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Article ; Online: Rapid COVID-19 Prognostic Blood Test for Disease Severity Using Epigenetic Immune System Biomarkers.

Marsh, Adam G / Anderson, G Mark / Izdepski, Erich J

Delaware journal of public health

2020 Volume 6, Issue 2, Page(s) 26–29

Abstract: Objective: To develop a novel whole-blood epigenetic biomarker of immune system status, or EpiMarker, that would indicate whether a person with a recent COVID-19 diagnosis is at risk for severe symptoms including Acute Respiratory Distress Syndrome.: ... ...

Abstract	Objective: To develop a novel whole-blood epigenetic biomarker of immune system status, or EpiMarker, that would indicate whether a person with a recent COVID-19 diagnosis is at risk for severe symptoms including Acute Respiratory Distress Syndrome. Methods: Using a novel methyl-sensitive restriction endonuclease approach to measure site-specific DNA methylation profiles, immune system phentoype EpiMarkers are identified using a machine-learning computational bioinformatics platform. The result is a diagnostic network of 20 to 40 immuno DNA methylation sites having the greatest predictive power for identifying patients whose COVID-19 disease will likely progress to ARDS requiring ICU/intubation care. Results: Immune system status in peripheral whole blood provides a sensitive and responsive sentinel signal reflecting how different functional pathways are currently being regulated in a subject. Deciphering this signal status of how immune cells are set to respond provides deep functional information regarding patient health and potential disease phenotypes resulting from a cytokine storm characteristic of a hyper immune inflammatory response to COVID-19 infection. Conclusions: The ability to identify future potential changes in patient health using this novel EpiMarker technology opens new avenues for defending populations from severe disease risks of Acute Respiratory Distress Syndrome. Policy implications: A successful EpiMarker Assay for COVID-19 disease severity risk would allow for two important applications: (1) patients could be triaged early in the course of infection to allow for critical decisions for allocating resources, both in terms of hospital infrastructure (ICU beds, ventilators) and therapeutic drug treatments; and (2) pre-infection, individuals could be screened to identify personnel at low-risk for mission critical assignments (first responders, doctors, nurses, military personnel, etc.) during future pandemics and ongoing battles with viral pathogens like influenza.
Language	English
Publishing date	2020-07-01
Publishing country	United States
Document type	Journal Article
ISSN	2639-6378
ISSN (online)	2639-6378
DOI	10.32481/djph.2020.07.08
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Article ; Online: Inhibition of tissue factor signaling in breast tumour xenografts induces widespread changes in the microRNA expression profile.

D'Asti, Esterina / Anderson, G Mark / Rak, Janusz

Biochemical and biophysical research communications

2017 Volume 494, Issue 3-4, Page(s) 700–705

Abstract: Tissue factor (TF) is a transmembrane receptor for coagulation factor VII/VIIa and is frequently overexpressed by cancer cells. The TF/VIIa complex acts as the main initiator of the clotting cascade in blood and a trigger of intracellular signaling that ... ...

Abstract	Tissue factor (TF) is a transmembrane receptor for coagulation factor VII/VIIa and is frequently overexpressed by cancer cells. The TF/VIIa complex acts as the main initiator of the clotting cascade in blood and a trigger of intracellular signaling that changes gene expression and the cellular phenotype. However, pathways mediating these changes are still poorly characterized and especially the impact of TF signals on regulatory microRNA (miR) networks in cancer remains unknown. We show that the monoclonal antibody that selectively neutralises the signaling (but not coagulant) function of human TF (CNTO 2559) inhibits progression of MDA-MB-231 breast cancer xenografts in mice and prolongs animal survival. CNTO 2559 blocks FVIIa-induced expression of interleukin 8 (IL-8) by cancer cells without impacting factor Xa (FXa) generation. Notably, acute exposure of MDA-MB-231 tumour xenografts to CNTO 2559 systemic injections triggers wide spread changes in the tumour miR profile including alterations in 75 miRs (55 downregulated) and impacting several miR-regulated and cancer-related pathways. These results suggest that TF signaling in the tumour microenvironment may provoke vast changes in the miR profile of cancer cells, affect disease biology, and reflect tumour interaction with the coagulation system, thereby presenting itself as a possible biomarker.
Language	English
Publishing date	2017-12-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	205723-2
ISSN	1090-2104 ; 0006-291X ; 0006-291X
ISSN (online)	1090-2104 ; 0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2017.10.139
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Article ; Online: Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET.

