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Article ; Online: Cancer cell autophagy, reprogrammed macrophages, and remodeled vasculature in glioblastoma triggers tumor immunity.

Chryplewicz, Agnieszka / Scotton, Julie / Tichet, Mélanie / Zomer, Anoek / Shchors, Ksenya / Joyce, Johanna A / Homicsko, Krisztian / Hanahan, Douglas

Cancer cell

2022 Volume 40, Issue 10, Page(s) 1111–1127.e9

Abstract: Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities ... ...

Abstract	Glioblastoma (GBM) is poorly responsive to therapy and invariably lethal. One conceivable strategy to circumvent this intractability is to co-target distinctive mechanistic components of the disease, aiming to concomitantly disrupt multiple capabilities required for tumor progression and therapeutic resistance. We assessed this concept by combining vascular endothelial growth factor (VEGF) pathway inhibitors that remodel the tumor vasculature with the tricyclic antidepressant imipramine, which enhances autophagy in GBM cancer cells and unexpectedly reprograms immunosuppressive tumor-associated macrophages via inhibition of histamine receptor signaling to become immunostimulatory. While neither drug is efficacious as monotherapy, the combination of imipramine with VEGF pathway inhibitors orchestrates the infiltration and activation of CD8 and CD4 T cells, producing significant therapeutic benefit in several GBM mouse models. Inclusion up front of immune-checkpoint blockade with anti-programmed death-ligand 1 (PD-L1) in eventually relapsing tumors markedly extends survival benefit. The results illustrate the potential of mechanism-guided therapeutic co-targeting of disparate biological vulnerabilities in the tumor microenvironment.
MeSH term(s)	Animals ; Antidepressive Agents, Tricyclic/metabolism ; Antidepressive Agents, Tricyclic/therapeutic use ; Autophagy ; B7-H1 Antigen/metabolism ; Glioblastoma/pathology ; Imipramine/metabolism ; Imipramine/therapeutic use ; Immune Checkpoint Inhibitors ; Immunotherapy ; Macrophages/metabolism ; Mice ; Neoplasm Recurrence, Local/drug therapy ; Programmed Cell Death 1 Receptor ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A/metabolism
Chemical Substances	Antidepressive Agents, Tricyclic ; B7-H1 Antigen ; Immune Checkpoint Inhibitors ; Programmed Cell Death 1 Receptor ; Vascular Endothelial Growth Factor A ; Imipramine (OGG85SX4E4)
Language	English
Publishing date	2022-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2022.08.014
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dual Targeting of the Autophagic Regulatory Circuitry in Gliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit.

Shchors, Ksenya / Massaras, Aristea / Hanahan, Douglas

Cancer cell

2015 Volume 28, Issue 4, Page(s) 456–471

Abstract: The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and ... ...

Abstract	The associations of tricyclic antidepressants (TCAs) with reduced incidence of gliomas and elevated autophagy in glioma cells motivated investigation in mouse models of gliomagenesis. First, we established that imipramine, a TCA, increased autophagy and conveyed modest therapeutic benefit in tumor-bearing animals. Then we screened clinically approved agents suggested to affect autophagy for their ability to enhance imipramine-induced autophagy-associated cell death. The anticoagulant ticlopidine, which inhibits the purinergic receptor P2Y12, potentiated imipramine, elevating cAMP, a modulator of autophagy, reducing cell viability in culture, and increasing survival in glioma-bearing mice. Efficacy of the combination was obviated by knockdown of the autophagic regulatory gene ATG7, implicating cell-lethal autophagy. This seemingly innocuous combination of TCAs and P2Y12 inhibitors may have applicability for treating glioma.
MeSH term(s)	Animals ; Anticoagulants/administration & dosage ; Anticoagulants/pharmacology ; Antidepressive Agents, Tricyclic/administration & dosage ; Antidepressive Agents, Tricyclic/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/administration & dosage ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Autophagy/drug effects ; Autophagy-Related Protein 7 ; Brain Neoplasms/drug therapy ; Brain Neoplasms/mortality ; Brain Neoplasms/pathology ; Cell Survival/drug effects ; Drug Repositioning ; Drug Synergism ; Gene Knockdown Techniques ; Glioma/drug therapy ; Glioma/mortality ; Glioma/pathology ; Imipramine/administration & dosage ; Imipramine/pharmacology ; Mice ; Microtubule-Associated Proteins/genetics ; Survival Analysis ; Ticlopidine/administration & dosage ; Ticlopidine/pharmacology ; Xenograft Model Antitumor Assays
Chemical Substances	Anticoagulants ; Antidepressive Agents, Tricyclic ; Atg7 protein, mouse ; Microtubule-Associated Proteins ; Autophagy-Related Protein 7 (EC 6.2.1.45) ; Imipramine (OGG85SX4E4) ; Ticlopidine (OM90ZUW7M1)
Language	English
Publishing date	2015-10-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2015.08.012
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Article: Tumor angiogenesis: cause or consequence of cancer?

