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Ovarian cancer cells stimulate uPA gene expression in fibroblastic stromal cells via multiple paracrine and autocrine mechanisms.

Casslén, Vera LU ; Ahmadi, Sara LU ; Åsander Frostner, Eleonor LU and Casslén, Bertil LU (2009) In Gynecologic Oncology 115. p.121-126
Abstract
OBJECTIVES: Expression of uPA mRNA is massively up-regulated in the stroma of poorly differentiated ovarian tumors. We hypothesized that this expression was induced by paracrine signals from the epithelial tumor cells, and established an in vitro model of ovarian cancer microenvironment to study intercellular cross-talk. METHODS: ES-2 clear cell carcinoma cells were grown in tissue culture inserts in a double-chamber system with fibroblastic stromal LEP cells embedded in Matrigel. Binding-site directed antibodies were used to neutralize soluble cytokines in ES-2 conditioned medium (CM) before incubation with LEP cells. Real time PCR measured uPA mRNA in LEP cells, as well as mRNA for cytokines in both cell types. RESULTS: Co-culture with... (More)
OBJECTIVES: Expression of uPA mRNA is massively up-regulated in the stroma of poorly differentiated ovarian tumors. We hypothesized that this expression was induced by paracrine signals from the epithelial tumor cells, and established an in vitro model of ovarian cancer microenvironment to study intercellular cross-talk. METHODS: ES-2 clear cell carcinoma cells were grown in tissue culture inserts in a double-chamber system with fibroblastic stromal LEP cells embedded in Matrigel. Binding-site directed antibodies were used to neutralize soluble cytokines in ES-2 conditioned medium (CM) before incubation with LEP cells. Real time PCR measured uPA mRNA in LEP cells, as well as mRNA for cytokines in both cell types. RESULTS: Co-culture with ES-2 cells as well as incubation with ES-2 CM induced uPA mRNA in LEP cells about two-fold. In short time (12 h) incubation of LEP cells with CM, antibodies to EGF and bFGF reduced induction of uPA mRNA, suggesting that these cytokines function as paracrine signals. EGF mRNA and bFGF mRNA were also found in ES-2 cells. At longer incubation (24 h) antibodies to bFGF, HB-EGF, HGF, IGF-1, and IL-1alpha reduced uPA mRNA induction, suggesting an autocrine function for these cytokines in LEP cells. In fact, expression of the same five cytokines was up-regulated in LEP cells exposed to CM. CONCLUSION: We identified two cytokines as paracrine signals, and five cytokines as autocrine signals in ovarian cancer cell induced up-regulation of uPA mRNA in stromal fibroblastic cells. It is crucial to understand intra-tumoral cross-talk, since it can offer new therapeutic approaches. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Gynecologic Oncology
volume
115
pages
121 - 126
publisher
Academic Press
external identifiers
  • wos:000269965700023
  • pmid:19631971
  • scopus:69249215169
ISSN
1095-6859
DOI
10.1016/j.ygyno.2009.06.026
language
English
LU publication?
yes
id
ab66caca-8be0-4efe-a876-7c8719a18ff1 (old id 1452784)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19631971?dopt=Abstract
date added to LUP
2009-08-05 10:35:44
date last changed
2017-01-01 07:35:14
@article{ab66caca-8be0-4efe-a876-7c8719a18ff1,
  abstract     = {OBJECTIVES: Expression of uPA mRNA is massively up-regulated in the stroma of poorly differentiated ovarian tumors. We hypothesized that this expression was induced by paracrine signals from the epithelial tumor cells, and established an in vitro model of ovarian cancer microenvironment to study intercellular cross-talk. METHODS: ES-2 clear cell carcinoma cells were grown in tissue culture inserts in a double-chamber system with fibroblastic stromal LEP cells embedded in Matrigel. Binding-site directed antibodies were used to neutralize soluble cytokines in ES-2 conditioned medium (CM) before incubation with LEP cells. Real time PCR measured uPA mRNA in LEP cells, as well as mRNA for cytokines in both cell types. RESULTS: Co-culture with ES-2 cells as well as incubation with ES-2 CM induced uPA mRNA in LEP cells about two-fold. In short time (12 h) incubation of LEP cells with CM, antibodies to EGF and bFGF reduced induction of uPA mRNA, suggesting that these cytokines function as paracrine signals. EGF mRNA and bFGF mRNA were also found in ES-2 cells. At longer incubation (24 h) antibodies to bFGF, HB-EGF, HGF, IGF-1, and IL-1alpha reduced uPA mRNA induction, suggesting an autocrine function for these cytokines in LEP cells. In fact, expression of the same five cytokines was up-regulated in LEP cells exposed to CM. CONCLUSION: We identified two cytokines as paracrine signals, and five cytokines as autocrine signals in ovarian cancer cell induced up-regulation of uPA mRNA in stromal fibroblastic cells. It is crucial to understand intra-tumoral cross-talk, since it can offer new therapeutic approaches.},
  author       = {Casslén, Vera and Ahmadi, Sara and Åsander Frostner, Eleonor and Casslén, Bertil},
  issn         = {1095-6859},
  language     = {eng},
  pages        = {121--126},
  publisher    = {Academic Press},
  series       = {Gynecologic Oncology},
  title        = {Ovarian cancer cells stimulate uPA gene expression in fibroblastic stromal cells via multiple paracrine and autocrine mechanisms.},
  url          = {http://dx.doi.org/10.1016/j.ygyno.2009.06.026},
  volume       = {115},
  year         = {2009},
}