Neijssen, Joost / Cardoso, Rosa M F / Chevalier, Kristen M / Wiegman, Luus / Valerius, Thomas / Anderson, G Mark / Moores, Sheri L / Schuurman, Janine / Parren, Paul W H I / Strohl, William R / Chiu, Mark L

The Journal of biological chemistry

2021 Volume 296, Page(s) 100641

Abstract: A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung ... ...

Abstract	A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non-small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain-Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.
MeSH term(s)	Animals ; Antibodies, Bispecific/pharmacology ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Carcinoma, Non-Small-Cell Lung/immunology ; Carcinoma, Non-Small-Cell Lung/metabolism ; Carcinoma, Non-Small-Cell Lung/pathology ; Cell Proliferation ; Drug Discovery ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/immunology ; Female ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Lung Neoplasms/pathology ; Mice ; Proto-Oncogene Proteins c-met/antagonists & inhibitors ; Proto-Oncogene Proteins c-met/immunology ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
Chemical Substances	Antibodies, Bispecific ; amivantamab-vmjw ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1) ; MET protein, human (EC 2.7.10.1) ; Proto-Oncogene Proteins c-met (EC 2.7.10.1)
Language	English
Publishing date	2021-04-08
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2021.100641
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Article ; Online: Crystal structure of tissue factor in complex with antibody 10H10 reveals the signaling epitope.

Teplyakov, Alexey / Obmolova, Galina / Malia, Thomas J / Wu, Bingyuan / Zhao, Yonghong / Taudte, Susann / Anderson, G Mark / Gilliland, Gary L

Cellular signalling

2017 Volume 36, Page(s) 139–144

Abstract: Tissue factor (TF) initiates the extrinsic pathway of blood coagulation through sequential binding and activation of coagulation factors VII (FVII) and X (FX). In addition, through activation of G-protein-coupled protease activated receptors (PARs) TF ... ...

Abstract	Tissue factor (TF) initiates the extrinsic pathway of blood coagulation through sequential binding and activation of coagulation factors VII (FVII) and X (FX). In addition, through activation of G-protein-coupled protease activated receptors (PARs) TF induces cell signaling that is related to cancer, angiogenesis and inflammation. Monoclonal antibodies (mAbs) proved to be a useful tool for studying the interplay between TF signaling and coagulation. MAb 10H10 is unique in that it blocks the signaling pathway and thus inhibits angiogenesis and tumor growth without interfering with coagulation. It was also presumed that mAb 10H10 recognizes the cryptic pool of TF devoid of procoagulant activity. The crystal structure of the 10H10 Fab was determined in the absence and in the presence of the TF extracellular domain (ECD). The structures show that the antibody operates by the key-and-lock mechanism causing no conformational changes in either Fab or TF. The TF:10H10 interface is extensive and includes five segments of TF in both the N-terminal and C-terminal domains of the ECD. Neither the known epitope of FVII, nor the putative epitope of FX overlaps with the 10H10 binding site. The 10H10 epitope points to the likely location of the PAR2 exosite. It is also the hypothetical site of TF interaction with integrins that may play a major role in the encryption-decryption process.
MeSH term(s)	Animals ; Antibodies, Monoclonal/metabolism ; Crystallography, X-Ray ; Epitopes/metabolism ; Humans ; Immunoglobulin Fab Fragments/chemistry ; Immunoglobulin Fab Fragments/metabolism ; Mice ; Models, Molecular ; Protein Structure, Secondary ; Signal Transduction ; Thromboplastin/chemistry ; Thromboplastin/metabolism
Chemical Substances	Antibodies, Monoclonal ; Epitopes ; Immunoglobulin Fab Fragments ; Thromboplastin (9035-58-9)
Language	English
Publishing date	2017-05-05
Publishing country	England
Document type	Journal Article
ZDB-ID	1002702-6
ISSN	1873-3913 ; 0898-6568
ISSN (online)	1873-3913
ISSN	0898-6568
DOI	10.1016/j.cellsig.2017.05.004
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Article: The contribution of tumor and host tissue factor expression to oncogene-driven gliomagenesis

Magnus, Nathalie / Meehan, Brian / Garnier, Delphine / Hashemi, Maryam / Montermini, Laura / Lee, Tae Hoon / Milsom, Chloe / Pawlinski, Rafal / Ohlfest, John / Anderson, G. Mark / Mackman, Nigel / Rak, Janusz

Biochemical and biophysical research communications. 2014 Nov. 14, v. 454

2014

Abstract: Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic ... ...

