| 1. |
- Almstedt, Elin, 1988-, et al.
(författare)
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Integrative discovery of treatments for high-risk neuroblastoma
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723 .- 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.
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| 2. |
- Da Silva, Stéphanie, et al.
(författare)
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A novel topical PPARγ agonist induces PPARγ-activity in ulcerative colitis mucosa and prevents and reverses inflammation in induced-colitis models
- 2018
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Ingår i: Inflammatory Bowel Diseases. - : Lippincott Williams & Wilkins. - 1078-0998 .- 1536-4844. ; 24:4, s. 792-805
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peroxisome proliferator-activated receptor-gamma (PPARγ) exerts anti-inflammatory effects and is therefore a potential target in ulcerative colitis (UC). A novel PPARγ agonist (AS002) developed for local action was evaluated ex vivo in biopsies from UC patients and in vivo in mice with low-grade dextran sodium sulfate (DSS)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis.Methods: Colonic biopsies from UC patients (n = 18) and healthy controls (n = 6) were incubated with AS002 or rosiglitazone (positive control) to measure mRNA expression of the PPARγ-responsive gene ADIPOPHILIN and protein levels of UC-related cytokines (enzyme-linked immunosorbent assay). AS002 absorption was determined in the colonic mucosa of UC patients. DSS-colitis mice received PPARγ agonists or vehicle daily by intrarectal administration starting 2 days before induction of colitis (preventive) or from days 3 to 8 (curative). Myeloperoxidase (MPO) and cytokine levels in colonic mucosa were determined. In addition, AS002 effects were studied in TNBS colitis.Results: AS002 displayed an absorption pattern of a lipophilic drug totally metabolized in the mucosa. AS002 and rosiglitazone increased ADIPOPHILIN mRNA expression (3-fold) and decreased TNF-α, IL-1β, and IL-13 levels in human UC biopsies. In DSS, in both preventive and curative treatment and in TNBS colitis, AS002 protected against macroscopic and histological damage and lowered MPO and TNF-α, IL-1β, and IL-13 levels.Conclusions: AS002 triggers anti-inflammatory PPARγ activity in the human colonic mucosa of UC patients and prevents and reverses colitis in mice. Our data suggest that AS002 has potential for topical maintenance treatment of UC, which warrants further studies in vivo in patients.
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| 3. |
- Kronblad, Åsa, et al.
(författare)
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Regional cyclin D1 overexpression or hypoxia correlate inversely with heterogeneous oestrogen receptor-alpha expression in human breast cancer.
- 2003
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Ingår i: In Vivo. - 0258-851X. ; 17:4, s. 311-8
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Tidskriftsartikel (refereegranskat)abstract
- Substance P (SP) has been implicated in the pathophysiology of ulcerative colitis (UC) and it has been suggested that blocking of its effect would be advantageous in this disease. Eosinophils have also been implicated in the pathophysiology of UC. In the present study, specimens from the sigmoid colon of UC patients were investigated by the use of antisera against SP and the neurokinin-1 receptor (NK-1R) and staining for demonstration of eosinophils. The degrees of SP innervation and NK-1R immunoreaction, as well as the levels of eosinophil infiltration, varied between different patients. Interestingly, NK-1R immunoreaction in the epithelium was often seen to be the most marked where there were numerous eosinophils in the underlying mucosa and where the mucosa showed a marked morphologic derangement. The observations suggest that there are marked fluctuations in effects of SP and eosinophils during the disease. The infiltrating eosinophils may be involved in the destruction of the mucosal tissue. Furthermore, for the majority of cases where there is marked derangement of the mucosa, it is apparent that there is an upregulation of the NK-1 receptor in the epithelium in parallel with the infiltration of the eosinophils.
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| 4. |
- Agarwal, Shruti, et al.
(författare)
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The activation loop tyrosine 823 is essential for the transforming capacity of the c-Kit oncogenic mutant D816V.
