PMID- 16424011
OWN - NLM
STAT- MEDLINE
DCOM- 20060214
LR  - 20220227
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 66
IP  - 2
DP  - 2006 Jan 15
TI  - The gene expression program of prostate fibroblast senescence modulates 
      neoplastic epithelial cell proliferation through paracrine mechanisms.
PG  - 794-802
AB  - 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.
FAU - Bavik, Claes
AU  - Bavik C
AD  - Division of Human Biology, Fred Hutchinson Cancer Research Center, University of 
      Washington, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
FAU - Coleman, Ilsa
AU  - Coleman I
FAU - Dean, James P
AU  - Dean JP
FAU - Knudsen, Beatrice
AU  - Knudsen B
FAU - Plymate, Steven
AU  - Plymate S
FAU - Nelson, Peter S
AU  - Nelson PS
LA  - eng
GR  - CA 015704/CA/NCI NIH HHS/United States
GR  - CA 85859/CA/NCI NIH HHS/United States
GR  - CA 97186/CA/NCI NIH HHS/United States
GR  - DK 65204/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Culture Media, Conditioned)
RN  - 0 (RNA, Small Interfering)
SB  - IM
MH  - Cell Proliferation
MH  - Cell Transformation, Neoplastic
MH  - Cellular Senescence/*physiology
MH  - Culture Media, Conditioned
MH  - DNA Damage
MH  - Epithelial Cells/physiology
MH  - Fibroblasts/*physiology
MH  - *Gene Expression Profiling
MH  - Humans
MH  - Male
MH  - Oxidative Stress
MH  - Prostate/*cytology/physiology
MH  - Prostatic Neoplasms/pathology/*physiopathology
MH  - RNA, Small Interfering
EDAT- 2006/01/21 09:00
MHDA- 2006/02/16 09:00
CRDT- 2006/01/21 09:00
PHST- 2006/01/21 09:00 [pubmed]
PHST- 2006/02/16 09:00 [medline]
PHST- 2006/01/21 09:00 [entrez]
AID - 66/2/794 [pii]
AID - 10.1158/0008-5472.CAN-05-1716 [doi]
PST - ppublish
SO  - Cancer Res. 2006 Jan 15;66(2):794-802. doi: 10.1158/0008-5472.CAN-05-1716.