Loss of ovarian function promotes angiogenesis in human ovarian carcinoma

Schiffenbauer, Yael S.; Abramovitch, Rinat; Meir, Gila; Nevo, Nava; Holzinger, Michael; Itin, Ahuva; Keshet, Eli; Neeman, Michal

doi:10.1073/pnas.94.24.13203

Cited by 96 publications

(87 citation statements)

References 21 publications

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“…18,19 Moreover, it has been suggested that loss of ovarian function promotes tumorigenesis by resulting in increased gonadotropins, which promote vascularization via increased levels of VEGF. 20 Recent data also have supported the finding that testosterone replacement in castrated rats increases mRNA levels of VEGF. 21 This phase 2 study evaluated the hypothesis that the inhibition of the androgen axis could result in a decrease in tumor recurrence by inhibiting AR, reducing circulating gonadotropins, and suppressing androgen-mediated VEGF production.…”

supporting

confidence: 55%

“…VEGF levels were found to have considerable interpatient variability and did not exhibit decreases as a result of suppression of the androgen axis, as hypothesized. 20 FIGURE 2. Serum levels of (A) luteinizing hormone (LH; in mIU/mL), (B) follicle-stimulating hormome (FSH; in mIU/mL), (C) vascular endothelial growth factor (VEGF; in pg/mL), (D) testosterone (TEST; in ng/dL), and (E) androstenedione (ANDRO; in ng/dL).…”

Section: Discussionmentioning

confidence: 99%

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A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission

Levine

Park

Juretzka

et al. 2007

Cancer

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The mechanism of the gas‐phase elimination kinetics of 2‐ethoxypyridine has been studied through the electronic structure calculations using density functional methods: B3LYP/6‐31G(d,p), B3LYP/6‐31++G(d,p), B3PW91/6‐31G(d,p), B3PW91/6‐31++G(d,p), MPW1PW91/6‐31G(d,p), MPW1PW91/6‐31++G(d,p), PBEPBE/6‐31G(d,p), PBEPBE/6‐31++G(d,p), PBE1PBE1/6‐31G(d,p), and PBE1PBE1/6‐31++G(d,p). The elimination reaction of 2‐ethoxypyridine occurs through a six‐centered transition state geometry involving the pyridine nitrogen, the substituted carbon of the aromatic ring, the ethoxy oxygen, two carbons of the ethoxy group, and a hydrogen atom, which migrates from the ethoxy group to the nitrogen to give 2‐pyridone and ethylene. The reaction mechanism appears to occur with the participation of π‐electrons, similar to alkyl vinyl ether elimination reaction, with simultaneous ethylene formation and hydrogen migration to the pyridine nitrogen producing 2‐pyridone. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011

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supporting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission

Levine

Park

Juretzka

et al. 2007

Cancer

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“…These hormones have been shown to stimulate the growth of normal and [35,36]. However, little was known about the mechanism of FSH stimulation on VEGF expression.…”

Section: Discussionmentioning

confidence: 99%

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

et al. 2008

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There is evidence to suggest that follicle-stimulating hormone (FSH) can facilitate the neovascularization of ovarian cancers by increasing vascular endothelial growth factor (VEGF) expression in cancer cells, although the underlying molecular mechanism of this process is not well known. Therefore, we investigated the effect of FSH on VEGF expression in the ovarian cancer cell lines SKOV-3 and ES-2. Treatment with FSH significantly increased VEGF expression in a dose-and time-dependent manner. In addition, FSH treatment enhanced the expression of survivin and hypoxiainducible factor-1 (HIF-1α). Knockdown of survivin or HIF-1α suppressed VEGF expression, but only knockdown of survivin inhibited FSH-stimulated VEGF expression. Pretreatment with LY294002, a phosphoinositide 3-kinase (PI3K)/AKT inhibitor, neutralized the enhanced expression of survivin induced by FSH, but treatment with U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, had no such effect. We further showed that ovarian serous cystadenocarcinoma samples had much higher incidence of positive AKT and phosphorylated AKT (pAKT) protein staining than did benign ovarian cystadenoma samples (p < 0.01). The 5-year survival rate was only about 15% in patients with ovarian serous cystadenocarcinoma who had AKT and pAKT expression, whereas it was about 80% in those who did not have AKT or pAKT expression. Taken together, these results indicate that FSH increases the expression of VEGF by upregulating the expression of survivin, which is activated by the PI3K/AKT signaling pathway. Understanding the role of the PI3K/AKT pathway in FSH-stimulated expression of survivin and VEGF will be beneficial for evaluating the prognosis for patients with ovarian serous cystadenocarcinoma and for pursuing effective treatment against this disease.