Shchors, Ksenya / Evan, Gerard

Cancer research

2007 Volume 67, Issue 15, Page(s) 7059–7061

Abstract: Both tumors and normal tissues need a blood supply for oxygen, nutrients, and waste removal. However, whereas normal vasculature is hierarchically assembled into efficient networks of arteries, capillaries, and veins, the blood vessels of tumors are a ... ...

Abstract	Both tumors and normal tissues need a blood supply for oxygen, nutrients, and waste removal. However, whereas normal vasculature is hierarchically assembled into efficient networks of arteries, capillaries, and veins, the blood vessels of tumors are a mess-chaotic, leaky, inefficient, and barely making do. Why the difference? Do tumor vessels lack the signals to mature or, instead, is their maturation actively suppressed? What triggers and maintains tumor vasculature? In a recent study using a switchable Myc-driven mouse tumor model, we addressed these fundamental questions. We identified the inflammatory cytokine interleukin-1beta as an essential initiating trigger of vascular endothelial growth factor-dependent angiogenesis. Here, we consider how kinetic studies using regulatable forms of Myc or other oncogenes can shed new light on the way tumors initiate and maintain their aberrant blood supplies.
MeSH term(s)	Angiogenesis Inducing Agents/therapeutic use ; Angiogenesis Inhibitors/therapeutic use ; Animals ; Humans ; Neoplasms/blood supply ; Neovascularization, Pathologic/drug therapy
Chemical Substances	Angiogenesis Inducing Agents ; Angiogenesis Inhibitors
Language	English
Publishing date	2007-08-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-07-2053
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Article ; Online: Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness.

Sabelström, Hanna / Petri, Rebecca / Shchors, Ksenya / Jandial, Rahul / Schmidt, Christin / Sacheva, Rohit / Masic, Selma / Yuan, Edith / Fenster, Trenten / Martinez, Michael / Saxena, Supna / Nicolaides, Theodore P / Ilkhanizadeh, Shirin / Berger, Mitchel S / Snyder, Evan Y / Weiss, William A / Jakobsson, Johan / Persson, Anders I

Cell reports

2019 Volume 28, Issue 8, Page(s) 2064–2079.e11

Abstract: Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem- ... ...

Abstract	Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM.
MeSH term(s)	Animals ; Astrocytoma/genetics ; Astrocytoma/pathology ; Benzamides/pharmacology ; Brain Neoplasms/genetics ; Brain Neoplasms/pathology ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Survival/drug effects ; Diphenylamine/analogs & derivatives ; Diphenylamine/pharmacology ; Disease Progression ; Female ; Glioblastoma/genetics ; Glioblastoma/pathology ; Humans ; MAP Kinase Signaling System/drug effects ; Male ; Mice, Nude ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Neoplasm Invasiveness ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Neurogenesis/drug effects ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Phenotype ; Protein Kinase Inhibitors/pharmacology ; Radiation Tolerance/drug effects ; SOX9 Transcription Factor/metabolism
Chemical Substances	Benzamides ; MIRN124 microRNA, human ; MicroRNAs ; Protein Kinase Inhibitors ; SOX9 Transcription Factor ; mirdametinib (86K0J5AK6M) ; Diphenylamine (9N3CBB0BIQ)
Language	English
Publishing date	2019-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2019.07.071
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Article: Mechanisms of c-myc-mediated transcriptional repression of growth arrest genes.

