Expression of Vascular Endothelial Growth Factor Receptors in Human Prostate Cancer

Ferrer, Fernando; Miller, Lauri J.; Albertsen, Peter C.; Laudone, Vincent P.; Lindquist, R. K.; Kreutzer, Donald L.

doi:10.1097/00005392-199904010-00222

Cited by 43 publications

(59 citation statements)

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“…VEGF A is not only the most potent angiogenic factor, but is also thought to participate in the formation of fibroblastic stroma via a pronounced hyperpermeability effect on small blood vessels, leading to fibrin leakage with subsequent organization by granulation tissue which turns into fibroblastic connective tissue (72,73). Moreover, an autocrine function of VEGF on prostate cancer cell proliferation has been suggested by the demonstration of the high affinity receptors VEGFR-1 and VEGFR-2 on prostate cancer cells (74,75). VEGFR-1 has been found to be slightly expressed in PC-3 but not expressed in LNCaP and DU-145 cells (76).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…24) Several studies on the expression of VEGFR-1 in prostate tissues have been reported. [25][26][27][28] One immunohistochemical investigation showed that the VEGFR-1 was expressed in normal prostatic epithelium, while 56% of cancer samples were negative, including all those with a Gleason score of >8. 26) Huss et al conducted in situ analyses of prostate tissues from the transgenic adenocarcinoma of mouse prostate (TRAMP) model, and identified decreased expression of the VEGFR-1, but up-regulation of VEGFR-2 during progression, calling this a "progression switch."…”

Section: Discussionmentioning

confidence: 99%

Aberrant methylation of the vascular endothelial growth factor receptor‐1 gene in prostate cancer

et al. 2003

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Transcriptional silencing of cancer-related genes by DNA methylation is observed in various cancers. To identify genes controlled by methylation in prostate cancer, we used cDNA microarray analysis to investigate gene expression in prostate cancer cell lines LNCaP and DU145 treated with a methyltransferase inhibitor alone or together with a histone deacetylase inhibitor. We detected significant changes (3.4-5.7%) in gene expression in prostate cancer cell lines with the drug treatments. Among the affected genes, that for the vascular endothelial growth factor receptor 1 (VEGFR-1) was re-expressed in LNCaP and DU145 after the drug treatments. Bisulfite sequencing revealed the promoter and exon 1 of the VEGFR-1 to be hypermethylated in the cell lines. These results support the idea that methylation is associ- rostate cancer is not as commonly diagnosed in Japanese as in Caucasians or African-Americans, but the number of cases is increasing every year. Genetic alterations, such as point mutations, loss of heterozygosity, and homozygous deletions in many tumor suppressor genes, are associated with carcinogenesis.1) Many studies have provided evidence of such genetic alterations in prostate cancers.2) More recently, it has also been reported that inactivation of tumor suppressor genes by epigenetic promoter methylation plays an important role in carcinogenesis and tumor progression.3) DNA methylation, especially in CpG-rich 5′ regions, inhibits transcription by interfering with the initiation or by reducing the binding affinity of sequence-specific transcription factors. 4)In prostate cancer, inactivation by aberrant methylation has been reported for many genes, such as RARβ2, GSTP1, E-cadherin and RASSF1A. [5][6][7][8][9] Restriction landmark genomic scanning (RLGS), 9) methylated CpG island amplification (MCA)/ representational difference analysis (RDA), 10) methylation-sensitive (MS)/RDA, 11) and differential methylation hybridization (DMH) 12) have been employed to find genes whose expression is regulated by DNA methylation.To identify cancer-related genes controlled by epigenetic alteration in prostate cancer, we have performed screening by cDNA microarray analysis in prostate cancer cell lines treated with a methyltransferase or/and a histone deacetylase inhibitor. We detected significant re-expression of the vascular endothelial growth factor receptor 1 (VEGFR-1) gene in cells treated with drugs. VEGFR-1, also called Flt-1, is a tyrosine kinase receptor for VEGF which plays an important role in tumor angiogenesis and growth. 13,14) Several studies have pointed to altered expression and function of VEGF or its receptor (VEGFR-1, -2) in prostate cancer. In this study, we analyzed the methylation status of the 5′ region of VEGFR-1 in prostate cancer cell lines and primary prostate samples. Materials and MethodsCell lines and primary prostatic samples. Prostate cancer cell lines, LNCaP, DU145 and PC-3, were obtained from the American Type Tissue Culture Collection (Rockville, MD) and cultured in RPMI 1640 medium s...

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“…[13][14][15][16][17] Increasing evidence suggests, however, that certain cancer cells of different origin, including leukemic cells, also express VEGF receptors on their surface. [18][19][20][21][22][23] On the other hand, VEGF is secreted by virtually all cancer cells as a homodimeric glycoprotein which is able to bind VEGFR-1 and other components of the VEGF receptors family with high affinity. 14,24 The simultaneous presence of a receptor and the ability to secrete the ligand for it, suggests the possible presence of an autocrine loop important for the growth of cancer cells expressing these receptors.…”

Section: Figurementioning

confidence: 99%

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4

et al. 2003

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The mechanism by which aplidine, a marine natural product in early clinical development as an anticancer agent, induces cell growth inhibition and apoptosis has been investigated in the human leukemia cell line MOLT-4. This cell line is characterized not only by the ability to secrete VEGF, but also for the presence on its surface of the VEGF receptor-1 (VEGFR-1). Previous studies from our laboratory concerned with evaluating early changes in gene expression induced by aplidine in MOLT-4 cells have shown that the drug decreases the expression of VEGFR-1 (Marchini et al. Proc Am Assoc Cancer Res 2000; 41: 833). Here, we report the ability of aplidine to block the VEGF/VEGFR-1 loop. We found that aplidine blocked VEGF secretion that was temporally followed by a decrease in both VEGF and VEGFR-1 production. Aplidine did not directly affect either VEGF transcription or stabilization of its mRNA. Transfection of MOLT-4 cells with an antisense VEGF cDNA construct, resulted in inhibition of colony formations. One clone, transfected with sense VEGF cDNA, secreting 8-10 times more VEGF than parental cells, was less sensitive to aplidineinduced cytotoxicity and apoptosis than control cells. Moreover, addition of VEGF in the medium decreased the activity of aplidine in MOLT-4 cells. These data demonstrate that aplidine inhibits the growth and induces apoptosis in MOLT-4 cells through the inhibition of VEGF secretion which blocks the VEGF/VEGFR-1 autocrine loop necessary for the growth of these cells.

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Expression of Vascular Endothelial Growth Factor Receptors in Human Prostate Cancer

Cited by 43 publications

References 0 publications

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

Tumour-stroma interactions between metastatic prostate cancer cells and fibroblasts

Aberrant methylation of the vascular endothelial growth factor receptor‐1 gene in prostate cancer

Aplidine, a new anticancer agent of marine origin, inhibits vascular endothelial growth factor (VEGF) secretion and blocks VEGF-VEGFR-1 (flt-1) autocrine loop in human leukemia cells MOLT-4

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