- 2015
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 34:35, s. 4581-4590
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Tidskriftsartikel (refereegranskat)abstract
- Oncogenic c-Kit mutations have been shown to display ligand-independent receptor activation and cell proliferation. A substitution of aspartate to valine at amino acid 816 (D816V) is one of the most commonly found oncogenic c-Kit mutations and is found in >90% of cases of mastocytosis and less commonly in germ-cell tumors, core-binding factor acute myeloid leukemia and mucosal melanomas. The mechanisms by which this mutation leads to constitutive activation and transformation are not fully understood. Previous studies have shown that the D816V mutation causes a structural change in the activation loop (A-loop), resulting in weaker binding of the A-loop to the juxtamembrane domain. In this paper, we have investigated the role of Y823, the only tyrosine residue in the A-loop, and its role in oncogenic transformation by c-Kit/D816V by introducing the Y823F mutation. Although dispensable for the kinase activity of c-Kit/D816V, the presence of Y823 was crucial for cell proliferation and survival. Furthermore, mutation of Y823 selectively downregulates the Ras/Erk and Akt pathways as well as the phosphorylation of STAT5 and reduces the transforming capacity of the D816V/c-Kit in vitro. We further show that mice injected with cells expressing c-Kit/D816V/Y823F display significantly reduced tumor size as well as tumor weight compared with controls. Finally, microarray analysis, comparing Y823F/D816V cells with cells expressing c-Kit/D816V, demonstrate that mutation of Y823 causes upregulation of proapoptotic genes, whereas genes of survival pathways are downregulated. Thus, phosphorylation of Y823 is not necessary for kinase activation, but essential for the transforming ability of the c-Kit/D816V mutant.Oncogene advance online publication, 1 December 2014; doi:10.1038/onc.2014.383.
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| 5. |
- Ahlqvist-Rastad, Jane, et al.
(författare)
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Erythropoietin therapy and cancer related anaemia : updated Swedish recommendations
- 2007
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Ingår i: Medical Oncology. - : Springer Science and Business Media LLC. - 1357-0560 .- 1559-131X. ; 24:3, s. 267-272
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Tidskriftsartikel (refereegranskat)abstract
- Due to concerns related to treatment with erythropoietin (EPO) and possible negative effects on tumour control, a workshop was organised by the Medical Products Agency of Sweden with the aim to revise national treatment guidelines if needed. In patients with solid tumours, conflicting results have been reported with respect to tumour control and survival. Until further notice it is therefore recommended that EPO should be used restrictively in the treatment of patients with cancer and that the anticipated improvement in quality of life should be evaluated against potential risks.
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| 6. |
- Alam, Muhammad Wasi, et al.
(författare)
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HIF2α contributes to antiestrogen resistance via positive bilateral crosstalk with EGFR in breast cancer cells.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:10, s. 50-11238
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Tidskriftsartikel (refereegranskat)abstract
- The majority of breast cancers express estrogen receptor α (ERα), and most patients with ERα-positive breast cancer benefit from antiestrogen therapy. The ERα-modulator tamoxifen and ERα-downregulator fulvestrant are commonly employed antiestrogens. Antiestrogen resistance remains a clinical challenge, with few effective treatments available for patients with antiestrogen-resistant breast cancer. Hypoxia, which is intrinsic to most tumors, promotes aggressive disease, with the hypoxia-inducible transcription factors HIF1 and HIF2 regulating cellular responses to hypoxia. Here, we show that the ERα-expressing breast cancer cells MCF-7, CAMA-1, and T47D are less sensitive to antiestrogens when hypoxic. Furthermore, protein and mRNA levels of HIF2α/HIF2A were increased in a panel of antiestrogen-resistant cells, and antiestrogen-exposure further increased HIF2α expression. Ectopic expression of HIF2α in MCF-7 cells significantly decreased sensitivity to antiestrogens, further implicating HIF2α in antiestrogen resistance. EGFR is known to contribute to antiestrogen resistance: we further show that HIF2α drives hypoxic induction of EGFR and that EGFR induces HIF2α expression. Downregulation or inhibition of EGFR led to decreased HIF2α levels. This positive and bilateral HIF2-EGFR regulatory crosstalk promotes antiestrogen resistance and, where intrinsic hypoxic resistance exists, therapy itself may exacerbate the problem. Finally, inhibition of HIFs by FM19G11 restores antiestrogen sensitivity in resistant cells. Targeting HIF2 may be useful for counteracting antiestrogen resistance in the clinic.
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| 7. |
- Allaoui, Roni, et al.
(författare)
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Cancer-associated fibroblast-secreted CXCL16 attracts monocytes to promote stroma activation in triple-negative breast cancers
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative (TN) breast cancers (ER â ' PR â ' HER2 â ') are highly metastatic and associated with poor prognosis. Within this subtype, invasive, stroma-rich tumours with infiltration of inflammatory cells are even more aggressive. The effect of myeloid cells on reactive stroma formation in TN breast cancer is largely unknown. Here, we show that primary human monocytes have a survival advantage, proliferate in vivo and develop into immunosuppressive myeloid cells expressing the myeloid-derived suppressor cell marker S100A9 only in a TN breast cancer environment. This results in activation of cancer-associated fibroblasts and expression of CXCL16, which we show to be a monocyte chemoattractant. We propose that this migratory feedback loop amplifies the formation of a reactive stroma, contributing to the aggressive phenotype of TN breast tumours. These insights could help select more suitable therapies targeting the stromal component of these tumours, and could aid prediction of drug resistance.
