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Article: New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth.

Rey, Veronica / Menendez, Sofia T / Estupiñan, Oscar / Rodriguez, Aida / Santos, Laura / Tornin, Juan / Martinez-Cruzado, Lucia / Castillo, David / Ordoñez, Gonzalo R / Costilla, Serafin / Alvarez-Fernandez, Carlos / Astudillo, Aurora / Braña, Alejandro / Rodriguez, Rene

Journal of clinical medicine

2019 Volume 8, Issue 4

Abstract: For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors ... ...

Abstract	For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors like chondrosarcoma which has few models available. Here we established and characterized new cell lines derived from two secondary (CDS06 and CDS11) and one dedifferentiated (CDS-17) chondrosarcomas as well as another line derived from a CDS-17-generated xenograft (T-CDS17). These lines displayed cancer stem cell-related and invasive features and were able to initiate subcutaneous and/or orthotopic animal models. Different mutations in Isocitrate Dehydrogenase-1 (
Language	English
Publishing date	2019-04-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm8040455
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Article: SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications.

Menendez, Sofia T / Rey, Veronica / Martinez-Cruzado, Lucia / Gonzalez, M Victoria / Morales-Molina, Alvaro / Santos, Laura / Blanco, Verónica / Alvarez, Carlos / Estupiñan, Oscar / Allonca, Eva / Rodrigo, Juan Pablo / García-Castro, Javier / Garcia-Pedrero, Juana Maria / Rodriguez, Rene

Cancers

2020 Volume 12, Issue 4

Abstract: Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features ... ...

Abstract	Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations.
Language	English
Publishing date	2020-04-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers12040964
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Article ; Online: Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations.

Martinez-Cruzado, Lucia / Tornin, Juan / Santos, Laura / Rodriguez, Aida / García-Castro, Javier / Morís, Francisco / Rodriguez, Rene

Scientific reports

2016 Volume 6, Page(s) 27878

Abstract: Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs ... ...

Abstract	Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution.
MeSH term(s)	Animals ; Cell Line, Tumor ; Humans ; Isoenzymes/antagonists & inhibitors ; Isoenzymes/genetics ; Isoenzymes/metabolism ; Lung Neoplasms/pathology ; Lung Neoplasms/secondary ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neoplastic Stem Cells/cytology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/transplantation ; RNA Interference ; RNA, Small Interfering/metabolism ; Retinal Dehydrogenase/antagonists & inhibitors ; Retinal Dehydrogenase/genetics ; Retinal Dehydrogenase/metabolism ; SOXB1 Transcription Factors/metabolism ; Sarcoma/metabolism ; Sarcoma/pathology ; Time-Lapse Imaging ; Transplantation, Heterologous
Chemical Substances	Isoenzymes ; RNA, Small Interfering ; SOX2 protein, human ; SOXB1 Transcription Factors ; aldehyde dehydrogenase 1 (EC 1.2.1.-) ; Retinal Dehydrogenase (EC 1.2.1.36)
Language	English
Publishing date	2016-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/srep27878
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Article ; Online: New Chondrosarcoma Cell Lines with Preserved Stem Cell Properties to Study the Genomic Drift During In Vitro/In Vivo Growth

Veronica Rey / Sofia T. Menendez / Oscar Estupiñan / Aida Rodriguez / Laura Santos / Juan Tornin / Lucia Martinez-Cruzado / David Castillo / Gonzalo R. Ordoñez / Serafin Costilla / Carlos Alvarez-Fernandez / Aurora Astudillo / Alejandro Braña / Rene Rodriguez

