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Book ; Online: Pattern Formation in Morphogenesis

Capasso, Vincenzo / Gromov, Misha / Harel-Bellan, Annick / Morozova, Nadya / Pritchard, Linda Louise

Problems and Mathematical Issues

(Springer Proceedings in Mathematics ; 15)

2013

Abstract: Pattern Formation in Morphogenesis is a rich source of interesting and challenging mathematical problems. The volume offers an interdisciplinary interaction space between biologists working in this field and mathematicians, who may propose solutions to ... ...

Author's details	edited by Vincenzo Capasso, Misha Gromov, Annick Harel-Bellan, Nadya Morozova, Linda Louise Pritchard
Series title	Springer Proceedings in Mathematics ; 15
Abstract	Pattern Formation in Morphogenesis is a rich source of interesting and challenging mathematical problems. The volume offers an interdisciplinary interaction space between biologists working in this field and mathematicians, who may propose solutions to the problems put forward by biologists. The main goal is to facilitate the process of cultivating a mutual recognition of the complementary skills between biologists and mathematicians, to the point where the resulting synergy generates new and novel discoveries in the field of Developmental Biology. Lastly, the volume shows how a combination of new discoveries in developmental biology and associated mathematical modeling and computational techniques has stimulated or may stimulate relevant advances in the field.
Keywords	Bioinformatics ; Mathematics ; Medicine ; Microbial genetics ; Technik / Wissen Mathematik
Language	English
Size	Online-Ressource (VIII, 289 p. 118 illus., 81 illus. in color), digital
Publisher	Springer
Publishing place	Berlin ;Heidelberg
Document type	Book ; Online
Note	Description based upon print version of record
ISBN	9783642201639 ; 9783642201646 ; 3642201636 ; 3642201644
DOI	10.1007/978-3-642-20164-6
Database	Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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Article ; Online: Kinetic signatures of microRNA modes of action.

Morozova, Nadya / Zinovyev, Andrei / Nonne, Nora / Pritchard, Linda-Louise / Gorban, Alexander N / Harel-Bellan, Annick

RNA (New York, N.Y.)

2012 Volume 18, Issue 9, Page(s) 1635–1655

Abstract: MicroRNAs (miRNAs) are key regulators of all important biological processes, including development, differentiation, and cancer. Although remarkable progress has been made in deciphering the mechanisms used by miRNAs to regulate translation, many ... ...

Abstract	MicroRNAs (miRNAs) are key regulators of all important biological processes, including development, differentiation, and cancer. Although remarkable progress has been made in deciphering the mechanisms used by miRNAs to regulate translation, many contradictory findings have been published that stimulate active debate in this field. Here we contribute to this discussion in three ways. First, based on a comprehensive analysis of the existing literature, we hypothesize a model in which all proposed mechanisms of microRNA action coexist, and where the apparent mechanism that is detected in a given experiment is determined by the relative values of the intrinsic characteristics of the target mRNAs and associated biological processes. Among several coexisting miRNA mechanisms, the one that will effectively be measurable is that which acts on or changes the sensitive parameters of the translation process. Second, we have created a mathematical model that combines nine known mechanisms of miRNA action and estimated the model parameters from the literature. Third, based on the mathematical modeling, we have developed a computational tool for discriminating among different possible individual mechanisms of miRNA action based on translation kinetics data that can be experimentally measured (kinetic signatures). To confirm the discriminatory power of these kinetic signatures and to test our hypothesis, we have performed several computational experiments with the model in which we simulated the coexistence of several miRNA action mechanisms in the context of variable parameter values of the translation.
MeSH term(s)	Kinetics ; MicroRNAs/metabolism ; Models, Biological ; Protein Biosynthesis/physiology
Chemical Substances	MicroRNAs
Language	English
Publishing date	2012-07-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.032284.112
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Article: Histone acetyltransferases and deacetylases in the control of cell proliferation and differentiation.

Lehrmann, Heike / Pritchard, Linda Louise / Harel-Bellan, Annick

Advances in cancer research

2002 Volume 86, Page(s) 41–65

Abstract: Histone acetylation and deacetylation are chromatin-modifying processes that have fundamental importance for transcriptional regulation. Transcriptionally active chromatin regions show a high degree of histone acetylation, whereas deacetylation events ... ...

