Down-regulation of vascular endothelial growth factor in renal cell carcinoma cells by glucocorticoids

Iwai, Aki; Fujii, Yasuhisa; Kawakami, Satoru; Takazawa, Ryoji; Kageyama, Yukio; Yoshida, Mitsuaki A.; Kihara, Kazunori

doi:10.1016/j.mce.2004.07.013

Cited by 45 publications

(41 citation statements)

References 24 publications

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“…Our group recently showed that glucocorticoids suppress VEGF gene expression and protein production in renal cell carcinoma cells in vitro (22). In the present study, we now postulate that the therapeutic effects of glucocorticoids on HRPC can be attributed to the direct inhibition of angiogenesis through glucocorticoid receptors by down-regulating two major angiogenic factors, VEGF and IL-8, in vitro and in vivo.…”

supporting

confidence: 52%

Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

Yano

Fujii

Iwai

et al. 2006

Clinical Cancer Research

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131

105

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Purpose: Glucocorticoids, such as prednisone, hydrocortisone, and dexamethasone, are known to produce some clinical benefit for patients with hormone-refractory prostate cancer (HRPC). However, the underlying mechanisms by which glucocorticoids affect HRPC growth are not well established as yet. Here, we hypothesize that the therapeutic effect of glucocorticoids on HRPC can be attributed to a direct inhibition of angiogenesis through the glucocorticoid receptor by down-regulating two major angiogenic factors, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8).Experimental Design: The effects of dexamethasone on VEGF and IL-8 expression and cell proliferation were examined using DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on DU145 xenografts were determined by analyzing VEGF and IL-8 gene expression, microvessel density, and tumor volume. Results: Dexamethasone significantly down-regulated VEGF and IL-8 gene expression by 50% (P < 0.001) and 89% (P < 0.001), respectively, and decreased VEGF and IL-8 protein production by 55% (P < 0.001) and 74% (P < 0.001), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF and IL-8 gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF and IL-8 expression. In DU145 xenografts, dexamethasone significantly decreased tumor volume and microvessel density and downregulated VEGF and IL-8 gene expression, whereas dexamethasone did not affect the in vitro proliferation of the cells. Conclusion: Glucocorticoids suppressed androgen-independent prostate cancer growth possibly due to the inhibition of tumor-associated angiogenesis by decreasingVEGF and IL-8 production directly through glucocorticoid receptor in vivo.

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supporting

confidence: 52%

Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

Yano

Fujii

Iwai

et al. 2006

Clinical Cancer Research

Self Cite

131

105

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“…In RCC, high GR expression is a positive prognostic marker. Initial studies, conducted in the early 1980s, and that discovered the presence of GRs in kidney tumors, were based on ligand-binding assays (59,60). GRs were found to be overexpressed in 66% of ccRCC cases, 26% of pRCC cases, 14% of oncocytomas and 6% of chRCC cases.…”

Section: Glucocorticoid Receptors (Gr)mentioning

confidence: 99%

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

Czarnecka

Niedzwiedzka

Porta

et al. 2016

International Journal of Oncology

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Abstract. Epidemiological, clinical, biochemical and genetic research has revealed that renal cell cancer (RCC) etiology is hormone-related. It was shown that hormone receptors are abnormally expressed in RCC cells. Abnormal endocrine stimulation also plays a significant role in RCC pathophysiology. Cellular proliferation, migration, angiogenesis, and drug resistance in RCC is modulated by para-and autocrine hormonal stimulation. In particular, RCC overexpression of gonadotropin-releasing hormone and its receptor was reported. On the contrary, corticotropin releasing hormone was reported to inhibit RCC cell proliferation and regulate angiogenesis. Overexpression of luteinizing hormone also promotes RCC tumor angiogenesis. Estrogen receptor α overexpression increases the transcriptional factor activity of hypoxia inducible factor HIF-1α, but estrogen receptor β has a cancer suppressive role. Glucocorticoid receptors and androgen receptor are markers of indolent RCC and assigned tumor suppressive activity. Proopiomelanocortin is upregulated in VHL-mutated renal cell carcinoma via Nur77 transcription factor signaling. In RCC, follicle-stimulating hormone receptor promotes angiogenesis and metastatic formation via VEGF release. Mineralocorticoid receptor overexpression promotes cell survival and increases RCC cell proliferation. Vitamin D receptor expression is downregulated or absent in RCC and differentiate subtypes of renal cell tumors. RAR-β promotes tumorigenesis but retinoic acid receptor γ expression correlates negatively with the TNM stage at diagnosis. Finally, progesterone receptor expression is negatively correlated with the cancer stage. Molecular data analysis revealed the possibility of renal cancer cell proliferation induction via hormone activated pathways. Inhibition of hormonal signaling may thus play a putative role in supportive therapies against this cancer type.

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“…To date, the effects of glucocorticoids have been proposed to be due to the inhibitory effects on adrenal androgen production (8,9) and cell proliferation of androgen-independent prostate cancer cells (10). More recently, our group showed that dexamethasone, a synthetic glucocorticoid, suppresses androgen-independent prostate cancer growth in vivo, possibly due to the inhibition of tumor-associated angiogenesis by decreasing vascular endothelial growth factor (VEGF) and interleukin-8 productions directly through glucocorticoid receptor (11), and that in renal cell carcinoma cell lines, dexamethasone suppresses VEGF expression in vitro (12).…”

mentioning

confidence: 99%

Glucocorticoids Suppress Tumor Lymphangiogenesis of Prostate Cancer Cells

Yano

Fujii

Iwai

et al. 2006

Clinical Cancer Research

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Purpose: Glucocorticoids such as prednisone, hydrocortisone, and dexamethasone are known to provide some clinical benefit for patients with hormone-refractory prostate cancer. However, the underlying mechanisms by which glucocorticoids affect hormone-refractory prostate cancer progression are not well established as yet. Our previous study has shown that glucocorticoids inhibit tumor angiogenesis possibly by down-regulation of vascular endothelial growth factor (VEGF) and interleukin 8. Here, we hypothesized that the therapeutic effect of dexamethasone on hormone-refractory prostate cancer can be partly attributed to a direct inhibition of lymphangiogenesis through the glucocorticoid receptor by down-regulating a major lymphangiogenic factor,VEGF-C. Experimental Design: The effects of dexamethasone on the expression of VEGF-C and its receptor, VEGF receptor-3 (VEGFR-3), were examined using an androgen-independent human prostate cancer cell line, DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on tumor-associated lymphangiogenesis in DU145 xenografts were determined by analyzing VEGF-C gene expression, lymphatic vessel density, and relative lymphatic vessel area. Results: Dexamethasone significantly down-regulated VEGF-C gene expression and protein production by 48% (P = 0.003) and 44% (P = 0.002), respectively, under normoxic condition.

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Down-regulation of vascular endothelial growth factor in renal cell carcinoma cells by glucocorticoids

Cited by 45 publications

References 24 publications

Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

Glucocorticoids Suppress Tumor Angiogenesis and In vivo Growth of Prostate Cancer Cells

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

Glucocorticoids Suppress Tumor Lymphangiogenesis of Prostate Cancer Cells

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