Journal of Clinical Medicine, Vol 8, Iss 4, p

2019 Volume 455

Abstract	For the cancer genomics era, there is a need for clinically annotated close-to-patient cell lines suitable to investigate altered pathways and serve as high-throughput drug-screening platforms. This is particularly important for drug-resistant tumors like chondrosarcoma which has few models available. Here we established and characterized new cell lines derived from two secondary (CDS06 and CDS11) and one dedifferentiated (CDS-17) chondrosarcomas as well as another line derived from a CDS-17-generated xenograft (T-CDS17). These lines displayed cancer stem cell-related and invasive features and were able to initiate subcutaneous and/or orthotopic animal models. Different mutations in Isocitrate Dehydrogenase-1 ( IDH1 ), Isocitrate Dehydrogenase-2 ( IDH2 ), and Tumor Supressor P53 ( TP53 ) and deletion of Cyclin Dependent Kinase Inhibitor 2A ( CDKN2A ) were detected both in cell lines and tumor samples. In addition, other mutations in TP53 and the amplification of Mouse Double Minute 2 homolog ( MDM2 ) arose during cell culture in CDS17 cells. Whole exome sequencing analysis of CDS17, T-CDS17, and matched patient samples confirmed that cell lines kept the most relevant mutations of the tumor, uncovered new mutations and revealed structural variants that emerged during in vitro/in vivo growth. Altogether, this work expanded the panel of clinically and genetically-annotated chondrosarcoma lines amenable for in vivo studies and cancer stem cell (CSC) characterization. Moreover, it provided clues of the genetic drift of chondrosarcoma cells during the adaptation to grow conditions.
Keywords	chondrosarcoma ; primary cell lines ; cancer stem cells ; whole exome sequencing ; genomic drift ; animal model ; cancer preclinical model ; Medicine ; R
Subject code	571
Language	English
Publishing date	2019-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Trabectedin and Campthotecin Synergistically Eliminate Cancer Stem Cells in Cell-of-Origin Sarcoma Models.

Martinez-Cruzado, Lucia / Tornin, Juan / Rodriguez, Aida / Santos, Laura / Allonca, Eva / Fernandez-Garcia, Maria Teresa / Astudillo, Aurora / Garcia-Pedrero, Juana Maria / Rodriguez, Rene

Neoplasia (New York, N.Y.)

2017 Volume 19, Issue 6, Page(s) 460–470

Abstract: Trabectedin has been approved for second-line treatment of soft tissue sarcomas. However, its efficacy to target sarcoma initiating cells has not been addressed yet. Here, we used pioneer models of myxoid/round cell liposarcoma (MRCLS) and ... ...

Abstract	Trabectedin has been approved for second-line treatment of soft tissue sarcomas. However, its efficacy to target sarcoma initiating cells has not been addressed yet. Here, we used pioneer models of myxoid/round cell liposarcoma (MRCLS) and undifferentiated pleomorphic sarcoma (UPS) developed from transformed human mesenchymal stromal/stem cells (MSCs) to evaluate the effect of trabectedin in the cell type responsible for initiating sarcomagenesis and their derived cancer stem cells (CSC) subpopulations. We found that low nanomolar concentrations of trabectedin efficiently inhibited the growth of sarcoma-initiating cells, induced cell cycle arrest, DNA damage and apoptosis. Interestingly, trabectedin treatment repressed the expression of multiple genes responsible for the development of the CSC phenotype, including pluripotency factors, CSC markers and related signaling pathways. Accordingly, trabectedin induced apoptosis and reduced the survival of CSC-enriched tumorsphere cultures with the same efficiency that inhibits the growth of bulk tumor population. In vivo, trabectedin significantly reduced the mitotic index of MRCLS xenografts and inhibited tumor growth at a similar extent to that observed in doxorubicin-treated tumors. Combination of trabectedin with campthotecin (CPT), a chemotherapeutic drug that shows a robust anti-tumor activity when combined with alkylating agents, resulted in a very strong synergistic inhibition of tumor cell growth and highly increased DNA damage and apoptosis induction. Importantly, the enhanced anti-tumor activity of this combination was also observed in CSC subpopulations. These data suggest that trabectedin and CPT combination may constitute a novel strategy to effectively target both the cell-of-origin and CSC subpopulations in sarcoma.
Language	English
Publishing date	2017-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2017.03.004
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Article: Osteosarcoma: Cells-of-Origin, Cancer Stem Cells, and Targeted Therapies.

Abarrategi, Ander / Tornin, Juan / Martinez-Cruzado, Lucia / Hamilton, Ashley / Martinez-Campos, Enrique / Rodrigo, Juan P / González, M Victoria / Baldini, Nicola / Garcia-Castro, Javier / Rodriguez, Rene

Stem cells international

2016 Volume 2016, Page(s) 3631764

Abstract: Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS ...

Abstract	Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell-of-origin, which are the normal cells that acquire the first cancer-promoting mutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell-of-origin. Both the cell-of-origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS-CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC-associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell-of-origin models, the properties of the OS-CSC and its niche, and potential new therapies able to target OS-CSCs.
Language	English
Publishing date	2016-06-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2573856-2
ISSN	1687-9678 ; 1687-966X
ISSN (online)	1687-9678
ISSN	1687-966X
DOI	10.1155/2016/3631764
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Article ; Online: Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma.