Abstract	Histone acetylation and deacetylation are chromatin-modifying processes that have fundamental importance for transcriptional regulation. Transcriptionally active chromatin regions show a high degree of histone acetylation, whereas deacetylation events are generally linked to transcriptional silencing. Many of the acetylating and deacetylating enzymes were originally identified as transcriptional coactivators or repressors. Their histone-modifying enzymatic activity was discovered more recently, opening up a whole new area of research. Histone acetyltransferases such as CREB-binding protein (CBP) and PCAF are involved in processes as diverse as promoting cell cycle progression and regulating differentiation. A controlled balance between histone acetylation and deacetylation seems to be essential for normal cell growth. Both histone acetyltransferases and deacetylases are involved in the development of diseases, including neurodegenerative disorders and cancer. Treatments that target these enzymes are already under clinical investigation.
MeSH term(s)	Acetylation ; Acetyltransferases/genetics ; Acetyltransferases/physiology ; Animals ; Cell Cycle/physiology ; Cell Differentiation/physiology ; Cell Division/physiology ; Cell Transformation, Neoplastic/genetics ; Chromatin/metabolism ; Chromatin/ultrastructure ; Gene Silencing/physiology ; Hematopoiesis ; Histone Acetyltransferases ; Histone Deacetylases/genetics ; Histone Deacetylases/physiology ; Histones/metabolism ; Humans ; Huntington Disease/metabolism ; Mice ; Multigene Family ; Muscle Proteins/physiology ; Neoplasm Proteins/physiology ; Neoplasms/enzymology ; Protein Processing, Post-Translational ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/physiology ; Transcription, Genetic/physiology
Chemical Substances	Chromatin ; Histones ; Muscle Proteins ; Neoplasm Proteins ; Saccharomyces cerevisiae Proteins ; Acetyltransferases (EC 2.3.1.-) ; Histone Acetyltransferases (EC 2.3.1.48) ; Histone Deacetylases (EC 3.5.1.98)
Language	English
Publishing date	2002-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	127-2
ISSN	2162-5557 ; 0065-230X
ISSN (online)	2162-5557
ISSN	0065-230X
DOI	10.1016/s0065-230x(02)86002-x
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Article ; Online: Preferential association of irreversibly silenced E2F-target genes with pericentromeric heterochromatin in differentiated muscle cells.

Guasconi, Valentina / Pritchard, Linda-Louise / Fritsch, Lauriane / Mesner, Larry D / Francastel, Claire / Harel-Bellan, Annick / Ait-Si-Ali, Slimane

Epigenetics

2010 Volume 5, Issue 8, Page(s) 704–709

Abstract: The heterochromatin-associated H3K9 tri-methylase Suv39h1 is involved in the permanent silencing of E2F target genes in differentiating but not in quiescent cells. Here, we tested the hypothesis that permanent silencing of E2F target genes is associated ... ...

Abstract	The heterochromatin-associated H3K9 tri-methylase Suv39h1 is involved in the permanent silencing of E2F target genes in differentiating but not in quiescent cells. Here, we tested the hypothesis that permanent silencing of E2F target genes is associated with their subnuclear positioning close to the pericentromeric heterochromatin compartment, enriched in Suv39h1. Using fluorescence in situ hybridization, we analyzed the subnuclear localization of three E2F target genes relative to the pericentromeric heterochromatin, in cycling fibroblasts or differentiating myoblasts. We observed that all three E2F-target genes have a tendency to relocate closer to the pericentromeric heterochromatin, only when cells differentiate and undergo an irreversible cell cycle withdrawal. These data suggest that repression of E2F target genes in cycling or in differentiating cells is achieved through distinct mechanisms. In differentiating cells, permanent silencing is driven by a Suv39h1-dependent H3K9 tri-methylation and positioning close to the heterochromatin compartment, whereas repression in cycling cells seems independent from subnuclear positioning and requires distinct H3K9 methylation levels.
MeSH term(s)	Cell Differentiation/physiology ; Cell Line ; E2F Transcription Factors/genetics ; E2F Transcription Factors/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Gene Silencing/physiology ; Heterochromatin/genetics ; Heterochromatin/metabolism ; Histones/metabolism ; Humans ; In Situ Hybridization, Fluorescence ; Methylation ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Muscle Cells/cytology ; Muscle Cells/metabolism ; Myoblasts/cytology ; Myoblasts/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism
Chemical Substances	E2F Transcription Factors ; Heterochromatin ; Histones ; Repressor Proteins ; SUV39H1 protein, human (EC 2.1.1.) ; Methyltransferases (EC 2.1.1.-)
Language	English
Publishing date	2010-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1559-2308
ISSN (online)	1559-2308
DOI	10.4161/epi.5.8.13025
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Article ; Online: Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness

