Estetrol: a natural SERM that may provide a safe therapeutic window for the treatment of menopausal symptoms
Conference (2015, October 24)Detailed reference viewed: 14 (0 ULg)
Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms
Gérard, Céline ; ; Tskitishvili, Ekaterine et al
in Oncotarget (2015)
Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a ... [more ▼]
Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERα) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms. [less ▲]Detailed reference viewed: 39 (3 ULg)
Mesenchymal stem cells shed amphiregulin at the surface of lung carcinoma cells in a juxtacrine manner .
Carnet, Oriane ; ; et al
in Neoplasia : An International Journal for Oncology Research (2015), 17(7), 552-63
Solid tumors comprise cancer cells and different supportive stromal cells, including mesenchymal stem cells (MSCs), which have recently been shown to enhance tumor growth and metastasis. We provide new ... [more ▼]
Solid tumors comprise cancer cells and different supportive stromal cells, including mesenchymal stem cells (MSCs), which have recently been shown to enhance tumor growth and metastasis. We provide new mechanistic insights into how bone marrow (BM)-derived MSCs co-injected with Lewis lung carcinoma cells promote tumor growth and metastasis in mice. The proinvasive effect of BM-MSCs exerted on tumor cells relies on an unprecedented juxtacrine action of BM-MSC, leading to the trans-shedding of amphiregulin (AREG) from the tumor cell membrane by tumor necrosis factor-α-converting enzyme carried by the BM-MSC plasma membrane. The released soluble AREG activates cancer cells and promotes their invasiveness. This novel concept is supported by the exploitation of different 2D and 3D culture systems and by pharmacological approaches using a tumor necrosis factor-α-converting enzyme inhibitor and AREG-blocking antibodies. Altogether, we here assign a new function to BM-MSC in tumor progression and establish an uncovered link between AREG and BM-MSC. [less ▲]Detailed reference viewed: 53 (9 ULg)
Estetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.
Gérard, Céline ; Blacher, Silvia ; et al
in Journal of Endocrinology (2015), 224(1), 86-95
Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol (EE) and estradiol (E2), E4 ... [more ▼]
Estetrol (E4) is a natural estrogen produced exclusively by the human fetal liver during pregnancy. Its physiological activity remains unknown. In contrast to ethinyl estradiol (EE) and estradiol (E2), E4 has a minimal impact on liver cells activity and could provide a better safety profile in contraception or hormone therapy. The aim of this study was to delineate if E4 exhibits an activity profile distinct from that of E2 on mammary gland. Compared to E2, E4 acted as a low affinity estrogen in both, human in vitro and murine in vivo, models. E4 was 100 times less potent than E2 to stimulate the proliferation of human breast epithelial (HBE) cells and murine mammary gland in vitro and in vivo, respectively. This effect was prevented by fulvestrant and by tamoxifen supporting the notion that ERalpha is the main mediator of the estrogenic effect of E4 on the breast. Interestingly, when E4 was administered along with E2, it significantly antagonized the strong stimulatory effect of E2 on HBE cells proliferation and on the growth of mammary ducts. This study characterizes for the first time the impact of E4 on mammary gland. Our results highlight that E4 is less potent than E2 and exhibits antagonistic properties towards the proliferative effect of E2 on breast epithelial cells. These data support E4 as a potential new estrogen for clinical use with a reduced impact on breast proliferation. [less ▲]Detailed reference viewed: 37 (15 ULg)
Estetrol attenuates neonatal hypoxic–ischemic brain injury
Tskitishvili, Ekaterine ; Nisolle, Michelle ; Munaut, Carine et al
in Experimental Neurology (2014), 261
Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim ... [more ▼]
Estetrol (E4) is a recently described natural estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. The aim of the present study was to define the importance of E4 in the attenuation of neonatal hypoxic-ischemic encephalopathy. Antioxidative effect of 650μM, 3.25mM and 6.5mM E4 on primary hippocampal cell cultures was studied before/after H202-induced oxidative stress. To examine oxidative stress and cell viability, lactate dehydrogenase activity and cell proliferation colorimetric assays were performed. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal hypoxic-ischemic encephalopathy model of 7-day-old newborn rat pups was used. The neuroprotective and therapeutic effects of estetrol before/after hypoxic-ischemic insult was studied in 1mg/kg/day, 5mg/kg/day, 10mg/kg/day, 50mg/kg/day E4 pretreated/treated groups and compared with the sham and the vehicle treated groups. The body temperature of the rat pups was examined along with their body and brain weights. Brains were studied at the level of the hippocampus and cortex. Intact cell counting and expressions of microtubule-associated protein-2, doublecortin and vascular-endothelial growth factor were evaluated by histo- and immunohistochemistry. ELISAs were performed on blood samples to detect concentrations of S100B and glial fibrillary acidic protein as brain damage markers. This work reveals for the first time that E4 significantly decreases LDH activity and enhances cell proliferation in primary hippocampal neuronal cell cultures in vitro, and decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. [less ▲]Detailed reference viewed: 35 (8 ULg)
Bone marrow-derived mesenchymal stem cells drive lymphangiogenesis.
