CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro.
The direct relationship between the aging process and the incidence and prevalence of both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) implies that certain risk factors associated with the development of both diseases increase with the aging process. In particular, both diseases share an overly proliferative phenotype, suggesting that mechanisms that normally act to suppress cellular proliferation are disrupted or rendered dysfunctional as a consequence of the aging process. We propose that one such mechanism involves changes in the prostate microenvironment, which 'evolves' during the aging process and disrupts paracrine interactions between epithelial and associated stromal fibroblasts. We show that stromal fibroblasts isolated from the prostates of men 63-81 years of age at the time of surgery express and secrete higher levels of the CXCL12 chemokine compared with those isolated from younger men, and stimulate CXCR4-mediated signaling pathways that induce cellular proliferation. These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.
Begley
Lesa
L
Department of Urology, The University of Michigan, Ann Arbor, 48109, USA.
Monteleon
Christine
C
Shah
Rajal B
RB
Macdonald
James W
JW
Macoska
Jill A
JA
D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation; D016922:Cellular Senescence; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011467:Prostate / Q000166:cytology*; D011470:Prostatic Hyperplasia / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D016328:NF-kappa B; D019718:Receptors, CXCR4; D048052:Mitogen-Activated Protein Kinase 3