Gest Caroline / Joimel Ulrich / Huang Limin / Pritchard Linda-Louise / Petit Alexandre / Dulong Charlène / Buquet Catherine / Hu Chao-Quan / Mirshahi Pezhman / Laurent Marc / Fauvel-Lafève Françoise / Cazin Lionel / Vannier Jean-Pierre / Lu He / Soria Jeannette / Li Hong / Varin Rémi / Soria Claudine

BMC Cancer, Vol 13, Iss 1, p

differences in MDA-MB-231 and MCF-7 breast cancer cell lines

2013 Volume 63

Abstract: Abstract Background Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. Methods This work was conducted ... ...

Abstract	Abstract Background Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. Methods This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA. Results Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells’ aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells’ aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness. Conclusions This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.
Keywords	Breast cancer ; Cancer aggressiveness ; Rac3 GTPases ; ERK ; NF-κB ; Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	616
Language	English
Publishing date	2013-02-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells

Vannier Jean-Pierre / Cazin Lionel / Blot Emmanuel / Laurent Marc / Alexandre Jérôme / Pritchard Linda-Louise / Soria Jeannette / Gest Caroline / Joimel Ulrich / Varin Rémi / Li Hong / Soria Claudine

BMC Cancer, Vol 10, Iss 1, p

proposed molecular mechanism and effect of tetrathiomolybdate

2010 Volume 375

Abstract: Abstract Background Infiltration by macrophages (Mφ) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mφ and aggressive breast cancer cells ( ...

Abstract	Abstract Background Infiltration by macrophages (Mφ) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mφ and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity. Methods Mφ coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mφ phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor α (TNFα) when stimulated by lipopolysaccharide/interferon γ (LPS/IFNγ); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mφ and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM. Results Incubation of Mφ with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mφ to switch from M1 Mφ towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNγ stimulation, an increased secretion of IL-10, a decreased secretion of TNFα in response to LPS/IFNγ and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR + and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines. Conclusions Cooperation between Mφ and MDA-MB-231 transformed M1 Mφ to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR + and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mφ phenotype or cytokine secretion profiles.
Keywords	Neoplasms. Tumors. Oncology. Including cancer and carcinogens ; RC254-282 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Oncology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences
Subject code	610
Language	English
Publishing date	2010-07-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets

Gest, Caroline / Mirshahi, Pezhman / Li, Hong / Pritchard, Linda-Louise / Joimel, Ulrich / Blot, Emmanuel / Chidiac, Jean / Poletto, Bernard / Vannier, Jean-Pierre / Varin, Remi / Mirshahi, Massoud / Cazin, Lionel / Pujade-Lauraine, Eric / Soria, Jeannette / Soria, Claudine

Cancer letters. 2012 Apr. 28, v. 317, no. 2

2012

Abstract: Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ... ...

Abstract	Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.
Keywords	animal ovaries ; cell invasion ; guanosinetriphosphatase ; models ; ovarian neoplasms ; patients ; secretion ; therapeutics
Language	English
Dates of publication	2012-0428
Size	p. 207-217.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2011.11.026
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Ovarian cancer: Stat3, RhoA and IGF-IR as therapeutic targets.

Cancer letters

2012 Volume 317, Issue 2, Page(s) 207–217

Abstract	Seeking to improve ovarian cancer therapy, we compared biological characteristics of the moderately-aggressive OVCAR-3 cell line with two highly aggressive ovarian cancer cell populations: the SK-OV-3 cell line, and HASCJ primary cells isolated from the ascitic fluid of a patient with FIGO stage IV ovarian cancer. Secretion of angiogenic factors was not discriminative, whereas cell invasion through Matrigel and vasculogenic mimicry were much greater in the more aggressive cells. Among 10 agents tested for their ability to decrease cancer cell aggressivity using these two models, inhibitors of Stat3, IGF-IR and Rho GTPase were found to be the most promising.
MeSH term(s)	Angiogenesis Inhibitors/pharmacology ; Angiogenesis Inhibitors/therapeutic use ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Drug Screening Assays, Antitumor/methods ; Female ; Humans ; Models, Biological ; Ovarian Neoplasms/drug therapy ; Ovarian Neoplasms/metabolism ; Ovarian Neoplasms/pathology ; Receptor, IGF Type 1/metabolism ; STAT3 Transcription Factor/metabolism ; Signal Transduction/drug effects ; Tumor Cells, Cultured ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Angiogenesis Inhibitors ; Antineoplastic Agents ; STAT3 Transcription Factor ; Receptor, IGF Type 1 (EC 2.7.10.1) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2012-04-28
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2011.11.026
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Article ; Online: Rac3 induces a molecular pathway triggering breast cancer cell aggressiveness: differences in MDA-MB-231 and MCF-7 breast cancer cell lines.