Abstract	Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic mutations occurring in different subsets of human brain tumors we investigated whether TF contributes to tumourigenesis driven by oncogenic activation of EGFR (EGFRvIII) and RAS pathways in the brain. Here we show that TF expression correlates with poor prognosis in glioma, but not in GBM. In situ, the TF protein expression is heterogeneously expressed in adult and pediatric gliomas. GBM cells harboring EGFRvIII (U373vIII) grow aggressively as xenografts in SCID mice and their progression is delayed by administration of monoclonal antibodies blocking coagulant (CNTO 859) and signaling (10H10) effects of TF in vivo. Mice in which TF gene is disrupted in the neuroectodermal lineage exhibit delayed progression of spontaneous brain tumors driven by oncogenic N-ras and SV40 large T antigen (SV40LT) expressed under the control of sleeping beauty transposase. Reduced host TF levels in low-TF/SCID hypomorphic mice mitigated growth of glioma subcutaneously but not in the brain. Thus, we suggest that tumor-associated TF may serve as therapeutic target in the context of oncogene-driven disease progression in a subset of glioma.
Keywords	adults ; angiogenesis ; antigens ; brain ; carcinogenesis ; coagulation ; disease course ; gene expression regulation ; genes ; humans ; mice ; monoclonal antibodies ; mutation ; neoplasms ; prognosis ; protein synthesis ; severe combined immunodeficiency ; thrombosis
Language	English
Dates of publication	2014-1114
Size	p. 262-268.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	205723-2
ISSN	0006-291X ; 0006-291X
ISSN (online)	0006-291X
ISSN	0006-291X
DOI	10.1016/j.bbrc.2014.10.041
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Article: Tumor necrosis factor-alpha in the pathogenesis and treatment of cancer.

Anderson, G Mark / Nakada, Marian T / DeWitte, Mark

Current opinion in pharmacology

2004 Volume 4, Issue 4, Page(s) 314–320

Abstract: The critical pathogenic role of tumor necrosis factor (TNF)alpha in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease is well established. The role played by TNFalpha in both the treatment and pathogenesis of cancer ... ...

Abstract	The critical pathogenic role of tumor necrosis factor (TNF)alpha in inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease is well established. The role played by TNFalpha in both the treatment and pathogenesis of cancer remains less understood. Recent advances help to create a framework for understanding seemingly paradoxical effects of TNFalpha as both an anti-tumour agent and a mediator of tumour growth. High pharmacological doses of TNFalpha combined with chemotherapy can regress otherwise intractable tumours, and efforts continue to optimize delivery to avoid severe toxicities. Mounting evidence demonstrates that pathophysiological concentrations of endogenous TNFalpha act to promote tumour genesis and growth. The cellular and molecular pathways mediating these phenomena are starting to be clarified. Current data support the continued development of both TNFalpha and anti-TNFalpha therapy for clinical treatment of cancers in distinct settings.
MeSH term(s)	Animals ; Humans ; Neoplasms/etiology ; Neoplasms/therapy ; Signal Transduction ; Tumor Necrosis Factor-alpha/antagonists & inhibitors ; Tumor Necrosis Factor-alpha/physiology ; Tumor Necrosis Factor-alpha/therapeutic use
Chemical Substances	Tumor Necrosis Factor-alpha
Language	English
Publishing date	2004-08
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2037057-X
ISSN	1471-4973 ; 1471-4892
ISSN (online)	1471-4973
ISSN	1471-4892
DOI	10.1016/j.coph.2004.04.004
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Article: Therapeutic potential of cytokine and chemokine antagonists in cancer therapy.

Yan, Li / Anderson, G Mark / DeWitte, Mark / Nakada, Marian T

European journal of cancer (Oxford, England : 1990)

2006 Volume 42, Issue 6, Page(s) 793–802

Abstract: A new paradigm is becoming widely accepted, that chronic inflammation, driven in part by chemokines and cytokines at the site of a tumour, may facilitate tumour progression instead of promoting anti-tumour immunity. Tumours and activated stromal cells ... ...

