| 1. |
- Dahl, Christina, et al.
(författare)
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Mutual Exclusivity Analysis of Genetic and Epigenetic Drivers in Melanoma Identifies a Link Between p14(ARF) and RAR beta Signaling
- 2013
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Ingår i: Molecular Cancer Research. - 1557-3125. ; 11:10, s. 1166-1178
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma genomes contain thousands of alterations including: mutations, copy number alterations, structural aberrations, and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non-random distribution patterns. Statistically significant mutual exclusivity was revealed among components of each of the p16(INK4A)-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways. In addition, an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor beta (RARB) and CDKN2A alterations affecting p14(ARF) (P < 0.0001), suggesting a functional link between RAR beta signaling and the melanoma-suppressive activities of p14(ARF). Mechanistically, all-trans retinoic acid (ATRA) treatment increased the expression of p14(ARF) in primary human melanocytes and the steady-state levels of p14(ARF) in these cells were shown to be regulated via RAR beta. Furthermore, the ability of ATRA to induce senescence is reduced in p14(ARF)-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARb-p14(ARF) signaling axis, independent of p16(INK4A) and p53 status. Implications: These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross-talk between RAR beta and p14(ARF) with potential implications for melanoma treatment.
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| 2. |
- Geretti, Elena, et al.
(författare)
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A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression
- 2010
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 8:8, s. 1063-1073
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Tidskriftsartikel (refereegranskat)abstract
- Neuropilins (NRP1 and NRP2) are coreceptors for vascular endothelial growth factor (VEGF) and mediate angiogenesis and tumor progression. VEGF binds to the NRP1 and NRP2 B domains. Previously, it was shown that mutagenesis of the soluble NRP2 B domain (MutB-NRP2) increased affinity to VEGF by 8-fold. Here, we show that MutB-NRP2 inhibited (125)I-VEGF binding to NRP1, NRP2, and VEGFR-2. It antagonized VEGF-induced VEGFR-2/NRP2 complex formation and inhibited VEGF-induced activation of AKT, a mediator of cell survival, without affecting activation of VEGFR-2. In three-dimensional embryoid bodies, a model of VEGF-induced angiogenesis, MutB-NRP2 inhibited VEGF-induced sprouting. When overexpressed in human melanoma cells, MutB-NRP2 inhibited tumor growth compared with control tumors. Avastin (bevacizumab), a monoclonal antibody to VEGF, inhibited VEGF interactions with VEGFR-2, but not with NRPs. The combination of MutB-NRP2 and Avastin resulted in an enhanced inhibition of human melanoma tumor growth compared with MutB-NRP2 treatment only or Avastin treatment only. In conclusion, these results indicate that MutB-NRP2 is a novel antagonist of VEGF bioactivity and tumor progression.
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| 3. |
- Johansson, Ann-Charlotte, et al.
(författare)
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Cancer-Associated Fibroblasts Induce Matrix Metalloproteinase-Mediated Cetuximab Resistance in Head and Neck Squamous Cell Carcinoma Cells
- 2012
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Ingår i: Molecular Cancer Research. - : American Association for Cancer Research. - 1541-7786 .- 1557-3125. ; 10:9, s. 1158-1168
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Tidskriftsartikel (refereegranskat)abstract
- A growing body of evidence suggests that components of the tumor microenvironment, including cancer-associated fibroblasts (CAF), may modulate the treatment sensitivity of tumor cells. Here, we investigated the possible influence of CAFs on the sensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines to cetuximab, an antagonistic epidermal growth factor receptor (EGFR) antibody. Cetuximab treatment caused a reduction in the proliferation rate of HNSCC cell lines, whereas the growth of HNSCC-derived CAF cultures was unaffected. When tumor cells were cocultured with CAFs in a transwell system, the cetuximab-induced growth inhibition was reduced, and a complete protection from growth inhibition was observed in one of the tumor cell lines investigated. Media that had been conditioned by CAFs offered protection from cetuximab treatment in a concentration-dependent manner, suggesting that the resistance to treatment was mediated by CAF-derived soluble factors. The coculture of HNSCC cell lines with CAFs resulted in an elevated expression of matrix metalloproteinase-1 (MMP-1) in both the tumor cells and CAFs. Moreover, the CAF-induced resistance was partly abolished by the presence of an MMP inhibitor. However, CAFs treated with siRNA targeting MMP-1 still protected tumor cells from cetuximab treatment, suggesting that several MMPs may cooperate to facilitate resistance or that the protective effect is mediated by another member of the MMP family. These results identify a novel CAF-dependent modulation of cetuximab sensitivity and suggest that inhibiting MMPs may improve the effects of EGFR-targeted therapy.