Gest, Caroline / Joimel, Ulrich / Huang, Limin / Pritchard, Linda-Louise / Petit, Alexandre / Dulong, Charlène / Buquet, Catherine / Hu, Chao-Quan / Mirshahi, Pezhman / Laurent, Marc / Fauvel-Lafève, Françoise / Cazin, Lionel / Vannier, Jean-Pierre / Lu, He / Soria, Jeannette / Li, Hong / Varin, Rémi / Soria, Claudine

BMC cancer

2013 Volume 13, Page(s) 63

Abstract: Background: Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood.: Methods: This work was conducted to ... ...

Abstract	Background: Rho GTPases are involved in cellular functions relevant to cancer. The roles of RhoA and Rac1 have already been established. However, the role of Rac3 in cancer aggressiveness is less well understood. Methods: This work was conducted to analyze the implication of Rac3 in the aggressiveness of two breast cancer cell lines, MDA-MB-231 and MCF-7: both express Rac3, but MDA-MB-231 expresses more activated RhoA. The effect of Rac3 in cancer cells was also compared with its effect on the non-tumorigenic mammary epithelial cells MCF-10A. We analyzed the consequences of Rac3 depletion by anti-Rac3 siRNA. Results: Firstly, we analyzed the effects of Rac3 depletion on the breast cancer cells' aggressiveness. In the invasive MDA-MB-231 cells, Rac3 inhibition caused a marked reduction of both invasion (40%) and cell adhesion to collagen (84%), accompanied by an increase in TNF-induced apoptosis (72%). This indicates that Rac3 is involved in the cancer cells' aggressiveness. Secondly, we investigated the effects of Rac3 inhibition on the expression and activation of related signaling molecules, including NF-κB and ERK. Cytokine secretion profiles were also analyzed. In the non-invasive MCF-7 line; Rac3 did not influence any of the parameters of aggressiveness. Conclusions: This discrepancy between the effects of Rac3 knockdown in the two cell lines could be explained as follows: in the MDA-MB-231 line, the Rac3-dependent aggressiveness of the cancer cells is due to the Rac3/ERK-2/NF-κB signaling pathway, which is responsible for MMP-9, interleukin-6, -8 and GRO secretion, as well as the resistance to TNF-induced apoptosis, whereas in the MCF-7 line, this pathway is not functional because of the low expression of NF-κB subunits in these cells. Rac3 may be a potent target for inhibiting aggressive breast cancer.
MeSH term(s)	Apoptosis ; Breast Neoplasms/enzymology ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Adhesion ; Cell Movement ; Cell Shape ; Cell Survival ; Collagen/metabolism ; Cytokines/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Female ; Humans ; MCF-7 Cells ; Matrix Metalloproteinase 9/metabolism ; NF-kappa B/metabolism ; Neoplasm Invasiveness ; RNA Interference ; Signal Transduction ; Time Factors ; Transfection ; Tumor Necrosis Factor-alpha/metabolism ; rac GTP-Binding Proteins/genetics ; rac GTP-Binding Proteins/metabolism ; rhoA GTP-Binding Protein/metabolism
Chemical Substances	Cytokines ; NF-kappa B ; RAC3 protein, human ; Tumor Necrosis Factor-alpha ; RHOA protein, human (124671-05-2) ; Collagen (9007-34-5) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; MMP9 protein, human (EC 3.4.24.35) ; Matrix Metalloproteinase 9 (EC 3.4.24.35) ; rac GTP-Binding Proteins (EC 3.6.5.2) ; rhoA GTP-Binding Protein (EC 3.6.5.2)
Language	English
Publishing date	2013-02-06
Publishing country	England
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/1471-2407-13-63
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Article ; Online: Stimulation of angiogenesis resulting from cooperation between macrophages and MDA-MB-231 breast cancer cells: proposed molecular mechanism and effect of tetrathiomolybdate.