Abstract	A new paradigm is becoming widely accepted, that chronic inflammation, driven in part by chemokines and cytokines at the site of a tumour, may facilitate tumour progression instead of promoting anti-tumour immunity. Tumours and activated stromal cells secrete pro-inflammatory chemokines and cytokines that act either directly or indirectly through stimulation of the vascular endothelium to recruit leukocytes to the tumour. After activation, these tumour-associated leukocytes release angiogenic factors, mitogens, proteolytic enzymes, and chemotactic factors, recruiting more inflammatory cells and stimulating angiogenesis to sustain tumour growth and facilitate tumour metastasis. Breaking this cycle by inhibiting targets such as cytokines, chemokines and other inflammatory mediators, either alone, or more realistically, in combination with other therapies, such as anti-angiogenic or cytotoxic agents, may provide highly efficacious therapeutic regimens for the treatment of malignancies. This article reviews anti-cytokine and anti-chemokine therapies being pursued in cancer, and discusses in more detail anti-tumour necrosis factor-alpha (TNF) approaches.
MeSH term(s)	Chemokines/antagonists & inhibitors ; Cytokines/antagonists & inhibitors ; Disease Progression ; Humans ; Inflammation/physiopathology ; Neoplasms/therapy ; Risk Factors
Chemical Substances	Chemokines ; Cytokines
Language	English
Publishing date	2006-04
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	82061-1
ISSN	1879-0852 ; 0959-8049 ; 0277-5379 ; 0964-1947
ISSN (online)	1879-0852
ISSN	0959-8049 ; 0277-5379 ; 0964-1947
DOI	10.1016/j.ejca.2006.01.013
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Article ; Online: Endothelial protein C receptor function in murine and human breast cancer development.

Schaffner, Florence / Yokota, Naho / Carneiro-Lobo, Tatiana / Kitano, Maki / Schaffer, Michael / Anderson, G Mark / Mueller, Barbara M / Esmon, Charles T / Ruf, Wolfram

PloS one

2013 Volume 8, Issue 4, Page(s) e61071

Abstract: Several markers identify cancer stem cell-like populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. Here, we show that the endothelial protein C receptor (EPCR), a stem cell marker in ... ...

Abstract	Several markers identify cancer stem cell-like populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. Here, we show that the endothelial protein C receptor (EPCR), a stem cell marker in hematopoietic, neuronal and epithelial cells, is crucial for breast cancer growth in the orthotopic microenvironment of the mammary gland. Mice with a hypomorphic allele of EPCR show reduced tumor growth in the PyMT-model of spontaneous breast cancer development and deletion of EPCR in established PyMT tumor cells significantly attenuates transplanted tumor take and growth. We find expansion of EPCR(+) cancer stem cell-like populations in aggressive, mammary fat pad-enhanced human triple negative breast cancer cells. In this model, EPCR-expressing cells have markedly increased mammosphere- and tumor-cell initiating activity compared to another stable progenitor-like subpopulation present at comparable frequency. We show that receptor blocking antibodies to EPCR specifically attenuate in vivo tumor growth initiated by either EPCR(+) cells or the heterogenous mixture of EPCR(+) and EPCR(-) cells. Furthermore, we have identified tumor associated macrophages as a major source for recognized ligands of EPCR, suggesting a novel mechanism by which cancer stem cell-like populations are regulated by innate immune cells in the tumor microenvironment.
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Antigens, CD/genetics ; Antigens, CD/metabolism ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cluster Analysis ; Disease Models, Animal ; Endothelial Protein C Receptor ; Female ; Gene Expression Profiling ; Glycoproteins/antagonists & inhibitors ; Glycoproteins/genetics ; Glycoproteins/metabolism ; Humans ; Macrophages/metabolism ; Macrophages/pathology ; Mammary Glands, Animal/metabolism ; Mice ; Neoplastic Stem Cells/metabolism ; Receptors, Cell Surface/antagonists & inhibitors ; Receptors, Cell Surface/genetics ; Receptors, Cell Surface/metabolism ; Transplantation, Heterologous ; Tumor Burden/genetics
Chemical Substances	Antigens, CD ; Endothelial Protein C Receptor ; Glycoproteins ; PROCR protein, human ; Procr protein, mouse ; Receptors, Cell Surface
Language	English
Publishing date	2013-04-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0061071
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Article ; Online: Tissue factor regulation by epidermal growth factor receptor and epithelial-to-mesenchymal transitions: effect on tumor initiation and angiogenesis.

Milsom, Chloe C / Yu, Joanne L / Mackman, Nigel / Micallef, Johann / Anderson, G Mark / Guha, Abhijit / Rak, Janusz W

Cancer research

2008 Volume 68, Issue 24, Page(s) 10068–10076

Abstract: ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue ... ...

