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See detailIdentification of predictive markers based on functional imaging of metastatic spreading at the time of surgery after neoadjuvant radiotherapy
LALLEMAND, François ULg; Leroi, Natacha ULg; Bahri, Mohamed Ali ULg et al

Poster (2015, January 27)

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery are driven by the occurrence of side effects or the ... [more ▼]

Neoadjuvant radiotherapy (NeoRT) improves tumor local control and tumor resection in many cancers. The timing between the end of the NeoRT and surgery are driven by the occurrence of side effects or the tumor downsizing. Some studies demonstrated that the timing of surgery and the RT schedule could influence tumor dissemination. Our aim is to evaluate with functional MRI the impact of the radiation treatment on the tumor microenvironment and subsequently to determine the best timing to perform surgery. We used a model of NeoRT, 4T1 cells were implanted in the flank of BalbC mice. Seven days after, tumors were irradiated with 2x5Gy than we surgically removed this lesion 11 days after RT. Diffusion Weighted (DW) and Dynamic Contrast Enhancement (DCE) -MRI was performed every 2 days during 11 days between RT and surgery. We developed a homemade “portacath” specifically dedicated for mice and for repetitive I.V. contrast agent injection. For DW-MRI, we performed sequences with 10 different B-value to achieve IntraVoxel Incoherent Motion analysis. For DCE-MRI, we used FSEMS sequence for keeping the same slices as with DW-MRI. For both images, we performed analysis on the entire tumor volume. We obtained very promising preliminary results showing good uniformity in the ADC (Attenuation Diffusion Coefficient). We succeeded to follow mice with imaging during the 11 days without major troubles. We observed less variability of the ADC signal during the 11 days in the irradiated tumors compared to the control. The signal to noise ratio was relatively poor for the diffusion sequence and need to be improved. For the first time, we demonstrate the feasibility of repetitive MRI functional imaging in a mice model of NeoRT. These results open perspectives for studying modifications of the tumor microenvironment induced by neoadjuvant RT. The techniques need to be improved and correlated to the tumor dissemination in function of the RT schedule and timing of surgery. [less ▲]

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See detailMesenchymal stem cells shed amphiregulin at the surface of lung carcinoma cells in a juxtacrine manner .
Carnet, Oriane ULg; Lecomte, Julie; Masset, Anne 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 ▲]

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See detailADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis.
Janssen, Lauriane; Dupont, Laura; Bekhouche, Mourad ULg et al

in Angiogenesis (2015)

The only documented activity of a subclass of ADAMTS proteases comprising ADAMTS2, 3 and 14 is the cleavage of the aminopropeptide of fibrillar procollagens. A limited number of in vitro studies suggested ... [more ▼]

The only documented activity of a subclass of ADAMTS proteases comprising ADAMTS2, 3 and 14 is the cleavage of the aminopropeptide of fibrillar procollagens. A limited number of in vitro studies suggested that ADAMTS3 is mainly responsible for procollagen II processing in cartilage. Here, we created an ADAMTS3 knockout mouse (Adamts3-/-) model to determine in vivo the actual functions of ADAMTS3. Heterozygous Adamts3+/- mice were viable and fertile, but their intercrosses demonstrated lethality of Adamts3-/- embryos after 15 days of gestation. Procollagens I, II and III processing was unaffected in these embryos. However, a massive lymphedema caused by the lack of lymphatics development, an abnormal blood vessel structure in the placenta and a progressive liver destruction were observed. These phenotypes are most probably linked to dysregulation of the VEGF-C pathways. This study is the first demonstration that an aminoprocollagen peptidase is crucial for developmental processes independently of its primary role in collagen biology and has physiological functions potentially involved in several human diseases related to angiogenesis and lymphangiogenesis. [less ▲]

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See detailMT4-MMP (MMP17) as a therapeutic target in metastatic solid tumors
Noël, Agnès ULg

Poster (2015)

Others and we have identified the glycosylphosphatidyl inositol (GPI) anchored MMP called MT4-MMP or MMP-17 as a main driver of cancer cell metastasis in breast (1-3), head and neck (4) and colon cancers ... [more ▼]