Joimel, Ulrich / Gest, Caroline / Soria, Jeannette / Pritchard, Linda-Louise / Alexandre, Jérôme / Laurent, Marc / Blot, Emmanuel / Cazin, Lionel / Vannier, Jean-Pierre / Varin, Rémi / Li, Hong / Soria, Claudine

BMC cancer

2010 Volume 10, Page(s) 375

Abstract: Background: Infiltration by macrophages (Mphi) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mphi and aggressive breast cancer cells ( ... ...

Abstract	Background: Infiltration by macrophages (Mphi) indicates a poor prognosis in breast cancers, in particular by inducing angiogenesis. Our study aimed 1) to investigate the mechanism by which cooperation between Mphi and aggressive breast cancer cells (MDA-MB-231) induces angiogenesis; 2) to examine the effect of tetrathiomolybdate (TM) on this angiogenic activity. Methods: Mphi coincubated with MDA-MB-231 were used as a model to mimic the inflammatory microenvironment. Angiogenesis induced by the culture media was tested in the chick chorioallantoic membrane (CAM). Mphi phenotype was evaluated by 1) expression of the M1 marker CD80, and secretion of interleukin 10 (IL-10), an M2 marker; 2) capacity to secrete Tumour Necrosis Factor alpha (TNFalpha) when stimulated by lipopolysaccharide/interferon gamma (LPS/IFNgamma); 3) ability to induce MDA-MB-231 apoptosis. To explore the molecular mechanisms involved, cytokine profiles of conditioned media from MDA-MB-231, Mphi and the coculture were characterised by an antibody cytokine array. All experiments were carried out both in presence and in absence of TM. Results: Incubation of Mphi with MDA-MB-231 induced a pro-angiogenic effect in the CAM. It emerged that the angiogenic activity of the coculture is due to the capacity of Mphi to switch from M1 Mphi towards M2, probably due to an increase in Macrophage Colony Stimulating Factor. This M1-M2 switch was shown by a decreased expression of CD80 upon LPS/IFNgamma stimulation, an increased secretion of IL-10, a decreased secretion of TNFalpha in response to LPS/IFNgamma and an inability to potentiate apoptosis. At the molecular level, the angiogenic activity of the coculture medium can be explained by the secretion of CXC chemokines/ELR+ and CC chemokines. Although TM did not modify either the M2 phenotype in the coculture or the profile of the secreted chemokines, it did decrease the angiogenic activity of the coculture medium, suggesting that TM inhibited angiogenic activity by interfering with the endothelial cell signalling induced by these chemokines. Conclusions: Cooperation between Mphi and MDA-MB-231 transformed M1 Mphi to an angiogenic, M2 phenotype, attested by secretion of CXC chemokines/ELR+ and CC chemokines. TM inhibited this coculture-induced increase in angiogenic activity, without affecting either Mphi phenotype or cytokine secretion profiles.
MeSH term(s)	Angiogenesis Inhibitors/pharmacology ; Animals ; Apoptosis/drug effects ; Breast Neoplasms/blood supply ; Breast Neoplasms/drug therapy ; Breast Neoplasms/pathology ; Cells, Cultured ; Chemokines/metabolism ; Chick Embryo ; Coculture Techniques ; Culture Media, Conditioned/pharmacology ; Cytokines/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Fluorescent Antibody Technique ; Humans ; Interferon-gamma/pharmacology ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects ; Macrophages/metabolism ; Macrophages/pathology ; Molybdenum/pharmacology ; Neovascularization, Pathologic/prevention & control ; Recombinant Proteins
Chemical Substances	Angiogenesis Inhibitors ; Chemokines ; Culture Media, Conditioned ; Cytokines ; Lipopolysaccharides ; Recombinant Proteins ; Molybdenum (81AH48963U) ; Interferon-gamma (82115-62-6) ; tetrathiomolybdate (91U3TGV99T)
Language	English
Publishing date	2010-07-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1471-2407
ISSN (online)	1471-2407
DOI	10.1186/1471-2407-10-375
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Inter-library loan at ZB MED

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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito

Inter-library loan at ZB MED

More links

Kategorien

Order via subito

Inter-library loan at ZB MED