Inhibition of angiogenesis by anti-tumor agents may play a role in tumor growth arrest. Tamoxifen and interferon-alpha/beta (IFN-alpha/beta) exhibit potentiated anti-proliferative activity against tumor cells. However, additional host-mediated effects such as modulation of angiogenesis may also inhibit tumor growth in vivo. The effect of tamoxifen and IFN-beta on angiogenesis induced by 2 human tumors, MCF-7 breast carcinoma (estradiol dependent) and NIH-OVCAR-3 ovarian carcinoma (estradiol independent), was assessed. Treatment of nude mice bearing MCF-7 tumors with tamoxifen resulted in a 68% decrease in the number of vessels at the tumor periphery. Treatment with IFN-beta yielded a 33% reduction. Treatment of nude mice bearing NIH-OVCAR-3 tumors with tamoxifen resulted in a 73% decrease in the number of vessels. Treatment with IFN-beta yielded a 57% reduction. Combination treatment resulted in augmented anti-angiogenic effects. As single agents, both tamoxifen and IFN-beta inhibited xenograft tumor growth. Ten weeks of tamoxifen treatment resulted in growth inhibition of MCF-7 and NIH-OVCAR-3 carcinomas by 85% and 66%, respectively. Ten weeks of IFN-beta treatment resulted in inhibition of growth of MCF-7 and NIH-OVCAR-3 carcinomas by 67% and 88%, respectively. The combination of tamoxifen and IFN-beta completely prevented growth of MCF-7 and NIH-OVCAR-3 carcinomas. The anti-angiogenic effects of tamoxifen and IFN-beta were additive. Inhibition of angiogenesis was detectable before measurable effects on tumor volume in both MCF-7 and NIH-OVCAR-3 tumors. Potentiation of anti-angiogenic effects by tamoxifen and IFN-beta, possibly resulting from enhanced IFN-induced gene expression, may contribute to anti-tumor activity in both estradiol-dependent and estradiol-independent tumors in vivo.
"OVCAR-3, was established 1982 from the malignant ascites of a patient with progressive adenocarcinoma of the ovary and were originally described as ER-positive . Later publications regarding ER expression and estrogen responsiveness are however contradictory, and some studies suggest that OVCAR-3 do not express a functional ER   . In our laboratory we could not detect ERa in OV- CAR-3 by immunocytochemistry (data not shown). "
[Show abstract][Hide abstract] ABSTRACT: There are several similarities between breast and ovarian cancer but anti-estrogen treatment is rarely used in ovarian cancer. We have previously shown that the most widely used anti-estrogen tamoxifen increased MMP-9 activity and endostatin generation in breast cancer. Here, we show that tamoxifen exposure of highly hormone responsive ovarian cancer cells decreased proliferation, and increased MMP-9 activity leading to increased levels of endostatin both in cell culture in vitro and in solid tumors of nude mice. Tamoxifen exposed tumors also exhibited significantly decreased tumor growth and vascularisation. Moreover, in ascites from ovarian cancer patients, MMP-9 was undetectable in majority of cases but a significant correlation of MMP-2 and endostatin was found. The effects on MMPs and endostatin generation are previously unknown mechanisms of estradiol and tamoxifen in ovarian cancer, which may have therapeutic implications in future anti-cancer options of hormone dependent ovarian cancer.
Cancer letters 11/2009; 292(1):32-40. DOI:10.1016/j.canlet.2009.11.002 · 5.62 Impact Factor
"The majority of primary breast tumours are oestrogen-dependent, and tamoxifen is the most commonly used antioestrogen therapy today. Numerous animal models of breast cancer have previously demonstrated a proangiogenic effect of oestrogens and an antiangiogenic effect of tamoxifen in vivo (Haran et al, 1994; Lindner and Borden, 1997; Guo et al, 2002; Dabrosin et al, 2003a, 2003b; Garvin and Dabrosin, 2003; Elkin et al, 2004). We have previously shown that oestradiol increases extracellular levels of VEGF while tamoxifen inhibits the secretion of VEGF in breast cancer in vivo (Garvin and Dabrosin, 2003). "
[Show abstract][Hide abstract] ABSTRACT: Angiogenesis is regulated by the balance between pro- and antiangiogenic factors. Vascular endothelial growth factor (VEGF), acting via the receptors VEGFR-1 and VEGFR-2, is a key mediator of tumour angiogenesis. The soluble form of the VEGF receptor-1 (sVEGFR-1) is an important negative regulator of VEGF-mediated angiogenesis. The majority of breast cancers are oestrogen dependent, but it is not fully understood how oestrogen and the antioestrogen, tamoxifen, affect the balance of angiogenic factors. Angiogenesis is a result of the interplay between cancer and endothelial cells, and sex steroids may exert effects on both cell types. In this study we show that oestradiol decreased secreted sVEGFR-1, increased secreted VEGF, and decreased the ratio of sVEGFR-1/VEGF in MCF-7 human breast cancer cells. The addition of tamoxifen opposed these effects. Moreover, human umbilical vein endothelial cells (HUVEC) incubated with supernatants from oestradiol-treated MCF-7 cells exhibited higher VEGFR-2 levels than controls. In vivo, MCF-7 tumours from oestradiol+tamoxifen-treated nude mice exhibited decreased tumour vasculature. Our results suggest that tamoxifen and oestradiol exert dual effects on the angiogenic environment in breast cancer by regulating cancer cell-secreted angiogenic ligands such as VEGF and sVEGFR-1 and by affecting VEGFR-2 expression of endothelial cells.
British Journal of Cancer 11/2005; 93(9):1005-10. DOI:10.1038/sj.bjc.6602824 · 4.84 Impact Factor
"73% in the NIH-OVCAR-3 tumours. In addition, tamoxifen treatment resulted in inhibition of growth for the MCF-7 tumours and NIH-OVCAR- 7 tumours by 67% and 88% respectively (Lindner, 1997). Tamoxifen and other anti-oestrogens inhibit angiogenesis in the chick egg chorio-allantoic membrane (Gagliardi, 1993). "
[Show abstract][Hide abstract] ABSTRACT: This paper explores the concept that endometrial breakthrough bleeding results from the stimulatory effects of oestrogen in the endometrium. Though 'progestin-only' contraceptive regimens have long been associated with user dissatisfaction because of unpredictable vaginal bleeding, it is likely that the substantial contribution of endogenous ovarian oestradiol during such treatments predisposes the bleeding problems. Oestrogen causes endometrial proliferation, hyperplasia and neoplasia if unopposed. Oestrogen allows production of growth factors supporting angiogenesis which results in an abundance of dilated or fragile endothelial surface blood vessels, predisposing this tissue to bleeding when these vessels lose competence.
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