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| 2. |
- Andersson, Mattias K, 1979, et al.
(författare)
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IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors
- 2019
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 8:8
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Tidskriftsartikel (refereegranskat)abstract
- Chromosome rearrangements resulting in pathogenetically important gene fusions are a common feature of many cancers. They are often potent oncogenic drivers and have key functions in central cellular processes and pathways and encode transcription factors, transcriptional co-regulators, growth factor receptors, tyrosine kinases, and chromatin modifiers. In addition to being useful diagnostic biomarkers, they are also targets for development of new molecularly targeted therapies. Studies in recent decades have shown that several oncogenic gene fusions interact with the insulin-like growth factor (IGF) signaling pathway. For example, the MYB-NFIB fusion in adenoid cystic carcinoma is regulated by IGF1R through an autocrine loop, and IGF1R is a downstream target of the EWSR1-WT1 and PAX3-FKHR fusions in desmoplastic small round cell tumors and alveolar rhabdomyosarcoma, respectively. Here, we will discuss the mechanisms behind the interactions between oncogenic gene fusions and the IGF signaling pathway. We will also discuss the role of therapeutic inhibition of IGF1R in fusion gene driven malignancies.
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| 3. |
- Andersson, Mattias K, 1979, et al.
(författare)
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The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response
- 2008
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Ingår i: BMC Cell Biology. - : Springer Science and Business Media LLC. - 1471-2121. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: FUS, EWS and TAF15 are structurally similar multifunctional proteins that were first discovered upon characterization of fusion oncogenes in human sarcomas and leukemias. The proteins belong to the FET (previously TET) family of RNA-binding proteins and are implicated in central cellular processes such as regulation of gene expression, maintenance of genomic integrity and mRNA/microRNA processing. In the present study, we investigated the expression and cellular localization of FET proteins in multiple human tissues and cell types. RESULTS: FUS, EWS and TAF15 were expressed in both distinct and overlapping patterns in human tissues. The three proteins showed almost ubiquitous nuclear expression and FUS and TAF15 were in addition present in the cytoplasm of most cell types. Cytoplasmic EWS was more rarely detected and seen mainly in secretory cell types. Furthermore, FET expression was downregulated in differentiating human embryonic stem cells, during induced differentiation of neuroblastoma cells and absent in terminally differentiated melanocytes and cardiac muscle cells. The FET proteins were targeted to stress granules induced by heat shock and oxidative stress and FUS required its RNA-binding domain for this translocation. Furthermore, FUS and TAF15 were detected in spreading initiation centers of adhering cells. CONCLUSION: Our results point to cell-specific expression patterns and functions of the FET proteins rather than the housekeeping roles inferred from earlier studies. The localization of FET proteins to stress granules suggests activities in translational regulation during stress conditions. Roles in central processes such as stress response, translational control and adhesion may explain the FET proteins frequent involvement in human cancer.
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| 5. |
- Olofsson, Anita, 1943, et al.
(författare)
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Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas.
- 2004
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Ingår i: International journal of oncology. - 1019-6439. ; 25:5, s. 1349-55
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid/round cell liposarcomas (MLS/RCLS) are characterized by chromosome translocations that result in formation of FUS-CHOP or EWSR1-CHOP fusion oncogenes. More than 95% of the tumors carry one of these fusion genes. FUS-CHOP transforms 3T3 cells and causes MLS/RCLS-like tumors in transgenic mice. The fusion oncoproteins act as abnormal transcription factors and are believed to induce abnormal expression of growth controlling genes as part of their transforming activities. The aim of this study was to search for recurrent abnormal expression patterns of cell cycle regulating proteins and growth factor receptors. A series of 14 MLS/RCLS, 2 MLS/RCLS derived cell lines and a FUS-CHOP transfected human sarcoma cell line were analyzed using immunohistochemistry, Western blotting, and cDNA microarray based screening. The results revealed a highly abnormal expression pattern of several growth controlling proteins. The G1 cyclins D1 and E and their associated kinases CDK4 and CDK2 were strongly overexpressed in all of the tumors. High expression levels were also found for Cdk4/6 inhibitor P16 and CDK2 inhibitors P27 and P57. The growth factor tyrosine kinase receptors PDGFRB and EGFR were present in most cells of all investigated tumors. We conclude that deregulation of G1 controlling proteins is common in MLS/RCLS and that aberrant expression of these proteins is of importance in the pathogenesis of this tumor type.