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| 8. |
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| 9. |
- Bergström, Tobias, 1980-
(författare)
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Modeling Neural Stem Cell and Glioma Biology
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is focused on neural stem cell (NSC) and glioma biology. I discuss how NSCs interact with extracellular matrix (ECM) proteins in the stem cell niche, and investigate the consequences of deregulated Platelet-derived growth factor (PDGF) signaling for embryonic NSCs in transgenic mice. Furthermore I present cell cultures of human glioblastoma multiforme (GBM) that models human disease, taking into account the heterogeneity of GBM. Finally, interactions between brain tumors and mast cells are studied using the glioma cultures.In paper I, the importance of NSC interactions with the ECM in the stem cell niche during development is discussed. Contacts between NSCs and the ECM in the subventricular zone (SVZ) are emerging as important regulatory mechanisms. We show that early postnatal neural stem and progenitor cells (NSPC) attach to collagen I, and that the adhesion is explained by higher expression of collagen receptor integrins compared to adult NSPC. Further, blood vessels in the SVZ express collagen I, indicating a possible functional relationship.Growth factors, e.g. PDGF, regulate NSC proliferation and differentiation. Aberrant activation of growth factor signaling pathways also plays a role in brain tumor formation. Paper II demonstrates that transgenic mice expressing PDGF-B at high levels in embryonic NSCs displayed mild neurological defects but no hyperplasia or brain tumors. This suggests that a high level of PDGF is not sufficient to induce brain tumors from NSCs without further mutations.Paper III presents a novel panel of human glioma stem cell (GSC) lines from GBM that display NSC markers in vitro and form secondary orthotopic tumors in vivo. GBM has recently been categorized in molecular subclasses and we demonstrate, for the first time, that these subclasses can be retained in vitro by stem cell culture conditions. We have thus generated models for research and drug development aiming at a focused treatment depending on GBM subtype.Interactions with the immune system are integral parts of tumorigenesis. Mast cells are found in glioma and in paper IV we demonstrate that the grade-dependent infiltration of mast cells is in part mediated by macrophage migration inhibitory factor and phosphorylation of STAT5.
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| 10. |
- Braekeveldt, Noémie, et al.
(författare)
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Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours
- 2016
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 375:2, s. 384-389
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of high-risk childhood neuroblastoma is a clinical challenge hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing.
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| 11. |
- Braekeveldt, Noémie, et al.
(författare)
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Neuroblastoma Patient-Derived Orthotopic Xenografts Retain Metastatic Patterns and Geno- and Phenotypes of Patient Tumours.
- 2015
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:5, s. 252-261
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose - positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers NCAM, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p, and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma. © 2014 Wiley Periodicals, Inc.
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| 12. |
- Braekeveldt, Noémie, et al.
(författare)
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Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
- 2018
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Ingår i: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
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Tidskriftsartikel (refereegranskat)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
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| 13. |
- Bäckman, Ulrika, 1971-
(författare)
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Treatment of Experimental Neuroblastoma with Angiogenic Inhibitors
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma is a childhood cancer that originates from neuroblasts in the peripheral nervous system. Neuroblastoma show considerable heterogeneity with respect to location, responsiveness to treatment and prognosis. Since current therapy involves drugs with risk of serious side effects in the growing child, there is a clinical need for more effective and less toxic treatment strategies.Angiogenesis, the formation of new blood vessels, is critical for tumor progression. Specific inhibition of tumor-induced angiogenesis should restrict growth of most solid tumors and thereby provide a new treatment strategy. The aim of this study was to investigate the effects of angiogenic inhibition in experimental neuroblastoma in mice.We found that experimental neuroblastomas expressed the perhaps most potent angiogenic growth factor, VEGF-A, and that plasma VEGF-A levels correlated with tumor size. SU5416, a novel antagonist of VEGFR-1 and 2, reduced angiogenesis and tumor growth in our model. We also investigated the properties of SU11657, a new, orally available, synthetic small molecule multi-targeted tyrosine kinase inhibitor. SU11657, at a well-tolerated dose, was more potent than SU5416 in reducing tumor growth rate and angiogenesis, even in MYCN-amplified tumors. Chemotherapeutics can also inhibit angiogenesis, when administrated daily in a non-toxic dose. CHS 828, a new chemotherapeutic, given orally, alone induced complete neuroblastoma regression in 44 % of the animals. Furthermore, the bisphosphonate zoledronic acid, developed to reduce bone resorption, showed anti-tumor activity in our model. Zoledronic acid was more potent than the angiogenic inhibitor TNP-470. Thus bisphosphonates may have other beneficial properties in patients with cancer apart from preventing bone resorption.In conclusion, SU5416, SU11657, CHS 828, and zoledronic acid represent new drugs with potent anti-tumor effects. Angiogenic inhibition as single therapy or in combination with chemotherapeutics may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood such as neuroblastoma.