Gartel, Andrei L / Shchors, Ksenya

Experimental cell research

2003 Volume 283, Issue 1, Page(s) 17–21

Abstract: Constitutive expression of the proto-oncogene c-myc results in oncogenic activation and contributes to progression of a wide range of human and animal tumors. Myc executes its multiple activities mostly through transcriptional regulation of the target ... ...

Abstract	Constitutive expression of the proto-oncogene c-myc results in oncogenic activation and contributes to progression of a wide range of human and animal tumors. Myc executes its multiple activities mostly through transcriptional regulation of the target genes. The special interest of this review is the mechanism of transcriptional repression of cell cycle inhibitors by Myc. Myc suppresses expression of cell cycle/growth arrest genes gas1, p15, p21, p27, and gadd34, -45, and -153. It appears that Myc represses growth arrest gene transcription by at least two distinct mechanisms. One mechanism is limited to the binding of Myc-Max heterodimers to the Inr element in their promoters and inhibition of Miz-1 or other transcriptional activators via the C-terminal domain of c-Myc. This mechanism requires DNA binding of the Myc-Max complex to Inr sequences. The other mechanism is dependent on c-Myc binding to the Sp1 transcription factor via the c-Myc central region and inhibition of Sp1 transcriptional activity. At this time it is not entirely clear which Sp1-containing promoters will be repressed by c-Myc and what other modes of c-Myc transcriptional repression may exist. The ability of c-Myc to repress transcription of growth arrest genes may contribute to its potential to promote proliferation and oncogenesis.
MeSH term(s)	Animals ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Division/genetics ; Cell Transformation, Neoplastic/genetics ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Eukaryotic Cells/metabolism ; Genes, Regulator/genetics ; Genes, cdc/physiology ; Humans ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; Repressor Proteins/genetics
Chemical Substances	Cell Cycle Proteins ; DNA-Binding Proteins ; Proto-Oncogene Proteins c-myc ; Repressor Proteins
Language	English
Publishing date	2003-02-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1493-x
ISSN	1090-2422 ; 0014-4827
ISSN (online)	1090-2422
ISSN	0014-4827
DOI	10.1016/s0014-4827(02)00020-4
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Article ; Online: Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer.

Brindle, Nicola R / Joyce, Johanna A / Rostker, Fanya / Lawlor, Elizabeth R / Swigart-Brown, Lamorna / Evan, Gerard / Hanahan, Douglas / Shchors, Ksenya

PloS one

2015 Volume 10, Issue 4, Page(s) e0120348

Abstract: Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L ... ...

Abstract	Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.
MeSH term(s)	Animals ; Cathepsin L/deficiency ; Cell Transformation, Neoplastic/genetics ; Cell Transformation, Neoplastic/metabolism ; Cell Transformation, Neoplastic/pathology ; Leukocytes/metabolism ; Leukocytes/pathology ; Mice ; Mice, Transgenic ; Neoplasms, Experimental/genetics ; Neoplasms, Experimental/metabolism ; Neoplasms, Experimental/pathology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/metabolism ; Pancreatic Neoplasms/pathology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; bcl-X Protein/genetics ; bcl-X Protein/metabolism
Chemical Substances	Myc protein, mouse ; Proto-Oncogene Proteins c-myc ; bcl-X Protein ; Cathepsin L (EC 3.4.22.15) ; Ctsl protein, mouse (EC 3.4.22.15)
Language	English
Publishing date	2015-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0120348
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Article ; Online: Driving Neuronal Differentiation through Reversal of an ERK1/2-miR-124-SOX9 Axis Abrogates Glioblastoma Aggressiveness

Hanna Sabelström / Rebecca Petri / Ksenya Shchors / Rahul Jandial / Christin Schmidt / Rohit Sacheva / Selma Masic / Edith Yuan / Trenten Fenster / Michael Martinez / Supna Saxena / Theodore P. Nicolaides / Shirin Ilkhanizadeh / Mitchel S. Berger / Evan Y. Snyder / William A. Weiss / Johan Jakobsson / Anders I. Persson

Cell Reports, Vol 28, Iss 8, Pp 2064-2079.e

2019 Volume 11

Abstract: Summary: Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains ...

