| 1. |
- Arildsen, Nicolai Skovbjerg, et al.
(författare)
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Simvastatin is a potential candidate drug in ovarian clear cell carcinomas
- 2020
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Ingår i: Oncotarget. - 1949-2553. ; 11:40, s. 3660-3674
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Tidskriftsartikel (refereegranskat)abstract
- Ovarian clear cell carcinomas (OCCC) constitute a rare subtype of epithelial ovarian cancer, lacking efficient treatment options. Based on previous studies, we assessed the anti-proliferative effect of simvastatin, a Rho GTPase interfering drug, in three OCCC cell lines: JHOC-5, OVMANA and TOV-21G, and one high-grade serous ovarian cancer (HGSOC) cell line, Caov3. We used the Rho GTPase interfering drug CID-1067700 as a control. All OCCC cell lines were more sensitive to single-agent simvastatin than the HGSOC cells, while all cell lines were less sensitive to CID-1067700 than to simvastatin. Combinations of carboplatin and simvastatin were generally antagonistic. Most treatments inhibited migration, while only simvastatin and CID-1067700 also disrupted actin organization in the OCCC cell lines. All treatments induced a G1 arrest in JHOC-5 and TOV-21G cells. Treatments with simvastatin consistently reduced c-Myc protein expression in all OCCC cell lines and displayed evidence of causing both caspase-mediated apoptotic cell death and autophagic response in a cell line dependent manner. Differences between cell lines in response to the treatments were observed and such differences, including e. g. prior treatment, should be investigated further. Conclusively, simvastatin efficiently controlled OCCC proliferation and migration, thus showing potential as a candidate drug for the treatment of OCCC.
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| 2. |
- Hollandsworth, Hannah M., et al.
(författare)
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Anti-carcinoembryonic antigen-related cell adhesion molecule antibody for fluorescence visualization of primary colon cancer and metastases in patient-derived orthotopic xenograft mouse models
- 2020
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 11:4, s. 429-439
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Tidskriftsartikel (refereegranskat)abstract
- Background: Monoclonal antibody (mAb) 6G5j is a novel anti-CEACAM monoclonal antibody. Our aim was to investigate mAb 6G5j binding characteristics and to validate fluorescence targeting of colorectal tumors and metastases in patient derived orthotopic xenograft (PDOX) models with fluorescently labeled 6G5j.Materials/Methods: The MAb 6G5j binding profile was analyzed with ELISA, Western blot and immunohistochemistry. MAb 6G5j was conjugated to near-infrared dye IR800CW (LI-COR). Western blotting was performed with various colon cancer cell lysates to determine CEACAM expression. Nude mice received orthotopic implantation of patient-derived primary colon cancer and patient-derived colon cancer metastases. Mice were administered varying doses of 6G5j-IR800CW via tail vein injection and imaged 24 and 48 hours later.Results: MAb 6G5j bound to human CEACAM1, 3, 5, 6 and 8. Western blotting demonstrated varied expression of CEACAMs in 15 of 16 colon cancer lysates. Dose and time-response imaging demonstrated optimal imaging 48 hours after administration of 50 μg 6G5j-IR800CW (Tumor-to-liver ratio (TLR) 3.17, SEM ± 0.45). Primary cancers and multiple metastases were fluorescently visualized.Conclusions: Anti-CEACAM antibody 6G5j binds multiple CEACAMs which may lead to improved detection of tumor margins for tumors and metastases that have variable expression of CEA and other CEACAMs. 6G5j mAb may be useful for colon cancer detection for pre-surgical diagnosis and fluorescence-guided surgery.
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| 3. |
- Merrigan, Stephanie L., et al.