Others and we have identified the glycosylphosphatidyl inositol (GPI) anchored MMP called MT4-MMP or MMP-17 as a main driver of cancer cell metastasis in breast (1-3), head and neck (4) and colon cancers (5). More recently, we demonstrated a functional link between MT4-MMP and EGFR signaling in promoting breast cancer cell proliferation in vivo and in 3D culture models. We found that MT4-MMP is a key partner of EGFR activation and signaling (6), which is independent of its enzymatic activity. In triple negative breast cancer (TNBC) cells, MT4-MMP promotes primary tumor growth and lung metastases (1,2). Herein, we investigated the clinical relevance of our finding by immunohistochemical (IHC) study of MT4-MMP and EGFR expression in human samples of several breast cancer subtypes including lobular and ductal carcinoma in situ, invasive carcinoma, triple negative ductal carcinoma and normal tissue. IHC staining of normal breast tissues with MT4-MMP antibody show no signal, whereas breast carcinomas are positives for MT4-MMP. Of note, a strong staining for MT4-MMP was observed in the triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. TNBC are known to express high level of EGFR and treatment options are limited due to the non-response of the TNBC patients to the EGFR targeted therapy. By investigating 86 TNBC tumors, we found a strong correlation between MT4-MMP and EGFR expression in a 68 % of TNBC tumors. In parallel to the human study, by exploring the mechanism of MT4-MMP trafficking and internalization, we found for the first time that MT4-MMP can be recycled at the cell surface. Mechanistically, MT4-MMP uses a unique endocytic pathway, which relies on CLIC/GEEC route. In addition to deeply investigating its internalization dynamics, we also explored the mode of its oligomerization and dimerization at the cell surface. Altogether, we are providing mechanistic insights on how MT4-MMP availability is regulated and revealing unique features of this MT-MMP among other MT-MMPs. These findings can be useful for designing therapeutics to block its presence at the cell surface, rather than merely blocking its enzymatic activity to block its pro-tumor effects. (1) Chabottaux et al., 2006, Cancer Res 66, 5165-5172; (2) Host et al., 2012, Int. J. Cancer 131(7):1537-48; (3) Rizki et al., 2008, Cancer Res 68, 1378-1387), (4) Huang et al., 2009, Neoplasia 11, 1371-1382) (5) Nimri et al., 2013, Mol Carcinog 52, 859-870 (6) Paye et al., 2014, Cancer Res. 74(23):6758-70 [less ▲]

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See detailESTETROL AND ITS NEUROPROTECTIVE EFFECT IN NEONATAL HYPOXIC-ISCHEMIC ENCEPHALOPATHY
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 12th World Congress of Perinatal Medicine, Madrid, 3-6 November 2015 (2015)

Perinatal hypoxic-ischemic encephalopathy (HIE) occurs in 1-8 cases per live 1000 births. Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes ... [more ▼]

Perinatal hypoxic-ischemic encephalopathy (HIE) occurs in 1-8 cases per live 1000 births. Brain hypoxia and ischemia due to systemic hypoxemia and reduced cerebral blood flow (CBF) are the primary causes of neonatal HIE accompanied by gray and white matter injuries occurring in neonates. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities. So far no medical treatment provides important neuroprotection against HIE. Studies of new neuroprotective agents in animal models of HIE may provide important information pertinent to the development of treatments for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. It has important antioxidative activity. In this study, in vitro we defined antioxidative effect of E4 on primary hippocampal cell cultures, taken from newborn rat pups, before/after induction of oxidative stress. To examine oxidative stress and cell viability, lactate dehydrogenase (LDH) activity and cell survival (MTS) assays were performed on primary neuronal cell cultures. To study the neuroprotective and therapeutic effects of E4 in vivo neonatal HIE model of 7-day-old newborn rat pups was used. Rat pups body temperatures were 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 markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of brain damage markers (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate for the first time that E4 has a significant neuroprotective and therapeutic effects. Also, E4 has powerful antioxidative and cell survival properties in vitro. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, E4 might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailHypoxic-Ischemic Encephalopathy and Premature Babies Brain Damage: Impact of Estetrol
Tskitishvili, Ekaterine ULg; Nisolle, Michelle ULg; Noël, Agnès ULg et al

in The 11th Congress of the European Society of Gynecology, Prague 21-24 October, 2015 (2015)

Neonatal hypoxic-ischemic brain injury remains a main problem of perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities ... [more ▼]

