Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo

doi:10.1053/ejso.2001.1177

European Journal of Surgical Oncology (EJSO)

Volume 27, Issue 8, December 2001, Pages 714-718

https://doi.org/10.1053/ejso.2001.1177 Get rights and content

Abstract

Introduction: Angiogenesis is fundamental to tumour growth and vascular endothelial growth factor (VEGF) is one of the most potent proangiogenic cytokines known. We have previously demonstrated that tamoxifen reduces serum VEGF in certain cancer patients. We hypothesized that tamoxifen may attenuate the angiogenetic response to VEGF. Methods: Human dermal microvessel endothelial primary cell cultures (HMEC) were incubated with tamoxifen (1.25–5.0 μg) or vehicle. Cell proliferation was quantified using 5-bromo-2′-deoxyuridine (BrdU) labelling endothelial cell proliferation assay. The effect of oral tamoxifen (20 mg/day) on VEGF-mediated angiogenesis in vivo was assessed using a Matrigel angiogenesis assay in the Sprague–Dawley rat. Results: Tamoxifen (5.0 μg/ml) significantly reduced HMEC proliferation over 24 h when compared with cells treated with vehicle alone. Oral administration of tamoxifen in the rat (20 mg/day) significantly reduced endothelial cell proliferation and migration in response to VEGF. Conclusion: Tamoxifen (5.0 μg/ml) reduces proliferation of a VEGF-dependent endothelial cell line in vitro. In vivo, orally administered tamoxifen reduces VEGF-mediated angiogenesis in the rat. These findings indicate that tamoxifen may directly inhibit the effect of VEGF on the endothelial cell, in addition to its previously described effect of reducing serum VEGF levels. This data supports a role for tamoxifen in modulation of the VEGF-dependent angiogenic response to surgical trauma, particularly as an adjuvant therapy for VEGF-dependent tumours.

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Citation Excerpt :
However, clinical trials have shown that tamoxifen decreases the risk of invasive breast cancer and reduces breast cancer related deaths due to its ability to reduce metastasis (Fisher et al., 1998; Group, 1998). Tamoxifen decreases endothelial cell proliferation and migration, thereby decreasing angiogenesis (McNamara et al., 2001). While it is clear that tamoxifen has anti-angiogenic effects, there is speculation whether this is independent of ER (Blackwell et al., 2000).
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Long-term safety and efficacy of a tamoxifen-based treatment strategy for idiopathic retroperitoneal fibrosis
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Tamoxifen may alter the balance of growth factors such that fibroblast proliferation is inhibited [38–41]. The antiangiogenic properties of tamoxifen may also contribute to its efficacy [42]. Because tamoxifen is an antiestrogen drug, it may also act as anti-inflammatory or immunosuppressive therapy in retroperitoneal fibrosis [43,44], which would explain the observed decrease in APR levels.
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Forty-seven (85%) patients reported substantial resolution of symptoms after median treatment duration of 3.0 weeks (IQR 1.4–4.8 weeks). Repeated CT scanning showed mass regression in 39 (71%) patients at 4 months and 47 (85%) patients at 8 months of follow-up, respectively. Nineteen (34.5%) patients did not meet the composite endpoint of treatment success, 56% of whom responded satisfactorily to second-line immunosuppressive treatment. Recurrence-free survival in patients with treatment success after post-treatment follow-up of 21 months (IQR 9.0–35.0 months) was 68%. Tamoxifen was well tolerated. Pulmonary embolism occurred in 2 patients receiving tamoxifen and in one patient receiving second-line treatment.
Tamoxifen is a safe and viable therapeutic option in the treatment of iRPF.
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In addition, tamoxifen reduced VEGF-driven migration of HEECs in vitro, indicating an inhibitory effect on angiogenesis. The obtained data are in line with previous reports suggesting that tamoxifen affects angiogenesis in various tissues in vivo and in vitro.5,26,34 For example, McNamara et al reported that tamoxifen has a direct inhibitory effect on VEGF-dependent proliferation in human dermal microvessel endothelial primary cells (HMECs) grown in vitro.26
The selective estrogen receptor modulator tamoxifen is used for the prevention and treatment of breast cancer. The adverse effects of tamoxifen include vaginal endometrial bleeding, endometrial hyperplasia, and cancer, conditions associated with angiogenesis. The aim of this study was to examine the effects of tamoxifen on cell migration and angiogenesis-related gene expression in human endometrial endothelial cells (HEECs). The regulatory effects of tamoxifen on endometrial stromal cells and HEECs were also examined. HEECs and stromal cells were isolated and grown in monocultures or co-cultures, and incubated with 0.1 to 100 μmol/L tamoxifen for 48 hours. Quantitative PCR demonstrated that tamoxifen decreased the mRNA expression of vascular endothelial growth factor-A (VEGF-A) and increased the mRNA expression of VEGF receptor–1 and placental growth factor (PLGF) in HEECs. Tamoxifen's effects on VEGF-A were inhibited when HEECs were co-cultured with stromal cells. In addition, tamoxifen reduced VEGF-induced HEEC migration. The tamoxifen-metabolizing enzymes CYP1A1 and CYP1B1 were detected by immunohistochemistry in and around endometrial blood vessels and by quantitative PCR in HEECs. Our data suggest that tamoxifen changes the regulation of angiogenesis in the endometrium, likely by reducing angiogenic activity. The results also indicate that endometrial stromal cells regulate some of tamoxifen's effects in HEECs, and the presence of tamoxifen-metabolizing enzymes suggests tamoxifen bioactivation in the endometrial vasculature in vivo. These findings may help to elucidate the mechanism of the bleeding disturbances associated with tamoxifen treatment.
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Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. We have previously reported that tamoxifen (TMX) induces apoptosis of cholangiocarcinoma cells and reduces cholangiocarcinoma tumorigenesis in mice. In the present studies, we determined the effect of combination therapy of TMX and gemcitabine (GMT), another chemotherapeutical reagent for many cancers, on cholangiocarcinoma tumorigenesis and investigated the responsible mechanisms. GMT inhibited cell growth and induced apoptosis of cholangiocarcinoma cells in a concentration-dependent manner. TMX enhanced GMT-induced apoptosis of cholangiocarcinoma cells. Consistently, GMT (15 mg/kg) inhibited cholangiocarcinoma tumorigenesis in nude mice by 50%. TMX (15 mg/kg) enhanced the inhibitory effect of GMT on tumorigenesis by 33%. The inhibition of tumor growth correlated with enhanced apoptosis in tumor tissues. To elucidate the mechanisms underlying the additive effects of TMX on GMT-induced apoptosis, we determined the activation of caspases in cholangiocarcinoma cells exposed to GMT, TMX, or both. Activation of caspases 9 and 3, as well as cytochrome c release to the cytosol, was demonstrated in cells exposed to both reagents. In contrast, TMX activated caspase 2, whereas GMT had no effect. Inhibition of caspase 2 activation decreased TMX-, but not GMT-, induced activation of caspase 3 and apoptosis of cholangiocarcinoma cells. Similarly, activation of caspase 2 was found in tumors from TMX-treated mice, but not GMT-treated mice. Therefore, the enhanced effect of TMX on GMT-induced cholangiocarcinoma cell death is partially mediated by activation of caspase 2. TMX and GMT both induce apoptosis and inhibit cholangiocarcinoma tumorigenesis, which may be attributed to the activation of distinct apoptosis signals by TMX and GMT. Our studies provide in vivo evidence and molecular insight to support the use of TMX and GMT in combination as an effective therapy for cholangiocarcinoma.