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| 6. |
- Persson, Fredrik, 1973, et al.
(författare)
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Characterization of the 12q amplicons by high-resolution, oligonucleotide array CGH and expression analyses of a novel liposarcoma cell line
- 2008
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Ingår i: Cancer Letters. - : Elsevier BV. - 0304-3835. ; 260:1-2, s. 37-47
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Tidskriftsartikel (refereegranskat)abstract
- The cytogenetic hallmark of well-differentiated liposarcoma (WDLS) is a giant marker chromosomes containing amplified genes from chromosome 12q13-q15. Here, we have employed SKY and high-resolution 244K oligonucleotide array CGH to characterize rearrangements and amplifications in a new WDLS cell line (GOT3) with a giant marker chromosome derived from chromosomes 12, 1, and X. The most prominent amplifications included 144 genes in 12q11-q21.2, 201 genes in 1q23.3-q44, and six genes in 13q32.1-q32.2. In the 12q amplicons, MDM2 showed the highest level of amplification followed by LYZ, HMGA2 (5'-part), TSPAN8, CNOT2, YEATS4, CDK4, GNS, HELB, and TSFM. Expression analysis of genes from the three major amplicons revealed that several highly amplified potential target genes, including HMGA2, MDM2, YEATS4, CDK4, PKP1, IPO9, and SOX21, were strongly overexpressed. Studies of cell cycle controlling proteins that interact with CDK4 and MDM2 revealed an abnormally strong expression of cyclins D1 and E. The selective high-level amplification of the 5'-part of HMGA2, including the DNA-binding domains, suggests that this gene is a major target of amplifications in WDLS. Our results also identify several novel candidate genes of potential pathogenetic and therapeutic importance for WDLS.
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| 7. |
- Safavi, Setareh, et al.
(författare)
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HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo
- 2016
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Ingår i: OncoTarget. - : Impact Journals, LLC. - 1949-2553. ; 7:1, s. 433-445
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Tidskriftsartikel (refereegranskat)abstract
- Myxoid sarcoma (MLS) is one of the most common types of malignant soft tissue tumors. MLS is characterized by the FUS-DDIT3 or EWSR1-DDIT3 fusion oncogenes that encode abnormal transcription factors. The receptor tyrosine kinase (RTK) encoding RET was previously identified as a putative downstream target gene to FUS-DDIT3 and here we show that cultured MLS cells expressed phosphorylated RET together with its ligand Persephin. Treatment with RET specific kinase inhibitor Vandetanib failed to reduce RET phosphorylation and inhibit cell growth, suggesting that other RTKs may phosphorylate RET. A screening pointed out EGFR and ERBB3 as the strongest expressed phosphorylated RTKs in MLS cells. We show that ERBB3 formed nuclear and cytoplasmic complexes with RET and both RTKs were previously reported to form complexes with EGFR. The formation of RTK hetero complexes could explain the observed Vandetanib resistence in MLS. EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death. Treatment of MLS xenograft carrying Nude mice resulted in massive necrosis, rupture of capillaries and hemorrhages in tumor tissues. We conclude that complex formation between RET and other RTKs may cause RTK inhibitor resistance. HSP90 inhibitors can overcome this resistance and are thus promising drugs for treatment of MLS/RCLS.
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| 9. |
- Andersson, Mattias K, 1979, et al.
(författare)
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Nuclear expression of FLT1 and its ligand PGF in FUS-DDIT3 carrying myxoid liposarcomas suggests the existence of an intracrine signaling loop.
