The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.

2.50
Hdl Handle:
http://hdl.handle.net/10146/68774
Title:
The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms.
Authors:
Bavik, Claes; Coleman, Ilsa; Dean, James P.; Knudsen, Beatrice; Plymate, Steven; Nelson, Peter S.
Abstract:
The 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.
Citation:
Cancer Res. 2006, 66 (2):794-802
Journal:
Cancer research
Issue Date:
15-Jan-2006
URI:
http://hdl.handle.net/10146/68774
DOI:
10.1158/0008-5472.CAN-05-1716
PubMed ID:
16424011
Additional Links:
http://cancerres.aacrjournals.org/cgi/content/full/66/2/794
Type:
Article
Language:
en
Description:
KEYWORDS - 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.
ISSN:
0008-5472
Appears in Collections:
Articles with annotation

Full metadata record

DC FieldValue Language
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.en
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

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