Abstract	ErbB oncogenes drive the progression of several human cancers. Our study shows that in human carcinoma (A431) and glioma (U373) cells, the oncogenic forms of epidermal growth factor receptor (EGFR; including EGFRvIII) trigger the up-regulation of tissue factor (TF), the transmembrane protein responsible for initiating blood coagulation and signaling through interaction with coagulation factor VIIa. We show that A431 cancer cells in culture exhibit a uniform TF expression profile; however, these same cells in vivo exhibit a heterogeneous TF expression and show signs of E-cadherin inactivation, which is coupled with multilineage (epithelial and mesenchymal) differentiation. Blockade of E-cadherin in vitro, leads to the acquisition of spindle morphology and de novo expression of vimentin, features consistent with epithelial-to-mesenchymal transition. These changes were associated with an increase in EGFR-dependent TF expression, and with enhanced stimulation of vascular endothelial growth factor production, particularly following cancer cell treatment with coagulation factor VIIa. In vivo, cells undergoing epithelial-to-mesenchymal transition exhibited an increased metastatic potential. Furthermore, injections of the TF-blocking antibody (CNTO 859) delayed the initiation of A431 tumors in immunodeficient mice, and reduced tumor growth, vascularization, and vascular endothelial growth factor expression. Collectively, our data suggest that TF is regulated by both oncogenic and differentiation pathways, and that it functions in tumor initiation, tumor growth, angiogenesis, and metastasis. Thus, TF could serve as a therapeutic target in EGFR-dependent malignancies.
MeSH term(s)	Animals ; Cadherins ; Carcinoma, Squamous Cell/blood supply ; Carcinoma, Squamous Cell/genetics ; Carcinoma, Squamous Cell/metabolism ; Carcinoma, Squamous Cell/pathology ; Cell Differentiation/physiology ; Cell Line, Tumor ; Epithelial Cells/pathology ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Flow Cytometry ; Glioma/blood supply ; Glioma/genetics ; Glioma/metabolism ; Glioma/pathology ; Humans ; Mesoderm/pathology ; Mice ; Mice, SCID ; Neoplasm Metastasis ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/metabolism ; Neovascularization, Pathologic/pathology ; Thromboplastin/biosynthesis ; Thromboplastin/genetics ; Up-Regulation ; Vascular Endothelial Growth Factor A/biosynthesis ; Vimentin/biosynthesis
Chemical Substances	Cadherins ; Vascular Endothelial Growth Factor A ; Vimentin ; epidermal growth factor receptor VIII ; Thromboplastin (9035-58-9) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2008-12-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-08-2067
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Article ; Online: Contribution of host-derived tissue factor to tumor neovascularization.

Yu, Joanne / May, Linda / Milsom, Chloe / Anderson, G Mark / Weitz, Jeffrey I / Luyendyk, James P / Broze, George / Mackman, Nigel / Rak, Janusz

Arteriosclerosis, thrombosis, and vascular biology

2008 Volume 28, Issue 11, Page(s) 1975–1981

Abstract: Objective: The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study.: Methods and results: We compared tumor growth, vascularity, and responses to ... ...

Abstract	Objective: The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study. Methods and results: We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types of transplantable tumors (LLC, B16F1, and ES teratoma) or metastasis were unchanged in low-TF mice. However, several unexpected tumor/context-specific alterations were observed in these mice, including: (1) reduced tumor blood vessel size in B16F1 tumors; (2) larger spleen size and greater tolerance to CTX toxicity in the LLC model; (3) aborted tumor growth after inoculation of TF-deficient tumor cells (ES TF(-/-)) in low-TF mice. TF-deficient tumor cells grew readily in mice with normal TF levels and attracted exclusively host-related blood vessels (without vasculogenic mimicry). We postulate that this complementarity may result from tumor-vascular transfer of TF-containing microvesicles, as we observed such transfer using human cancer cells (A431) and mouse endothelial cells, both in vitro and in vivo. Conclusions: Our study points to an important but context-dependent role of host TF in tumor formation, angiogenesis and therapy.
MeSH term(s)	Animals ; Antineoplastic Agents, Alkylating/pharmacology ; Carcinoma, Lewis Lung/blood supply ; Carcinoma, Lewis Lung/drug therapy ; Carcinoma, Lewis Lung/metabolism ; Carcinoma, Lewis Lung/pathology ; Cell Line, Tumor ; Cell Survival ; Cyclophosphamide/pharmacology ; Embryonic Stem Cells/metabolism ; Endothelial Cells/metabolism ; Humans ; Melanoma, Experimental/blood supply ; Melanoma, Experimental/drug therapy ; Melanoma, Experimental/metabolism ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred C57BL ; Mice, SCID ; Neoplasm Metastasis ; Neoplastic Stem Cells/metabolism ; Neovascularization, Pathologic/metabolism ; Secretory Vesicles/metabolism ; Teratoma/blood supply ; Teratoma/drug therapy ; Teratoma/metabolism ; Teratoma/pathology ; Thromboplastin/deficiency ; Thromboplastin/metabolism ; Time Factors
Chemical Substances	Antineoplastic Agents, Alkylating ; Cyclophosphamide (8N3DW7272P) ; Thromboplastin (9035-58-9)
Language	English
Publishing date	2008-09-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.108.175083
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