- 2010
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Ingår i: BMC cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The FUS-DDIT3 fusion oncogene encodes an abnormal transcription factor that has a causative role in the development of myxoid/round-cell liposarcomas (MLS/RCLS). We have previously identified FLT1 (VEGFR1) as a candidate downstream target gene of FUS-DDIT3. The aim of this study was to investigate expression of FLT1 and its ligands in MLS cells. Methods: HT1080 human fibrosarcoma cells were transiently transfected with FUS-DDIT3-GFP variant constructs and FLT1 expression was measured by quantitative real-time PCR. In addition, FLT1, PGF, VEGFA and VEGFB expression was measured in MLS/RCLS cell lines, MLS/RCLS tumors and in normal adiopocytes. We analyzed nine cases of MLS/RCLS and one cell line xenografted in mice for FLT1 protein expression using immunohistochemistry. MLS/RCLS cell lines were also analyzed for FLT1 by immunofluorescence and western blot. MLS/RCLS cell lines were additionally treated with FLT1 tyrosine kinase inhibitors and assayed for alterations in proliferation rate. Results: FLT1 expression was dramatically increased in transfected cells stably expressing FUS-DDIT3 and present at high levels in cell lines derived from MLS. The FLT1 protein showed a strong nuclear expression in cells of MLS tissue as well as in cultured MLS cells, which was confirmed by cellular fractionation. Tissue array analysis showed a nuclear expression of the FLT1 protein also in several other tumor and normal cell types including normal adipocytes. The FLT1 ligand coding gene PGF was highly expressed in cultured MLS cells compared to normal adipocytes while the other ligand genes VEGFA and VEGFB were expressed to lower levels. A more heterogeneous expression pattern of these genes were observed in tumor samples. No changes in proliferation rate of MLS cells were detected at concentrations for which the kinase inhibitors have shown specific inhibition of FLT1. Conclusions: Our results imply that FLT1 is induced as an indirect downstream effect of FUS-DDIT3 expression in MLS. This could be a consequence of the ability of FUS-DDIT3 to hijack parts of normal adipose tissue development and reprogram primary cells to a liposarcoma-like phenotype. The findings of nuclear FLT1 protein and expression of corresponding ligands in MLS and normal tissues may have implications for tissue homeostasis and tumor development through auto- or intracrine signaling.
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| 10. |
- Andersson, Mattias K, 1979, et al.
(författare)
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Proliferation of Ewing sarcoma cell lines is suppressed by the receptor tyrosine kinase inhibitors gefitinib and vandetanib
- 2008
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Tyrosine kinase inhibitors (TKIs) have gained much attention in recent years as targeted agents for the treatment of a wide range of human cancers. We have investigated the effect of the TKIs gefitinib and vandetanib on tumor cell lines derived from Ewing sarcoma, a highly malignant tumor affecting bone and soft tissue in children and young adults. Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase activity (EGFR) and vandetanib selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2) with additional activity against VEGFR-3, EGFR and RET kinase receptors. RESULTS: Two Ewing sarcoma cell lines investigated showed high levels of nuclear EGFR expression as well as moderate expression in plasma membrane and cytoplasm. When treated with concentrations of 5 muM and more of either gefitinib or vandetanib, we observed a significant decrease in cell proliferation. However, there were no detectable changes in p44/42 MAPK and Akt-1 phosphorylation, or in the expression of cyclin D1 or c-Myc following gefitinib or vandetanib treatment. CONCLUSION: We conclude that Ewing sarcoma tumor cell proliferation is not highly sensitive to inhibition of EGFR signaling alone or the simultaneous inhibition of VEGFR receptors, EGFR and RET kinase. Decreased tumor cell proliferation could be achieved with gefitinib and vandetanib, but only at higher doses where non-specific effects of the compounds may be overriding. As Ewing tumor cells do not seem to depend on EGFR and VEGFR pathways for survival, other key factors in the cellular signaling of Ewing sarcoma should be targeted in order to obtain a potent therapeutic response.
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