Stromal inhibition of epithelial cell growth in the prostate; overview of an experimental study

Kooistra, A.; Romijn, J. A.; Schröder, Fritz H.

doi:10.1007/bf00941995

Cited by 19 publications

(14 citation statements)

References 52 publications

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“…The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay was used to assess cell proliferation (Kooistra et al, 1997;Maeshima et al, 2002). Following a 48-h exposure to various inhibitors or diluents, MTT was added (final concentration, 0.5 mg/ml) to individual cultures for an additional 30 min.…”

Section: Methodsmentioning

confidence: 99%

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Zhuang

Schnellmann

2005

J Pharmacol Exp Ther

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Primary cultures of renal proximal tubules are known to recapitulate several early events in the process of renal regeneration following injury. In this study, we show that suramin, a polysulfonated naphthylurea, stimulates outgrowth, scattering, and proliferation of primary cultures of renal proximal tubule cells (RPTC). These responses were comparable to those produced by epidermal growth factor (EGF). However, AG-1478 [4-(3Ј-chloroanilino)-6,7-dimethoxy-quinazoline], a specific inhibitor of the EGF receptor, blocked EGF but not suramin-induced RPTC outgrowth, scattering, and proliferation. Suramin stimulated phosphorylation of Akt, a downstream kinase of phosphoinositide 3-kinase (PI3K), extracellular signaling-regulated kinase 1/2 (ERK1/2), and Src, but not the EGF receptor. Blockade of Src, but not the EGF receptor, inhibited Akt and ERK1/2 phosphorylation. Furthermore, inactivation of PI3K with LY294002 [2-(4morpholinyl)-8-phenyl-4H-1-benzopyran-4-one] blocked suramin-induced RPTC outgrowth, scattering, and proliferation, whereas blockade of ERK1/2 had no effect. These data identify novel effects of suramin in RPTC outgrowth, scattering, and proliferation. Furthermore, suramininduced outgrowth, scattering, and proliferation of RPTC are through Src-mediated activation of the PI3K pathway but not ERK1/2 or the EGF receptor.

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Section: Methodsmentioning

confidence: 99%

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Zhuang

Schnellmann

2005

J Pharmacol Exp Ther

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“…27,37). Prostate fibroblasts can influence prostate carcinoma cell growth by modifying proliferation or apoptosis via paracrine mechanisms (38)(39)(40)(41). Using SELDI-TOF mass spectrometry we found a number of differences in gene expression at the proteome level not only between normal and neoplastic epithelial cells but also between normal and peritumoural stromal cells (42).…”

Section: Introductionmentioning

confidence: 99%

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

Kaminski

Hahne²,

Haddouti³

et al. 2006

Int J Mol Med

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Abstract.Previous work has shown the importance of tumourstroma interactions for prostate cancer development at the primary site. The aim of the present study was to find out whether evidence can be found for a tumour-stroma crosstalk also between metastatic prostate cancer cell lines and non-prostatic stromal fibroblasts which are encountered by metastatic cells at most sites. We addressed this issue in cell culture systems using 3 metastatic human prostate cancer cell lines (LnCaP, PC-3 and DU-145) on the one hand, and a human fibroblast line (HFF, human foreskin fibroblasts) on the other. We incubated fibroblasts with tumour cell-and tumour cells with fibroblast-conditioned media and evaluated several parameters important for the establishment of metastases such as cell proliferation, migration and expression of matrix degrading proteases. We also determined in the conditioned media the concentrations of several growth factors and cytokines which might be responsible for the observed effects. We found that media conditioned by all 3 metastatic prostate cancer cell lines stimulated fibroblast proliferation which corresponds to fibrous stroma induction in vivo. DU-145 cell conditioned media induced in fibroblasts expression of mmp-1 mRNA known to be important for tumour invasion. ELISA assays revealed that tumour cells secrete bFGF, PDGF and TNF· known to stimulate fibroblast proliferation and/or MMP-1 expression. Cultivation of DU-145 carcinoma cells in fibroblast conditioned medium resulted in an enhanced proliferation and anchorage-independent growth of this cell line in soft agar. Fibroblast conditioned medium also increased migration of PC-3 cells in the wound assay and slightly augmented mmp-1 expression. KGF (able to stimulate proliferation of normal and neoplastic prostate epithelial cells) was secreted by fibroblasts at higher concentrations than by all 3 tumour cell lines. In addition, fibroblasts secreted TNF·, bFGF, PDGF, HGF and also VEGF, the most important factor for tumour vascularization. Our results provide evidence that tumour-stroma interactions do not only exist at the primary site but also between metastatic prostate cancer cell lines and their fibroblastic microenvironment. These interactions, which are mediated through secreted factors, affect several steps of the metastatic cascade including proliferation, anchorage-independent growth, migration and the secretion of matrix-degrading proteases.