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“…Despite these observations, whether gonadotropins may play a role in normal OSE biology and ovarian tumorigenesis remains to be fully elucidated and the exact mechanism of the response to gonadotropins is not clearly understood. The growth of human ovarian carcinoma has been promoted by elevated levels of gonadotropins through induction of tumor angiogenesis in vivo (Schiffenbauer et al 1997, Zygmunt et al 2002, and the level of vascular endothelial growth factor (VEGF) was significantly elevated in both low malignant potential (LMP) and serous ovarian carcinoma (Wang et al 2002). In addition, gonadotropin-induced stimulation results in an increase in the expression of integrin subunit alpha (v) and CD44, the cell surface hyaluronan receptor in MLS human epithelial ovarian carcinoma cells (Schiffenbauer et al 2002).…”

Section: Discussionmentioning

confidence: 99%

Gonadotropins upregulate the epidermal growth factor receptor through activation of mitogen-activated protein kinases and phosphatidyl-inositol-3-kinase in human ovarian surface epithelial cells

Choi¹

2005

Endocrine Related Cancer

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Gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) have been implicated as probable risk factors in epithelial ovarian carcinomas, most of which are derived from ovarian surface epithelium (OSE). Since epidermal growth factor (EGF) increases the growth of ovarian surface epithelial cells, we determined the effect of gonadotropins on the expression of epidermal growth factor receptor (EGFR). We investigated the basal levels of EGFR mRNA and protein, and the mechanisms involved in the regulation of EGFR at the transcriptional and translational levels by FSH and LH. The immortalized OSE cell lines (IOSE) derived from normal OSE cells by transfecting SV40 T-antigen (IOSE-80 and IOSE-80PC, a post-crisis line) and ovarian cancer cell lines were employed. A significantly lower level of EGFR was observed in both IOSE-80 and IOSE-80PC cells when compared with the ovarian cancer cell lines, OVCAR-3 and SKOV-3. Treatment of IOSE-80PC cells with FSH and LH (10 -7 and 10 -6 g/ml) resulted in a significant increase in EGFR mRNA at 24 h and EGFR protein at 48 h, whereas the treatment with gonadotropins for 24-48 h induced a mild increase in EGFR in OVCAR-3, but not in SKOV-3 cells. In addition, IOSE-80PC cells treated with gonadotropins and EGF (10 nM) exhibited an additive stimulation of mitogenesis. Further, FSH and LH significantly increased activities of various kinases at 5-10 min, and pre-treatments with LY294002 (an inhibitor of PI3K) or PD98059 (an inhibitor of ERK1/2) partially blocked the gonadotropin-induced up-regulation of EGFR in IOSE-80PC cells. We investigated whether the effect of gonadotropins on EGFR mRNA levels is induced by increased transcription and/or by altered mRNA stability. Treatment of IOSE-80PC cells with FSH (10 -7 and 10 -6 g/ml) significantly enhanced the activity of the EGFR promoter (120 and 140% increase, respectively) at 24 h, and treatment with LH (10 -7 g/ml) for 24 h induced an increase in the activity of EGFR promoter (30%) in these cells. On the other hand, LH resulted in a significant increase in EGFR mRNA stability in the decay curves. Taken together, these results suggest that the effect of gonadotropins on the expression of EGFR may affect cell growth via ERK-1/-2 and PI3K pathways in preneoplastic ovarian surface epithelial cells, and that FSH and LH increase EGFR mRNA by different mechanisms. The former increased EGFR gene transcription essentially, whereas the latter mainly enhanced EGFR mRNA stability.

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Loss of ovarian function promotes angiogenesis in human ovarian carcinoma

Cited by 96 publications

References 21 publications

A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission

A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission

Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma

Gonadotropins upregulate the epidermal growth factor receptor through activation of mitogen-activated protein kinases and phosphatidyl-inositol-3-kinase in human ovarian surface epithelial cells

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