the presence of high numbers of inflammatory cells. Additionally, structural alterations were observed in the aged prostate. Fluorescence and ultrastructural microscopic analysis revealed a collagen matrix network significantly disrupted in the aged prostate. It is plausible that both the alteration in the collagenous stroma and the infiltration of inflammatory cells are likely to be acting in concert with one another to produce fundamental changes in both the prostate epithelial and stromal cells that can lead to prostate tumorigenesis and/or progression. We propose that these changes contribute in a coordinated way to induce and/or sustain prostate tumorigenesis-on one hand by altering the extracellular matrix and, on the other, signaling through the NK-kB pathway for immune infiltration. Taken together, these observations may aid in a better understanding of the causative role of aging in human prostate cancer development and progression
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