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“…The role of stromal cells play in PCa is controversial (15). Androgen, acting through AR, promotes proliferation in PCa epithelial cells; however, its effects on prostate stromal cells are less understood.…”

Section: Resultsmentioning

confidence: 99%

Regulation of a Novel Androgen Receptor Target Gene, the Cyclin B1 Gene, through Androgen-Dependent E2F Family Member Switching

Zhang

Ren³

et al. 2012

Molecular and Cellular Biology

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The malignant transformation of human prostatic epithelium is associated with the loss of androgen receptor (AR) in the surrounding stroma. However, the function and mechanisms of AR signaling in prostate cancer (PCa) stroma remain elusive. Here we report, by using proteomics pathway array analysis (PPAA), that androgen and its receptor inhibit the proliferation of prostate stromal cells through transcriptional suppression of cyclin B1, and we confirmed our findings at mRNA and protein levels using AR-negative or -positive primary prostate stromal cells. Furthermore, AR showed a negative correlation with cyclin B1 expression in stroma of human PCa samples in vivo. Mechanistically, we identify cyclin B1 as a bona fide AR target gene in prostate stromal cells. The negative regulation of cyclin B1 by AR is mediated through switching between E2F1 and E2F4 on the promoter of cyclin B1. E2F1 binds to the cyclin B1 promoter and maintains its expression and subsequent cell cycle progression in AR-negative stromal cells or AR-positive stromal cells when androgens are depleted. Upon stimulation with androgen in ARpositive stromal cells, E2F1 is displaced from the binding site by AR and replaced with E2F4, leading to the recruitment of the silencing mediator for retinoid and thyroid hormone receptor (SMRT)/histone deacetylase 3 (HDAC3) corepressor complex and repression of cyclin B1 at the chromatin level. The switch between E2F1 and E2F4 at the E2F binding site of the cyclin B1 promoter coincides with an androgen-dependent interaction between AR and E2F1 as well as the cytoplasmic-to-nuclear translocation of E2F4. Thus, we identified a novel mechanism for E2F factors in the regulation of cell cycle gene expression and cell cycle progression under the control of AR signaling. E 2F transcription factors control the expression of key components of the DNA replication machinery as well as the G 1 /S and G 2 /M cell cycle transitions (34,42). Eight members of the E2F family have been characterized (28). E2F1 to E2F6 form heterodimers with either DP-1 or DP-2 protein (3) to bind DNA and activate or repress gene expression. The retinoblastoma (pRB) tumor suppressor and the related p107 and p130 proteins (termed pocket proteins) bind to particular E2Fs in vivo and recruit corepressor complexes that contain histone deacetylases (HDACs), mediating the active repression of E2F-responsive genes (1, 34).E2F proteins are divided into two subcategories with opposing functions in transcriptional activation in vivo. E2F1, E2F2, and E2F3 (termed activator E2Fs) play a key role in promoting the activation of E2F-responsive genes, cell cycle entry, and cell growth. The conditional ablation of E2F3 in mice lacking E2F1 and E2F2 results in mouse embryonic fibroblasts (MEFs) that are unable to proliferate (38). MEFs lacking E2F3 alone display a slow-growth phenotype (11). On the other hand, E2F4 to E2F8 appear to be involved primarily in the transcriptional repression of E2F-responsive genes. The activator E2Fs contain nuclear localization sign...

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Stromal inhibition of epithelial cell growth in the prostate; overview of an experimental study

Cited by 19 publications

References 52 publications

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Suramin Promotes Proliferation and Scattering of Renal Epithelial Cells

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

Regulation of a Novel Androgen Receptor Target Gene, the Cyclin B1 Gene, through Androgen-Dependent E2F Family Member Switching

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