Neonatal hypoxic-ischemic brain injury remains a main problem of perinatal medicine. About 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities mostly in the form of motor and cognitive delays. The nature of the deficits is dependent on the gestational age and severity of the insult, though it is s seldom reported in preterm infants. No medical treatment provides important neuroprotection against HIE. Studies in animal models of HIE may provide important information for the development of treatment for this pathological condition. Estetrol (E4) is a recently described estrogen with four hydroxyl-groups that is synthesized exclusively during pregnancy by the human fetal liver. In this study, we defined the antioxidative effect of E4 in primary hippocampal cell cultures taken from newborn rat pups (in vitro) and evaluated its neuroprotective and therapeutic potency in neonatal HIE model of the immature newborn rat (in vivo). Lactate Dehydrogenase (LDH) and cell survival (MTS) assays were performed on primary neuronal cell cultures. Rat pups body temperatures were 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 markers for neuronal cell viability (microtubule-associated protein-2 (MAP-2)), neurogenesis (doublecortin (DCX)) and angiogenesis (vascular-endothelial growth factor (VEGF)) were evaluated by histo- and immunohistochemistry. The serum levels of two markers of brain damage (S100B and glial fibrillary acidic protein (GFAP)) were measured by ELISA. Our results demonstrate that E4 has a significant neuroprotective and therapeutic dose-dependent effects. Estetrol has powerful antioxidative and cell survival effects in vitro. It decreases the early gray matter loss and promotes neuro- and angiogenesis in vivo. Estetrol treatment has no effects on body weight, brain weight or body temperature. Taken together, Estetrol might become an important safe and physiological substance to treat neonatal HIE. [less ▲]

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See detailThe Cancer Cell Oxygen Sensor PHD2 Promotes Metastasis via Activation of Cancer-Associated Fibroblasts.
Kuchnio, Anna; Moens, Stijn; Bruning, Ulrike et al

in Cell Reports (2015), 12(6), 992-1005

Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model ... [more ▼]

Several questions about the role of the oxygen sensor prolyl-hydroxylase 2 (PHD2) in cancer have not been addressed. First, the role of PHD2 in metastasis has not been studied in a spontaneous tumor model. Here, we show that global PHD2 haplodeficiency reduced metastasis without affecting tumor growth. Second, it is unknown whether PHD2 regulates cancer by affecting cancer-associated fibroblasts (CAFs). We show that PHD2 haplodeficiency reduced metastasis via two mechanisms: (1) by decreasing CAF activation, matrix production, and contraction by CAFs, an effect that surprisingly relied on PHD2 deletion in cancer cells, but not in CAFs; and (2) by improving tumor vessel normalization. Third, the effect of concomitant PHD2 inhibition in malignant and stromal cells (mimicking PHD2 inhibitor treatment) is unknown. We show that global PHD2 haplodeficiency, induced not only before but also after tumor onset, impaired metastasis. These findings warrant investigation of PHD2's therapeutic potential. [less ▲]

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See detailIn vitro evaluation of the anti-apoptotic drug Z-VAD-FMK on human ovarian granulosa cell lines for further use in ovarian tissue transplantation.
Fransolet, Maïté ULg; HENRY, Laurie ULg; Labied, Soraya et al

in Journal of Assisted Reproduction & Genetics (2015)

PURPOSE: Because ovarian granulosa cells are essential for oocyte survival, we examined three human granulosa cell lines as models to evaluate the ability of the pan-caspase inhibitor benzyloxycarbonyl ... [more ▼]

PURPOSE: Because ovarian granulosa cells are essential for oocyte survival, we examined three human granulosa cell lines as models to evaluate the ability of the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (Z-VAD-FMK) to prevent primordial follicle loss after ovarian tissue transplantation. METHODS: To validate the efficacy of Z-VAD-FMK, three human granulosa cell lines (GC1a, HGL5, COV434) were treated for 48 h with etoposide (50 mug/ml) and/or Z-VAD-FMK (50 muM) under normoxic conditions. To mimic the ischemic phase that occurs after ovarian fragment transplantation, cells were cultured without serum under hypoxia (1 % O2) and treated with Z-VAD-FMK. The metabolic activity of the cells was evaluated by WST-1 assay. Cell viability was determined by FACS analyses. The expression of apoptosis-related molecules was assessed by RT-qPCR and Western blot analyses. RESULTS: Our assessment of metabolic activity and FACS analyses in the normoxic experiments indicate that Z-VAD-FMK protects granulosa cells from etoposide-induced cell death. When cells are exposed to hypoxia and serum starvation, their metabolic activity is reduced. However, Z-VAD-FMK does not provide a protective effect. In the hypoxic experiments, the number of viable cells was not modulated, and we did not observe any modifications in the expressions of apoptosis-related molecules (p53, Bax, Bcl-xl, and poly (ADP-ribose) polymerase (PARP)). CONCLUSION: The death of granulosa cell lines was not induced in our ischemic model. Therefore, a protective effect of Z-VAD-FMK in vitro for further use in ovarian tissue transplantation could not be directly confirmed. It will be of interest to potentially use Z-VAD-FMK in vivo in xenograft models. [less ▲]

