Glucocorticoids Suppress Tumor Lymphangiogenesis of Prostate Cancer Cells

• Published in: Clinical cancer research Vol. 12; no. 20; pp. 6012 - 6017
• Main Authors: YANO, Akihiro, FUJII, Yasuhisa, IWAI, Aki, KAWAKAMI, Satoru, KAGEYAMA, Yukio, KIHARA, Kazunori
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2006
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Dexamethasone - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Genitourinary cancers: prostate; Glucocorticoids - pharmacology; Growth factors and receptors; Gynecology. Andrology. Obstetrics; Humans; Lymphatic Metastasis - prevention & control; Male; Male genital diseases; Medical sciences; Mice; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Prostatic Neoplasms - pathology; Reverse Transcriptase Polymerase Chain Reaction; Steroid hormones and receptors; Transplantation, Heterologous; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Vascular Endothelial Growth Factor C - genetics; Vascular Endothelial Growth Factor Receptor-3 - genetics; Prostate tumor; Urinary system disease; Prostate disease; Malignant tumor; Lymphangiogenesis; Male genital diseases; Glucocorticoid; Tumor cell
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0749

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. Similarly, hydrocortisone down-regulated VEGF-C gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even
under hypoxia-like conditions, dexamethasone inhibited VEGF-C gene expression. In DU145 xenografts, dexamethasone significantly down-regulated VEGF-C gene expression and decreased lymphangiogenesis. Dexamethasone did not affect VEGFR-3 gene expression in vitro and in vivo .
Conclusion: Glucocorticoids suppressed tumor-associated lymphangiogenesis by down-regulating VEGF-C through glucocorticoid receptor in
androgen-independent prostate cancer cells in vivo .