Maertens, Ludovic ; Erpicum, Charlotte ; Detry, Benoît et al
in PLoS ONE (2014), 9(9), 106976
It is now well accepted that multipotent Bone-Marrow Mesenchymal Stem Cells (BM-MSC) contribute to cancer progression through several mechanisms including angiogenesis. However, their involvement during ... [more ▼]
It is now well accepted that multipotent Bone-Marrow Mesenchymal Stem Cells (BM-MSC) contribute to cancer progression through several mechanisms including angiogenesis. However, their involvement during the lymphangiogenic process is poorly described. Using BM-MSC isolated from mice of two different backgrounds, we demonstrate a paracrine lymphangiogenic action of BM-MSC both in vivo and in vitro. Co-injection of BM-MSC and tumor cells in mice increased the in vivo tumor growth and intratumoral lymphatic vessel density. In addition, BM-MSC or their conditioned medium stimulated the recruitment of lymphatic vessels in vivo in an ear sponge assay, and ex vivo in the lymphatic ring assay (LRA). In vitro, MSC conditioned medium also increased the proliferation rate and the migration of both primary lymphatic endothelial cells (LEC) and an immortalized lymphatic endothelial cell line. Mechanistically, these pro-lymphangiogenic effects relied on the secretion of Vascular Endothelial Growth Factor (VEGF)-A by BM-MSC that activates VEGF Receptor (VEGFR)-2 pathway on LEC. Indeed, the trapping of VEGF-A in MSC conditioned medium by soluble VEGF Receptors (sVEGFR)-1, -2 or the inhibition of VEGFR-2 activity by a specific inhibitor (ZM 323881) both decreased LEC proliferation, migration and the phosphorylation of their main downstream target ERK1/2. This study provides direct unprecedented evidence for a paracrine lymphangiogenic action of BM-MSC via the production of VEGF-A which acts on LEC VEGFR-2. [less ▲]Detailed reference viewed: 27 (4 ULg)
The uterine and vascular actions of estetrol delineate a distinctive profile of estrogen receptor alpha modulation, uncoupling nuclear and membrane activation.