(författare)
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Calcitriol and non-calcemic vitamin D analogue, 22-oxacalcitriol, attenuate developmental and pathological choroidal vasculature angiogenesis ex vivo and in vivo
- 2020
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Ingår i: Oncotarget. - : Impact Journals. - 1949-2553. ; 11:5, s. 493-509
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Tidskriftsartikel (refereegranskat)abstract
- Aberrant ocular angiogenesis can underpin vision loss in leading causes of blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has de novo anti-angiogenic properties. Here, our aim was to validate the ocular anti-angiogenic activity of biologically active vitamin D, calcitriol, and selected vitamin D analogue, 22-oxacalcitriol. Calcitriol induced a significant reduction in ex vivo mouse choroidal fragment sprouting. Viability studies in a human RPE cell line suggested non-calcemic vitamin D analogues including 22-oxacalcitriol have less off-target anti-proliferative activity compared to calcitriol and other analogues. Thereafter, the anti-angiogenic activity of 22-oxacalcitriol was demonstrated in an ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was found to be anti-angiogenic, inducing a dose-dependent reduction in choriocapillaris development. Subcutaneously administered calcitriol failed to attenuate mouse retinal vasculature development. However, calcitriol and 22-oxacalcitriol administered intraperitoneally, significantly attenuated lesion volume in the laser-induced choroidal neovascularisation mouse model. In summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications.
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| 4. |
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| 5. |
- Pudelko, L., et al.
(författare)
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Erratum : Glioblastoma and glioblastoma stem cells are dependent on functional MTH1 (Oncotarget (2017) 8 (84671-84684) DOI: 10.18632/oncotarget.19404)
- 2020
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Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 11:8
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Tidskriftsartikel (refereegranskat)abstract
- This article has been corrected: The Funding information has been updated. The complete Funding list is shown below: FUNDING This work was supported by the Karolinska Institutes KID funding (LP), the Seve Ballesteros Foundation to MS, the Marie Curie foundation (CIG-618751 MS), the Knut and Alice Wallenberg Foundation (KAW2014.273 TH), the Swedish Foundation for Strategic Research (RB13-0224 TH), the Swedish Cancer Society (TH), the Swedish Research Council (2015-00162 TH), the Göran Gustafsson Foundation (TH), the Swedish Children’s Cancer Foundation (to TH), the Swedish Pain Relief Foundation (PR20140048 TH), the Torsten and Ragnar Söderberg Foundation (TH), and the European Research Council (TAROX-695376).
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| 6. |
- Reis, Katarina, et al.
(författare)
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Inhibitors of cytoskeletal dynamics in malignant mesothelioma.
- 2020
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 11:50, s. 4637-4647
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Tidskriftsartikel (refereegranskat)abstract
- Malignant mesotheliomas (MMs) are highly aggressive mesenchymal tumors that originate from mesothelial cells lining serosal cavities; i.e., the pleura, peritoneum, and pericardium. Classically, there is a well-established link between asbestos exposure, oxidative stress, release of reactive oxygen species, and chronic inflammatory mediators that leads to progression of MMs. MMs have an intermediate phenotype, with co-expression of mesenchymal and epithelial markers and dysregulated communication between the mesothelium and the microenvironment. We have previously shown that the organization and function of key cytoskeletal components can distinguish highly invasive cell lines from those more indolent. Here, we used these tools to study three different types of small-molecule inhibitors, where their common feature is their influence on production of reactive oxygen species. One of these, imipramine blue, was particularly effective in counteracting some key malignant properties of highly invasive MM cells. This opens a new possibility for targeted inhibition of MMs based on well-established molecular mechanisms.
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| 7. |
- Vickman, R. E., et al.
(författare)
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Deconstructing tumor heterogeneity : The stromal perspective
- 2020
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Ingår i: Oncotarget. - : Impact Journals LLC. - 1949-2553. ; 11:40, s. 3621-3632
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Tidskriftsartikel (refereegranskat)abstract
- Significant advances have been made towards understanding the role of immune cell-tumor interplay in either suppressing or promoting tumor growth, progression, and recurrence, however, the roles of additional stromal elements, cell types and/or cell states remain ill-defined. The overarching goal of this NCI-sponsored workshop was to highlight and integrate the critical functions of non-immune stromal components in regulating tumor heterogeneity and its impact on tumor initiation, progression, and resistance to therapy. The workshop explored the opposing roles of tumor supportive versus suppressive stroma and how cellular composition and function may be altered during disease progression. It also highlighted microenvironment-centered mechanisms dictating indolence or aggressiveness of early lesions and how spatial geography impacts stromal attributes and function. The prognostic and therapeutic implications as well as potential vulnerabilities within the heterogeneous tumor microenvironment were also discussed. These broad topics were included in this workshop as an effort to identify current challenges and knowledge gaps in the field. Copyright:
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