Neutralizing VEGF bioactivity with a soluble chimeric VEGF‐receptor protein flt(1‐3)IgG inhibits testosterone‐stimulated prostate growth in castrated mice

Lissbrant, Ingela Franck; Hammarsten, Peter; Lissbrant, Erik; Ferrara, Napoleone; Rudolfsson, Stina Häggström; Bergh, Anders

doi:10.1002/pros.10312

Cited by 41 publications

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“…Actin was used as a control for equal loading. Table 1 Relative differences of hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor-A (VEGF-A) mRNA in the rat ventral and dorsolateral prostate lobes at different times after castration and at different times after testosterone treatment (nZ5-9 rats), for details see text be inhibited by blocking VEGF (Lissbrant et al 2004), demonstrating that testosterone-stimulated VP growth is angiogenesis dependent and that VEGF is a central mediator of this effect. Direct effects of androgens on prostate blood vessels are, however, also possible as mural cells in prostate blood vessels express AR (Johansson et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…And if so how? These questions are largely unanswered, but the observations that testosterone stimulates secretion of the potent angiogenic and vasodilatory factor, vascular endothelial growth factor (VEGF) from glandular epithelial cells in castrated animals (Joseph et al 1997, Häggström et al 1999, and that neutralization of VEGF bioactivity with a soluble VEGF receptor chimerical protein, mflt(1-3)IgG inhibits testosterone-stimulated prostate growth (Lissbrant et al 2004) suggest that androgen receptor (AR)-positive epithelial cells may use VEGF as a signal to regulate the prostate vasculature. Tissue hypoxia generally increases the levels of hypoxia-inducible factor 1a (HIF-1a) and this is the major stimulator of VEGF, and other angiogenesis stimulators, secretion in various tissues (Dor et al 2001, Giordano & Johnson 2001, Semensa 2003.…”

Section: Introductionmentioning

confidence: 99%

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Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1α

Rudolfsson¹,

Bergh²

2007

Journal of Endocrinology

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Testosterone-stimulated growth of the ventral prostate (VP) in castrated rats is preceded by angiogenesis, but the mechanisms coordinating vascular and tissue growth are unknown. Adult rats were castrated and some treated with testosterone. Tissue hypoxia was studied morphologically using the hypoxia marker pimonidazole (Hypoxyprobe), hypoxia-inducible factor-1 (HIF-1) a, vascular endothelial growth factor (VEGF), and carbonicanhydrase 9 (CA-9) levels by western blotting and quantitative RT-PCR. In the intact untreated prostate, most glands were unstained by the hypoxia marker but already 1 day after castration most epithelial cells in the VP were stained. Seven days after castration prostate glands were apparently normoxic again, and HIF-1a, VEGF, and CA-9 were decreased. Treatment of 7-day castrated rats with testosterone resulted in increased epithelial hypoxyprobe staining and increased HIF-1a, VEGF, and CA-9 levels. The transient increase in tissue hypoxia after testosterone treatment is probably caused by a temporary mismatch between oxygen consumption and supply. Treatment of prostate epithelial cells in vitro under normoxic conditions also increased HIF-1a, and this could be blocked if epidermal growth factor receptor (EGFR) signaling was blocked with gefitinib. In vivo gefitinib could, however, not block the testosterone induced increase in HIF-1a. Testosterone may thus induce HIF1a and its downstream angiogenesis promoting genes by at least two mechanisms, hypoxia and EGFR signaling. Transient epithelial cell hypoxia could by rapidly increasing HIF-1a and VEGF be an essential coordinator of testosterone-stimulated vascular and glandular growth.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1α

Rudolfsson¹,

Bergh²

2007

Journal of Endocrinology

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“…37 Most recently, it was shown that anti-VEGF treatment inhibits testosterone-stimulated prostate growth in castrated mice. 38 Although angiogenic signalling molecules differ in their regulation by androgens (eg, castration was found to inhibit VEGF, but not bFGF, in the androgenresponsive PC-82 and A-2 human prostatic cancers when grown in SCID mice 9 ), when taken together, these reports suggest that androgen withdrawal leads to vascular regression. This regression occurs by downregulation of VEGF expression in normal and malignant cells, firstly causing apoptosis of endothelial cells of immature vessels and then by contributing to the formation of a 39 Hypoxic conditions create a microenvironment in which tumour cells become less dependent on angiogenesis, but more resistant to apoptosis, more capable of existing under hypoxic conditions and more malignant because of the development of genomic instability and mutant genotypes impacting on apoptosis/survival signalling pathways.…”