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| 4. |
- Kirik, Ufuk, et al.
(författare)
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Discovery-based Protein Expression Profiling Identifies Distinct Subgroups and Pathways in Leiomyosarcomas.
- 2014
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Ingår i: Molecular Cancer Research. - 1557-3125. ; 12:12, s. 1729-1739
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin. A substantial portion of these tumors exhibits complex karyotypes and lack characterized chromosomal aberrations. Owing to such properties, both histopathological and molecular classification of these tumors has been a significant challenge. This study examines the protein expression of a large number of human softtissue sarcomas, including subtype heterogeneity, using 2D-gel proteomics. In addition, detailed proteome profiles of a subset of pleomorphic STS specimens using an in-depth mass-spectrometry approach and identified subgroups within the leiomyosarcomas with distinct protein expression patterns. Pathways analysis indicates that key biological nodes like apoptosis, cytoskeleton remodeling and telomere regulation are differentially regulated among these subgroups. Finally, investigating the Kirik et al. Protein profiling of leiomyosarcoma Page 2 of 24 similarities between protein expression of leiomyosarcomas and undifferentiated pleomorphic sarcomas (UPS) revealed similar protein expression profiles for these tumors, in comparison to pleomorphic leiomyosarcomas. Implications: These results suggest that UPS tumors share a similar lineage as leiomyosarcomas, and are likely to originate from different stages of differentiation from mesenchymal stem cells to smooth muscle cells.
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| 5. |
- Pietras, Alexander, et al.
(författare)
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JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation.
- 2011
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Ingår i: Molecular Cancer Research. - 1557-3125. ; 9, s. 626-636
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Tidskriftsartikel (refereegranskat)abstract
- Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on icN1 stabilization by direct interaction with HIF proteins, little attention has been given to Notch ligand regulation during hypoxia. Here we show that the Notch ligand JAG2 is transcriptionally activated by hypoxia in a HIF-1α dependent manner. Hypoxic JAG2 induction resulted in elevated Notch activity in tumor cells, as was measured by increased icN1 levels and induction of the Notch target gene HEY1. In primary tumor material, JAG2 expression correlated with vascular development and angiogenesis gene signatures. In line with this, co-culture experiments of endothelial cells with hypoxic breast cancer cells displayed a reduction in number of capillary-like tubes formed upon JAG2 siRNA treatment of the breast cancer cells. Together these results suggest that a hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells.
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| 6. |
- Silverstein, Rebecca A., et al.
(författare)
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The Incorporation of 5-Fluorouracil into RNA Affects the Ribonucleolytic Activity of the Exosome Subunit Rrp6
- 2011
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 9:3, s. 332-340
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Tidskriftsartikel (refereegranskat)abstract
- 5-Fluorouracil (5FU) is a fluoropyrimidine used for the treatment of solid tumors. 5FU is a precursor of dTTP and UTP during biogenesis, and it interferes with both DNA and RNA metabolism. The RNA exosome, a multisubunit complex with ribonucleolytic activity, has been identified as one of the targets of 5FU in yeast. Studies in human cells have shown that the catalytic subunit of the nuclear exosome, Rrp6, is specifically targeted. Here, we have investigated the direct effect of 5FU on the activity of Rrp6 in Drosophila S2 cells, and we have identified two aspects of Rrp6 function that are altered by 5FU. First, gel filtration analysis revealed that the repertoire of multimolecular complexes that contain Rrp6 is modified by exposure to 5FU, which is consistent with the proposal that incorporation of 5FU into RNA leads to the sequestration of Rrp6 in ribonucleoprotein complexes. Second, the incorporation of 5FU into RNA renders the RNA less susceptible to degradation by Rrp6, as shown by Rrp6 activity assays in vitro. Our results imply that aberrant transcripts synthesized in 5FU-treated cells cannot be turned over efficiently by the surveillance machinery. Together with previous results on the mechanisms of action of 5FU, our findings suggest that the cytotoxicity of 5FU at the RNA level is the result of at least three different effects: the increased levels of retroviral transcripts with mutagenic potential, the reduced synthesis of ribosomes, and the inhibition of the nuclear RNA surveillance pathways. Drugs that reinforce any of these effects may boost the cytotoxicity of 5FU.
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| 7. |
- Zaslavsky, A, et al.
(författare)
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Regional control of tumor growth
- 2010
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Ingår i: Molecular cancer research : MCR. - 1557-3125. ; 8:9, s. 1198-1206
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Tidskriftsartikel (refereegranskat)
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