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^f1: Correspondence to: Ms Deborah McNamara, Department of Surgery, Mater Misericordiae Hospital, Eccles Street, Dublin 7, Ireland. Fax: 00 353 1 8034779;E-mail: [email protected]

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European Journal of Surgical Oncology (EJSO)

Abstract

References (15)

Antioestrogenic compounds inhibit estrogen-induced expressions of basic fibroblast growth factor and its mRNA in well-differentiated endometrial cancer cells

Gen Pharmacol

The effect of laparotomy and laparoscopy on the establishment of spontaneous tumour metastases

Surgery

Tamoxifen: teaching an old drug new tricks?

Nature Med

Antioestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors

Anticancer Res

Angiogenic factors

Science

Insulin-like growth factor I gene expression in the uterus is stimulated by tamoxifen and inhibited by the pure antioestrogen ICI 182780

Cancer Res

Induction of transforming growth factor β1 in human breast cancer in vivo following tamoxifen treatment

Cancer Res

Cited by (55)

Molecular analysis of vascular gene expression

Sex hormones and stroke: Beyond estrogens

Personalized in vitro cancer models to predict therapeutic response: Challenges and a framework for improvement

Long-term safety and efficacy of a tamoxifen-based treatment strategy for idiopathic retroperitoneal fibrosis

Tamoxifen modulates cell migration and expression of angiogenesis-related genes in human endometrial endothelial cells

Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

Regular ArticlesTamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo

Abstract

Gen Pharmacol

Surgery

Tamoxifen: teaching an old drug new tricks?

Nature Med

Antioestrogens inhibit endothelial cell growth stimulated by angiogenic growth factors

Anticancer Res

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Science

Insulin-like growth factor I gene expression in the uterus is stimulated by tamoxifen and inhibited by the pure antioestrogen ICI 182780

Cancer Res

Induction of transforming growth factor β1 in human breast cancer in vivo following tamoxifen treatment

Cancer Res

Regular Articles
Tamoxifen inhibits endothelial cell proliferation and attenuates VEGF-mediated angiogenesis and migration in vivo