Section: Angiogenesismentioning

confidence: 99%

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade

Woodward

Wachsberger

Burd

et al. 2005

Prostate Cancer Prostatic Dis

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“…The normal prostate secretes several angiogenesis-regulating factors (4). Prostate vasculature is an important regulator of the growth and regression of normal prostate tissue (5,6). Similarly, prostate tumor growth is dependent on angiogenesis and prostate cancer growth is inhibited by antiangiogenic therapy (4,6).…”

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confidence: 99%

Use of Preoperative Plasma Endoglin for Prediction of Lymph Node Metastasis in Patients with Clinically Localized Prostate Cancer

Karam

Svatek

Karakiewicz

et al. 2008

Clinical Cancer Research

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Purpose: Current predictive tools and imaging modalities are not accurate enough to preoperatively diagnose lymph node metastases in patients with prostate cancer.The aim of the study was to evaluate whether preoperative plasma endoglin improves the prediction of lymph node metastases in patients with clinically localized prostate cancer. Experimental Design: Endoglin levels were measured using a commercially available ELISA assay in banked plasma from 425 patients treated with radical prostatectomy and bilateral lymphadenectomy for clinically localized prostatic adenocarcinoma at two university hospitals between July 1994 and November 1997. Logistic regression analyses were undertaken to evaluate whether endoglin improves the accuracy of a standard preoperative model for prediction of lymph node metastasis and to build a predictive nomogram. Results: Preoperative plasma endoglin levels were higher in patients with higher preoperative total serum prostate-specific antigen (PSA; Spearman correlation coefficient 0.296, P < 0.001), positive surgical margins (P = 0.03), higher pathologic Gleason sum (P = 0.04), and lymph node metastasis (P < 0.001). In a preoperative multivariable logistic regression analysis that included PSA and clinical stage, only preoperative endoglin (odds ratio, 1.17; 95% confidence interval, 1.09-1.26; P < 0.001) and biopsy Gleason sum (odds ratio, 18.57; 95% confidence interval, 1.08-318.36; P = 0.04) were associated with metastasis to lymph nodes. The addition of endoglin to a standard preoperative model (including PSA, clinical stage, and biopsy Gleason sum) significantly improved its accuracy for prediction of lymph node metastasis from 89.4% to 97.8% (P < 0.001).Conclusions: Preoperative plasma endoglin improves the accuracy for prediction of pelvic lymph node metastasis in patients treated with radical prostatectomy for clinically localized prostate cancer by a statistically and clinically significant margin.Prostate cancer is the most commonly diagnosed noncutaneous cancer affecting an estimated 218,890 men in 2007 and is the second leading cause of cancer-related death in men in the United States (1). Although local therapies with curative intent, such as radical prostatectomy and radiotherapy, result in durable disease control in most men with pathologically localized prostate cancer, the presence of pelvic lymph node metastases entails a poor prognosis. It is of paramount importance to have an accurate prediction of lymph node metastasis for treatment planning. Preoperative imaging modalities are not accurate enough to diagnose lymph node metastases (2), especially in low-risk patients. Unfortunately, pelvic lymphadenectomy is not routinely done in the current era with the advent of pure and robot-assisted laparoscopic radical prostatectomy. A quantitative and standardized blood marker that can predict the presence of clinically occult lymph node metastases could assist clinicians in identifying patients who should undergo pelvic lymphadenectomy.Angiogenesis, the process o...

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Neutralizing VEGF bioactivity with a soluble chimeric VEGF‐receptor protein flt(1‐3)IgG inhibits testosterone‐stimulated prostate growth in castrated mice

Abstract: This study suggests that testosterone stimulates vascular growth in the ventral prostate lobe indirectly by increasing epithelial VEGF synthesis and that this is a necessary component in testosterone-stimulated prostate growth.

Cited by 41 publications

References 32 publications

Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1α

Testosterone-stimulated growth of the rat prostate may be driven by tissue hypoxia and hypoxia-inducible factor-1α

Effects of androgen suppression and radiation on prostate cancer suggest a role for angiogenesis blockade

Use of Preoperative Plasma Endoglin for Prediction of Lymph Node Metastasis in Patients with Clinically Localized Prostate Cancer

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