Abstract	Summary: Identifying cellular programs that drive cancers to be stem-like and treatment resistant is critical to improving outcomes in patients. Here, we demonstrate that constitutive extracellular signal-regulated kinase 1/2 (ERK1/2) activation sustains a stem-like state in glioblastoma (GBM), the most common primary malignant brain tumor. Pharmacological inhibition of ERK1/2 activation restores neurogenesis during murine astrocytoma formation, inducing neuronal differentiation in tumorspheres. Constitutive ERK1/2 activation globally regulates miRNA expression in murine and human GBMs, while neuronal differentiation of GBM tumorspheres following the inhibition of ERK1/2 activation requires the functional expression of miR-124 and the depletion of its target gene SOX9. Overexpression of miR124 depletes SOX9 in vivo and promotes a stem-like-to-neuronal transition, with reduced tumorigenicity and increased radiation sensitivity. Providing a rationale for reports demonstrating miR-124-induced abrogation of GBM aggressiveness, we conclude that reversal of an ERK1/2-miR-124-SOX9 axis induces a neuronal phenotype and that enforcing neuronal differentiation represents a therapeutic strategy to improve outcomes in GBM. : Sabelström et al. show that the loss of neurogenesis is reversible during neural stem cell-derived glioma formation. Pharmacological inhibition of ERK1/2 globally regulates miRNAs and induces neuronal differentiation, a process that is dependent on the modulation of an miR-124-SOX9 axis in glioblastoma (GBM) cells. The overexpression of miR-124 induces neuronal differentiation that abrogates GBM aggressiveness. Keywords: brain, cancer, differentiation, glioma, glioblastoma, microRNA, neural stem cell, neurogenesis, neuron, tumor
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer.

Nicola R Brindle / Johanna A Joyce / Fanya Rostker / Elizabeth R Lawlor / Lamorna Swigart-Brown / Gerard Evan / Douglas Hanahan / Ksenya Shchors

PLoS ONE, Vol 10, Iss 4, p e

2015 Volume 0120348

Abstract	Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Cell Death Inhibiting RNA (CDIR) modulates IFN-gamma-stimulated sensitization to Fas/CD95/Apo-1 and TRAIL/Apo-2L-induced apoptosis.

Shchors, Ksenya / Yehiely, Fruma / Deiss, Louis P

Cell cycle (Georgetown, Tex.)

2004 Volume 3, Issue 12, Page(s) 1606–1611

Abstract: ... Shchors et al., J Biol Chem 2002; 277:47061-72). IFN-gamma is known to sensitize cells to killing induced ...

Abstract	We have previously demonstrated that overexpression of Cell Death Inhibiting RNA (CDIR), a portion of the 3'untranslated region (UTR) of KIAA0425, inhibits Interferon-gamma (IFN-gamma) induced apoptosis in HeLa cells (Shchors et al., J Biol Chem 2002; 277:47061-72). IFN-gamma is known to sensitize cells to killing induced by the death receptor ligands such as Fas/APO-1/CD95 and TNF-related apoptosis-inducing ligand (TRAIL/Apo-2L). Here we report that while CDIR does not alter the response of cells to Fas or TRAIL, it significantly modulates IFN-gamma-induced sensitization of HeLa cells to these death-inducing ligands. Interestingly, while CDIR abrogates the IFN-gamma-modulated sensitization to Fas, it enhances the sensitization to TRAIL. Expression of CDIR did not alter initial steps of IFN-gamma signaling including induction of Signal Transducer and Activator-1 (Stat1), caspase-1 or Interferon Regulatory Factor-1 (IRF1) transcription. In contrast, although expression of CDIR does not affect the protein level of caspase-1 or STAT1, it does significantly reduce the level of IRF1 protein. Thus, CDIR mediates IFN-gamma-induced apoptosis, at least in part, by reducing the level of the pro-apoptotic tumor suppressor gene IRF1 via a post-transcriptional mechanism. Since tumor cells are often less sensitive to Fas and more sensitive to TRAIL than normal cells, we suggest that CDIR or CDIR-like activity could contribute to such a phenotype of tumor cells.
MeSH term(s)	Apoptosis/drug effects ; Apoptosis Regulatory Proteins/genetics ; Apoptosis Regulatory Proteins/metabolism ; Caspase 1/metabolism ; HeLa Cells ; Humans ; Immunization ; Interferon Regulatory Factor-1/genetics ; Interferon Regulatory Factor-1/metabolism ; Interferon-gamma/antagonists & inhibitors ; Interferon-gamma/metabolism ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; RNA/pharmacology ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; TNF-Related Apoptosis-Inducing Ligand ; Transfection ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism ; fas Receptor/metabolism
Chemical Substances	Apoptosis Regulatory Proteins ; Interferon Regulatory Factor-1 ; Membrane Glycoproteins ; RNA, Messenger ; TNF-Related Apoptosis-Inducing Ligand ; TNFSF10 protein, human ; Tumor Necrosis Factor-alpha ; fas Receptor ; RNA (63231-63-0) ; Interferon-gamma (82115-62-6) ; Caspase 1 (EC 3.4.22.36)
Language	English
Publishing date	2004-12-15
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.3.12.1295
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Zs.A 5881: Show issues