Tornin, Juan / Martinez-Cruzado, Lucia / Santos, Laura / Rodriguez, Aida / Núñez, Luz-Elena / Oro, Patricia / Hermosilla, Maria Ana / Allonca, Eva / Fernández-García, Maria Teresa / Astudillo, Aurora / Suarez, Carlos / Morís, Francisco / Rodriguez, Rene

Oncotarget

2016 Volume 7, Issue 21, Page(s) 30935–30950

Abstract: Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and ... ...

Abstract	Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.
MeSH term(s)	ATP-Binding Cassette Transporters/metabolism ; Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Doxorubicin/pharmacokinetics ; Drug Resistance, Neoplasm ; Female ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice, Inbred NOD ; Mice, SCID ; NF-kappa B p50 Subunit/metabolism ; Neoplastic Stem Cells/drug effects ; Plicamycin/analogs & derivatives ; Plicamycin/pharmacokinetics ; Plicamycin/therapeutic use ; Proto-Oncogene Proteins c-myc/metabolism ; Receptor, Notch1/metabolism ; SOXB1 Transcription Factors/metabolism ; Sarcoma, Experimental/drug therapy ; Sarcoma, Experimental/genetics ; Sarcoma, Experimental/metabolism ; Signal Transduction/drug effects ; Sp1 Transcription Factor/metabolism ; Xenograft Model Antitumor Assays
Chemical Substances	ATP-Binding Cassette Transporters ; Antineoplastic Agents ; MYC protein, human ; NF-kappa B p50 Subunit ; NFKB1 protein, human ; NOTCH1 protein, human ; Proto-Oncogene Proteins c-myc ; Receptor, Notch1 ; SOX2 protein, human ; SOXB1 Transcription Factors ; Sp1 Transcription Factor ; SP1 protein, human ; demycarosyl-3D-digitoxosylmithramycin SK ; Doxorubicin (80168379AG) ; Plicamycin (NIJ123W41V)
Language	English
Publishing date	2016-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.8817
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Article ; Online: Bone microenvironment signals in osteosarcoma development.

Alfranca, Arantzazu / Martinez-Cruzado, Lucia / Tornin, Juan / Abarrategi, Ander / Amaral, Teresa / de Alava, Enrique / Menendez, Pablo / Garcia-Castro, Javier / Rodriguez, Rene

Cellular and molecular life sciences : CMLS

2015 Volume 72, Issue 16, Page(s) 3097–3113

Abstract: The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is ... ...

Abstract	The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome.
MeSH term(s)	Bone and Bones/physiology ; Cellular Microenvironment/physiology ; Homeostasis/physiology ; Humans ; Models, Biological ; Neoplasm Metastasis/physiopathology ; Osteosarcoma/physiopathology ; Signal Transduction/physiology
Language	English
Publishing date	2015-05-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-015-1918-y
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Article ; Online: FUS-CHOP Promotes Invasion in Myxoid Liposarcoma through a SRC/FAK/RHO/ROCK-Dependent Pathway.

Tornin, Juan / Hermida-Prado, Francisco / Padda, Ranjit Singh / Gonzalez, M Victoria / Alvarez-Fernandez, Carlos / Rey, Veronica / Martinez-Cruzado, Lucia / Estupiñan, Oscar / Menendez, Sofia T / Fernandez-Nevado, Lucia / Astudillo, Aurora / Rodrigo, Juan P / Lucien, Fabrice / Kim, Yohan / Leong, Hon S / Garcia-Pedrero, Juana Maria / Rodriguez, Rene

Neoplasia (New York, N.Y.)

2017 Volume 20, Issue 1, Page(s) 44–56

Abstract: Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one ... ...

