Show simple item record

dc.contributor.authorBavik, Claes
dc.contributor.authorColeman, Ilsa
dc.contributor.authorDean, James P.
dc.contributor.authorKnudsen, Beatrice
dc.contributor.authorPlymate, Steven
dc.contributor.authorNelson, Peter S.
dc.date.accessioned2009-05-22T08:55:21Z
dc.date.available2009-05-22T08:55:21Z
dc.date.issued2006-01-15
dc.identifier.citationCancer Res. 2006, 66 (2):794-802en
dc.identifier.issn0008-5472
dc.identifier.pmid16424011
dc.identifier.doi10.1158/0008-5472.CAN-05-1716
dc.identifier.urihttp://hdl.handle.net/10146/68774
dc.descriptionKEYWORDS - CLASSIFICATION: Biology;cytology;Cell Aging;Cell Proliferation;Cell Transformation,Neoplastic;Culture Media;Culture Media,Conditioned;DNA Damage;Epithelial Cells;Fibroblasts;Gene Expression Profiling;Humans;lifestyle modulation of cancer & cancer biomarkers;Male;mechanisms of carcinogenesis;Oxidative Stress;pathology;physiology;physiopathology;Prostate;Prostatic Neoplasms;Research;RNA,Small Interfering;Washington.en
dc.description.abstractThe greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.
dc.language.isoenen
dc.relation.urlhttp://cancerres.aacrjournals.org/cgi/content/full/66/2/794en
dc.subject.meshCell Aging
dc.subject.meshCell Proliferation
dc.subject.meshCell Transformation, Neoplastic
dc.subject.meshCulture Media, Conditioned
dc.subject.meshDNA Damage
dc.subject.meshEpithelial Cells
dc.subject.meshFibroblasts
dc.subject.meshGene Expression Profiling
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshOxidative Stress
dc.subject.meshProstate
dc.subject.meshProstatic Neoplasms
dc.subject.meshRNA, Small Interfering
dc.titleThe gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.en
dc.typeArticleen
dc.identifier.journalCancer researchen
html.description.abstractThe greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.


Files in this item

Thumbnail
Name:
CANCER RES794.pdf
Size:
1.140Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record