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Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

Elo, Teresa D.; Valve, Eeva M.; Seppanen, Jani A.; Vuorikoski, Heikki J.; Makela, Sari I.; Poutanen, Matti; Kujala, Paula M. and Härkönen, Pirkko LU (2010) In Neoplasia 12(11). p.94-915
Abstract
Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelial morphology progressing from atypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation... (More)
Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelial morphology progressing from atypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neoplasia
volume
12
issue
11
pages
94 - 915
publisher
Neoplasia Press
external identifiers
  • wos:000285208900007
  • scopus:78449263437
ISSN
1522-8002
DOI
10.1593/neo.10776
language
English
LU publication?
yes
id
610513b4-be83-406f-a464-72cacd4ca4ff (old id 1772443)
alternative location
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2978914
date added to LUP
2011-02-02 14:57:44
date last changed
2018-07-15 03:08:59
@article{610513b4-be83-406f-a464-72cacd4ca4ff,
  abstract     = {Expression of fibroblast growth factor 8 (FGF-8) is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG) mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelial morphology progressing from atypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN) lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.},
  author       = {Elo, Teresa D. and Valve, Eeva M. and Seppanen, Jani A. and Vuorikoski, Heikki J. and Makela, Sari I. and Poutanen, Matti and Kujala, Paula M. and Härkönen, Pirkko},
  issn         = {1522-8002},
  language     = {eng},
  number       = {11},
  pages        = {94--915},
  publisher    = {Neoplasia Press},
  series       = {Neoplasia},
  title        = {Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice},
  url          = {http://dx.doi.org/10.1593/neo.10776},
  volume       = {12},
  year         = {2010},
}