; ; et al
in EMBO molecular medicine (2014), 6(10), 1328-46
Estetrol (E4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor alpha (ERalpha) ligand-binding domain ... [more ▼]
Estetrol (E4) is a natural estrogen with a long half-life produced only by the human fetal liver during pregnancy. The crystal structures of the estrogen receptor alpha (ERalpha) ligand-binding domain bound to 17beta-estradiol (E2) and E4 are very similar, as well as their capacity to activate the two activation functions AF-1 and AF-2 and to recruit the coactivator SRC3. In vivo administration of high doses of E4 stimulated uterine gene expression, epithelial proliferation, and prevented atheroma, three recognized nuclear ERalpha actions. However, E4 failed to promote endothelial NO synthase activation and acceleration of endothelial healing, two processes clearly dependent on membrane-initiated steroid signaling (MISS). Furthermore, E4 antagonized E2 MISS-dependent effects in endothelium but also in MCF-7 breast cancer cell line. This profile of ERalpha activation by E4, uncoupling nuclear and membrane activation, characterizes E4 as a selective ER modulator which could have medical applications that should now be considered further. [less ▲]Detailed reference viewed: 26 (3 ULg)
Estradiol promotes the growth of Estrogen Receptor (ER)-negative tumors through host ERα driven angiogenesis
Conference (2014)Detailed reference viewed: 13 (2 ULg)
Estradiol promotes the growth of Estrogen Receptor (ER)-negative tumors through host ERα driven angiogenesis
Conference (2013)Detailed reference viewed: 11 (1 ULg)
Differential expression of Vegfr-2 and its soluble form in preeclampsia.
Munaut, Carine ; LORQUET, Sophie ; Pequeux, Christel et al
in PLoS ONE (2012), 7(3), 33475
Background: Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably ... [more ▼]
Background: Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta. METHODOLOGY/PRINCIPAL FINDINGS: By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR-2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction. [less ▲]Detailed reference viewed: 57 (7 ULg)
MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis
Maquoi, Erik ; ; et al
in Oncogene (2012), 31(4), 480-93
As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic ... [more ▼]
As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminal-like breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis. [less ▲]Detailed reference viewed: 88 (21 ULg)
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Pequeux, Christel ; ; Blacher, Silvia et al
in Cancer Research (2012), 72(12), 3010-3019
Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro ... [more ▼]
Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro-tumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17beta-estradiol (E2) impacts the microenvironment and modulates tumor development of ERalpha-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERalpha-deficient mice, demonstrating a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERalpha was deficient in Tie2- positive cells, but still expressed by bone marrow derived cells. These results were extended by clinical evidence of ERalpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore suggest that E2 promotes the growth of ERalpha-negative cancer cells through the activation of stromal ERα (not hematopoiteic but Tie2-dependent expression of ERalpha), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumor demand preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. [less ▲]Detailed reference viewed: 41 (13 ULg)
Estradiol promotes the growth of estrogen receptor (ER)-negative tumors throughout host ERalpha driven angiogenesis
Conference (2011)Detailed reference viewed: 14 (0 ULg)
TGFbeta-receptor-dependent angiostimulation through the hyperglycosylated isoform of human chorionic gonadotropin.
; ; et al
in Placenta (2011), 32(9), 44Detailed reference viewed: 6 (0 ULg)
Soluble forms of VEGF receptor-1 and -2 promote vascular maturation via mural cell recruitment.
Conference (2010)Detailed reference viewed: 12 (0 ULg)
Aetiology and physiopathology of preeclampsia and related forms.
Lorquet, Sophie ; Pequeux, Christel ; Munaut, Carine et al
in Acta Clinica Belgica (2010), 65(4), 237-41
Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and oedema, resolves on placental delivery. Its pathogenesis is thought to be associated to a hypoxic placenta ... [more ▼]
Preeclampsia, a pregnancy-specific syndrome characterized by hypertension, proteinuria and oedema, resolves on placental delivery. Its pathogenesis is thought to be associated to a hypoxic placenta. Placental hypoxia is responsible for the maternal vascular dysfunction via the increased placental release of anti-angiogenic factors such as soluble flt1 and endoglin. These soluble receptors bind VEGF, PLGF and TGFbeta1 and 3 in the maternal circulation, causing endothelial dysfunction in many maternal tissues. Despite these recent and important new molecular findings, it is important to consider that normal pregnancy is also characterized by systemic inflammation, oxidative stress and alterations in levels of angiogenic factors and vascular reactivity. Both the placenta and maternal vasculatures are major sources of reactive oxygen and nitrogen species which can produce powerful pro-oxidants that covalently modify proteins and alter vascular function in preeclampsia. Finally, the recent demonstration of activating auto-antibodies to the Angiotensin 1 receptor that experimentally play a major pathogenic role in preeclampsia further indicates the pleiotropism of aetiologies of this condition. [less ▲]Detailed reference viewed: 131 (3 ULg)
Soluble forms of VEGF receptor-1 and -2 promote vascular maturation via mural cell recruitment.