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See detailEndothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer.
Bovy, Nicolas ULg; Blomme, Benoît ULg; Freres, Pierre ULg et al

in Oncotarget (2015)

The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for ... [more ▼]

The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for the development of new anti-cancer therapies. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression. They are secreted into the extracellular medium in vesicles called exosomes, which allow communication between cells via the transfer of their cargo. Consequently, we hypothesized that circulating endothelial miRNAs could be transferred to tumor cells and modify their phenotype. Using exogenous miRNA, we demonstrated that endothelial cells can transfer miRNA to tumor cells via exosomes. Using miRNA profiling, we identified miR-503, which exhibited downregulated levels in exosomes released from endothelial cells cultured under tumoral conditions. The modulation of miR-503 in breast cancer cells altered their proliferative and invasive capacities. We then identified two targets of miR-503, CCND2 and CCND3. Moreover, we measured increased plasmatic miR-503 in breast cancer patients after neoadjuvant chemotherapy, which could be partly due to increased miRNA secretion by endothelial cells. Taken together, our data are the first to reveal the involvement of the endothelium in the modulation of tumor development via the secretion of circulating miR-503 in response to chemotherapy treatment. [less ▲]

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See detailSoluble factors regulated by epithelial-mesenchymal transition mediate tumour angiogenesis and myeloid cell recruitment.
Suarez-Carmona, Meggy ULg; Bourcy, Morgane ULg; LESAGE, J et al

in Journal of Pathology (The) (2015)

Epithelial-to-mesenchymal transition (EMT) programs provide cancer cells with invasive and survival capacities that might favor metastatic dissemination. Whilst signaling cascades triggering EMT have been ... [more ▼]

Epithelial-to-mesenchymal transition (EMT) programs provide cancer cells with invasive and survival capacities that might favor metastatic dissemination. Whilst signaling cascades triggering EMT have been extensively studied, the impact of EMT on the crosstalk between tumor cells and the tumor microenvironment remains elusive. We aimed to identify EMT-regulated soluble factors that facilitate the recruitment of host cells in the tumor. Our findings indicate that EMT phenotypes relate to the induction of a panel of secreted mediators, namely IL-8, IL-6, sICAM-1, PAI-1 and GM-CSF, and implicate the EMT-transcription factor Snail as a regulator of this process. We further show that EMT-derived soluble factors are pro-angiogenic in vivo (in the mouse ear sponge assay), ex vivo (in the rat aortic ring assay) and in vitro (in a chemotaxis assay). Additionally, conditioned medium from EMT-positive cells stimulates the recruitment of myeloid cells. In a bank of 40 triple-negative breast cancers, tumors presenting features of EMT were significantly more angiogenic and infiltrated by a higher quantity of myeloid cells compared to tumors with little or no EMT. Taken together, our results show that EMT programs trigger the expression of soluble mediators in cancer cells that stimulate angiogenesis and recruit myeloid cells in vivo, which might in turn favor cancer spread. [less ▲]

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See detailEstetrol is a weak estrogen antagonizing estradiol-dependent mammary gland proliferation.
Gérard, Céline ULg; Blacher, Silvia ULg; Communal, Laudine 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 ▲]

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See detailInfluence of mouse strain on ovarian tissue recovery after engraftment with angiogenic factor.
Fransolet, Maïté ULg; Henry, Laurie ULg; Labied, Soraya et al

in Journal of Ovarian Research (2015), 8(1), 14

BACKGROUND: For women facing gonadotoxic treatment, cryopreservation of ovarian tissue with subsequent retransplantation during remission is a promising technique for fertility preservation. However ... [more ▼]