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Article: The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta.

Shchors, Ksenya / Shchors, Elena / Rostker, Fanya / Lawlor, Elizabeth R / Brown-Swigart, Lamorna / Evan, Gerard I

Genes & development

2006 Volume 20, Issue 18, Page(s) 2527–2538

Abstract: Although induction of blood vessel growth is acknowledged as a pivotal requirement for the evolution of macroscopic tumors, the events that trigger onset of tumor angiogenesis remain largely obscure. The pervasive Myc oncoprotein is itself a potent ... ...

Abstract	Although induction of blood vessel growth is acknowledged as a pivotal requirement for the evolution of macroscopic tumors, the events that trigger onset of tumor angiogenesis remain largely obscure. The pervasive Myc oncoprotein is itself a potent inducer of angiogenesis in a wide range of tissues. We have used a reversibly switchable mouse transgenic model of Myc-dependent beta-cell carcinogenesis to delineate the kinetics and causal sequence of angiogenic processes following acute Myc activation. We show that onset of endothelial cell proliferation is induced shortly after Myc-induced cell cycle entry of beta cells. Endothelial cell proliferation is not indirectly induced by local tissue hypoxia but instead via a diffusible angiogenic signal produced by Myc-expressing beta cells. This signal triggers the release of pre-existing, sequestered VEGF from the islet extracellular matrix, that then homes to the endothelial compartment where it induces endothelial cell proliferation. Myc activation in beta cells rapidly induces expression and release of the proinflammatory cytokine interleukin 1beta (IL-1beta). We show that IL-1beta is the principal effector downstream of Myc responsible for triggering rapid onset of islet angiogenesis. Together, our data delineate a complete pathway in vivo by which the highly pleiotropic Myc oncoproteins elicits coexpansion of the vascular compartment during tumorigenic progression.
MeSH term(s)	Animals ; Cell Proliferation ; Endothelial Cells/pathology ; Gene Expression Regulation, Neoplastic ; Genes, myc ; In Vitro Techniques ; Insulinoma/blood supply ; Insulinoma/etiology ; Insulinoma/genetics ; Insulinoma/physiopathology ; Interleukin-1/physiology ; Islets of Langerhans/blood supply ; Mice ; Mice, Transgenic ; Neovascularization, Pathologic/etiology ; Neovascularization, Pathologic/genetics ; Neovascularization, Pathologic/physiopathology ; Pancreatic Neoplasms/blood supply ; Pancreatic Neoplasms/etiology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/physiopathology ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/physiology ; Vascular Endothelial Growth Factor A/physiology ; bcl-X Protein/genetics
Chemical Substances	Bcl2l1 protein, mouse ; Interleukin-1 ; Myc protein, mouse ; Proto-Oncogene Proteins c-myc ; Vascular Endothelial Growth Factor A ; bcl-X Protein ; vascular endothelial growth factor A, mouse
Language	English
Publishing date	2006-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.1455706
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

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