Abstract	Deregulated SRC/FAK signaling leads to enhanced migration and invasion in many types of tumors. In myxoid and round cell liposarcoma (MRCLS), an adipocytic tumor characterized by the expression of the fusion oncogene FUS-CHOP, SRC have been found as one of the most activated kinases. Here we used a cell-of-origin model of MRCLS and an MRCLS cell line to thoroughly characterize the mechanisms of cell invasion induced by FUS-CHOP using in vitro (3D spheroid invasion assays) and in vivo (chicken chorioallantoic membrane model) approaches. FUS-CHOP expression activated SRC-FAK signaling and increased the invasive ability of MRCLS cells. In addition, FAK expression was found to significantly correlate with tumor aggressiveness in sarcoma patient samples. The involvement of SRC/FAK activation in FUS-CHOP-mediated invasion was further confirmed using the SRC inhibitor dasatinib, the specific FAK inhibitor PF-573228, and FAK siRNA. Notably, dasatinib and PF573228 could also efficiently block the invasion of cancer stem cell subpopulations. Downstream of SRC/FAK signaling, we found that FUS-CHOP expression increases the levels of the RHO/ROCK downstream effector phospho-MLC2 (T18/S19) and that this activation was prevented by dasatinib or PF573228. Moreover, the ROCK inhibitor RKI-1447 was able to completely abolish invasion in FUS-CHOP-expressing cells. These data uncover the involvement of SRC/FAK/RHO/ROCK signaling axis in FUS-CHOP-mediated invasion, thus providing a rationale for testing inhibitors of this pathway as potential novel antimetastatic agents for MRCLS treatment.
MeSH term(s)	Acute-Phase Proteins/metabolism ; Focal Adhesion Kinase 1/metabolism ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Liposarcoma, Myxoid/genetics ; Liposarcoma, Myxoid/metabolism ; Liposarcoma, Myxoid/pathology ; Neoplastic Stem Cells/metabolism ; Oncogene Proteins, Fusion/genetics ; Oncogene Proteins, Fusion/metabolism ; RNA, Small Interfering/genetics ; RNA-Binding Protein FUS/genetics ; RNA-Binding Protein FUS/metabolism ; Signal Transduction ; Transcription Factor CHOP/genetics ; Transcription Factor CHOP/metabolism ; rho-Associated Kinases/metabolism ; src-Family Kinases/metabolism
Chemical Substances	Acute-Phase Proteins ; Oncogene Proteins, Fusion ; RNA, Small Interfering ; RNA-Binding Protein FUS ; TLS-CHOP fusion protein, human ; acute-phase protein rho ; Transcription Factor CHOP (147336-12-7) ; Focal Adhesion Kinase 1 (EC 2.7.10.2) ; PTK2 protein, human (EC 2.7.10.2) ; src-Family Kinases (EC 2.7.10.2) ; rho-Associated Kinases (EC 2.7.11.1)
Language	English
Publishing date	2017-11-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1483840-0
ISSN	1476-5586 ; 1522-8002
ISSN (online)	1476-5586
ISSN	1522-8002
DOI	10.1016/j.neo.2017.11.004
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Article ; Online: Osteosarcoma

Ander Abarrategi / Juan Tornin / Lucia Martinez-Cruzado / Ashley Hamilton / Enrique Martinez-Campos / Juan P. Rodrigo / M. Victoria González / Nicola Baldini / Javier Garcia-Castro / Rene Rodriguez

Stem Cells International, Vol

Cells-of-Origin, Cancer Stem Cells, and Targeted Therapies

2016 Volume 2016

Abstract	Osteosarcoma (OS) is the most common type of primary solid tumor that develops in bone. Although standard chemotherapy has significantly improved long-term survival over the past few decades, the outcome for those patients with metastatic or recurrent OS remains dismally poor and, therefore, novel agents and treatment regimens are urgently required. A hypothesis to explain the resistance of OS to chemotherapy is the existence of drug resistant CSCs with progenitor properties that are responsible of tumor relapses and metastasis. These subpopulations of CSCs commonly emerge during tumor evolution from the cell-of-origin, which are the normal cells that acquire the first cancer-promoting mutations to initiate tumor formation. In OS, several cell types along the osteogenic lineage have been proposed as cell-of-origin. Both the cell-of-origin and their derived CSC subpopulations are highly influenced by environmental and epigenetic factors and, therefore, targeting the OS-CSC environment and niche is the rationale for many recently postulated therapies. Likewise, some strategies for targeting CSC-associated signaling pathways have already been tested in both preclinical and clinical settings. This review recapitulates current OS cell-of-origin models, the properties of the OS-CSC and its niche, and potential new therapies able to target OS-CSCs.
Keywords	Internal medicine ; RC31-1245
Subject code	610
Language	English
Publishing date	2016-01-01T00:00:00Z
Publisher	Hindawi Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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