BACKGROUND: For women facing gonadotoxic treatment, cryopreservation of ovarian tissue with subsequent retransplantation during remission is a promising technique for fertility preservation. However, follicle loss within grafted ovarian tissue can be caused by ischemia and progressive revascularization. Several xenograft models using different immunodeficient rodent lines are suitable for studying ovarian tissue survival and follicular viability after frozen-thawed ovarian cortex transplantation. SCID mice, which are deficient for functional B and T cells, are the most commonly used mice for ovarian xenograft studies. However, due to incomplete immunosuppression, NOD-SCID mice displaying low NK cell function and an absence of circulating complement might be more appropriate. The present study aims to define the most appropriate immunodeficient mouse strain for ovarian tissue xenotransplantation by comparing ovarian graft recovery in SCID and NOD-SCID mice following engraftment in the presence of isoform 111 of vascular endothelial growth factor. METHODS: Sheep ovarian cortex fragments were embedded in a collagen matrix, with or without VEGF111, before being stitched onto the ovaries of SCID and NOD-SCID mice. Transplants were recovered after 3 days to study early revascularization or after 3 weeks to evaluate follicle preservation and tissue fibrosis through histological analyses. RESULTS: At day 3, vessels were largely reorganized in the ovarian grafts of both mouse strains. After 3 weeks, the cortical tissue was clearly identifiable in SCID mice but not in NOD-SCID mice. Upon VEGF111 treatment, vascularization was significantly improved 3 days after transplantation in SCID mice. This increase in vessel density was correlated with better follicular preservation in SCID mice 3 weeks after transplantation. Fibrosis was not decreased by VEGF treatment in either mouse strain. CONCLUSIONS: Tissue architecture and follicular morphology were better preserved in ovarian tissues grafted in SCID mice in comparison with NOD-SCID mice. Moreover, tissue revascularization was improved in SCID mice by VEGF111 graft treatment. Thus, we consider SCID mice to be the best murine model for studying ovarian tissue xenografts. [less ▲]

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See detailIsoform 165 of vascular endothelial growth factor in collagen matrix improves ovine cryopreserved ovarian tissue revascularisation after xenotransplantation in mice.
Henry, Laurie ULg; LABIED, Soraya ULg; Fransolet, Maïté ULg et al

in Reproductive biology and endocrinology (2015), 13(1), 15

BACKGROUND: Aggressive anti-cancer treatments can result in ovarian failure. Ovarian cryopreservation has been developed to preserve the fertility of young women, but early graft revascularisation still ... [more ▼]

BACKGROUND: Aggressive anti-cancer treatments can result in ovarian failure. Ovarian cryopreservation has been developed to preserve the fertility of young women, but early graft revascularisation still requires improvement. METHODS: Frozen/thawed sheep ovarian cortical biopsies were embedded in collagen matrix with or without isoform 165 of vascular endothelial growth factor (VEGF165) and transplanted into ovaries of immunodeficient mice. Ovaries were chosen as transplantation sites to more closely resemble clinical conditions in which orthotopic transplantation has previously allowed several spontaneous pregnancies. RESULTS: We found that VEGF165 significantly increased the number of Dextran-FITC positive functional vessels 3 days after grafting. Dextran- fluorescein isothiocyanate (FITC) positive vessels were detectable in 53% and 29% of the mice in the VEGF-treated and control groups, respectively. Among these positive fragments, 50% in the treated group displayed mature smooth-muscle-actin-alpha (alpha-SMA) positive functional vessels compared with 0% in the control group. CD31 positive murine blood vessels were observed in 40% of the VEGF165 transplants compared with 21% of the controls. After 3 weeks, the density of murine vessels was significantly higher in the VEGF165 group. CONCLUSION: The encapsulation of ovarian tissue in collagen matrix in the presence of VEGF165 before grafting has a positive effect on functional blood vessel recruitment. It can be considered as a useful technique to be improved and further developed before human clinical applications in female cancer patients in the context of fertility preservation. [less ▲]

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See detailA Membrane-Type-1 Matrix Metalloproteinase (MT1-MMP) - Discoidin Domain Receptor 1 Axis Regulates Collagen-Induced Apoptosis in Breast Cancer Cells.
Assent, Delphine; Bourgot, Isabelle ULg; Hennuy, Benoît ULg et al

in PloS one (2015), 10(3), 0116006

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To ... [more ▼]

During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we have previously demonstrated that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. Here we performed a transcriptomic analysis to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells. [less ▲]

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