LORQUET, Sophie ; ; Blacher, Silvia et al
in FASEB Journal (2010), 24(10), 3782-95
Two soluble forms of vascular endothelial growth factor (VEGF) receptors, sVEGFR-1 and sVEGFR-2, are physiologically released and overproduced in some pathologies. They are known to act as anti-VEGF ... [more ▼]
Two soluble forms of vascular endothelial growth factor (VEGF) receptors, sVEGFR-1 and sVEGFR-2, are physiologically released and overproduced in some pathologies. They are known to act as anti-VEGF agents. Here, we report that these soluble receptors contribute to vessel maturation by mediating a dialogue between endothelial cells (EC) and mural cells that leads to blood vessel stabilization. Through a multidisciplinary approach, we provide evidences that these soluble VEGF receptors promote mural cell migration through a paracrine mechanism involving interplay in EC between VEGF/VEGFR-2 and sphingosine-1- phosphate type-1 (S1P)/S1P1 pathways that leads to endothelial nitric oxyde synthase (eNOS) activation. This new paradigm is supported by the finding that sVEGFR-1 and -2: 1) induce an eNOS-dependent outgrowth of a mural cell network in an ex vivo model of angiogenesis, 2) increase the mural cell coverage of neovessels in vitro and in vivo, 3) promote mural cell migration towards EC, 4) stimulate endothelial S1P1 overproduction and eNOS activation that promote the migration and the recruitment of neighboring mural cells. These findings provide new insights into mechanisms regulating physiological and pathological angiogenesis and vessel stabilization. [less ▲]Detailed reference viewed: 145 (44 ULg)
Chorionic Gonadotropin Stimulation of Angiogenesis and Pericyte Recruitment
; Blacher, Silvia ; PERRIER d'HAUTERIVE, Sophie et al
in Journal of Clinical Endocrinology and Metabolism (2009), 94(11), 4567-74
During the periimplantation period, human chorionic gonadotropin (hCG) plays a key role by increasing the uterine blood flow through uterine vessel vasodilatation but also through angiogenesis. Indeed, we ... [more ▼]
During the periimplantation period, human chorionic gonadotropin (hCG) plays a key role by increasing the uterine blood flow through uterine vessel vasodilatation but also through angiogenesis. Indeed, we previously demonstrated that hCG contributes to endothelial cell recruitment and vessel formation. OBJECTIVE: In this study, hCG was proposed as an arteriogenic factor that could promote perivascular cell recruitment and vessel stabilization. DESIGN: The aortic ring assay, a three-dimensional ex vivo angiogenesis system mimicking all the steps of the angiogenesis process was used to study the impact of hCG on pericyte recruitment and vessel maturation. SETTING: The study was conducted at a university hospital laboratory. MAIN OUTCOME MEASURES: Perivascular cell proliferation, migration, and apposition were quantified by computerized image analysis. RESULTS: Physiological concentrations of hCG (10-400 IU/ml) significantly enhanced pericyte sprouting and migration and gave rise to the maturation and coverage of endothelial capillaries. In a three-dimensional coculture model of endothelial and perivascular cells, hCG enhanced vessel tube formation and endothelial/mural cell adhesion. In addition, hCG stimulated the proliferation of human umbilical vein endothelial cells and smooth muscle cells. The specificity of these effects was determined by using an anti-hCG blocking antibody. Signaling pathways implicated on this hCG effect is protein kinase A and phospholipase C/protein kinase C dependent for the proliferative effect but only phospholipase C/protein kinase C for the migrative process. CONCLUSIONS: Our findings highlight a novel paracrine role of this early embryonic signal in vessel maturation by stimulating perivascular cell recruitment, migration, and proliferation. [less ▲]Detailed reference viewed: 116 (23 ULg)