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| 14. |
- Carlson, Lena-Maria, et al.
(författare)
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Differentiation induced by physiological and pharmacological stimuli leads to increased antigenicity of human neuroblastoma cells
- 2008
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Ingår i: Cell Research. - : Springer Science and Business Media LLC. - 1748-7838 .- 1001-0602. ; 18:3, s. 398-411
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Tidskriftsartikel (refereegranskat)abstract
- Sympathetic neuronal differentiation is associated with favorable prognosis of neuroblastoma (NB), the most common extra-cranial solid tumor of early childhood. Differentiation agents have proved useful in clinical protocols of NB treatment, but using them as a sole treatment is not sufficient to induce tumor elimination in patients. Therefore, complementary approaches, such as immunotherapy, are warranted. Here we demonstrate that differentiation of NB cell lines and ex vivo isolated tumor cells in response to physiological or pharmacological stimuli is associated with acquisition of increased antigenicity. This manifests as increased expression of surface major histocompatibility class I complexes and ICAM-1 molecules and translates into increased sensitivity of NB cells to lysis by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. The latter is paralleled by enhanced ability of differentiated cells to form immune conjugates and bind increased amounts of granzyme B to the cell surface. We demonstrate, for the first time, that, regardless of the stimulus applied, the differentiation state in NBs is associated with increased tumor antigenicity that enables more efficient elimination of tumor cells by cytotoxic lymphocytes and paves the way for combined application of differentiation-inducing agents and immunotherapy as an auxiliary approach in NB patients.
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| 15. |
- Cetinkaya, Cihan, et al.
(författare)
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Combined IFN-gamma and retinoic acid treatment targets the N-Myc/Max/Mad1 network resulting in repression of N-Myc target genes in MYCN-amplified neuroblastoma cells
- 2007
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Ingår i: Molecular Cancer Therapeutics. - 1535-7163 .- 1538-8514. ; 6:10, s. 2634-2641
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Tidskriftsartikel (refereegranskat)abstract
- The MYCN protooncogene is involved in the control of cell proliferation, differentiation, and survival of neuroblasts. Deregulation of MYCN by gene amplification contributes to neuroblastoma development and is strongly correlated to advanced disease and poor outcome, emphasizing the urge for new therapeutic strategies targeting MYCN function. The transcription factor N-Myc, encoded by MYCN, regulates numerous genes together with its partner Max, which also functions as a cofactor for the Mad/Mnt family of Myc antagonists/transcriptional repressors. We and others have previously reported that IFN-gamma synergistically potentiates retinoic acid (RA)induced sympathetic differentiation and growth inhibition in neuroblastoma cells. This study shows that combined treatment of MYCN-amplified neuroblastorna cells with RA+IFN-gamma down-regulates N-Myc protein expression through increased protein turnover, up-regulates Mad1 mRNA and protein, and reduces N-Myc/Max heteroclimerization. This results in a shift of occupancy at the ornithine decarboxylase N-Myc/Mad1 target promoter in vivo from N-Myc/Max to Madl/Max predominance, correlating with histone H4 deacetylation, indicative of a chromatin structure typical of a transcriptionally repressed state. This is further supported by data showing that RA + IFN-gamma treatment strongly represses expression of N-Myc/Mad1 target genes ornithine decarboxylase and hTERT. Our results suggest that combined IFN-gamma and RA signaling can form a basis for new therapeutic strategies targeting N-Myc function for patients with high-risk, MYCN-amplified neuroblastoma.
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| 16. |
- Chabok, Abbas, 1964-, et al.
(författare)
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CT-colonography in the follow-up of acute diverticulitis : patient acceptance and diagnostic accuracy
- 2013
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 48:8, s. 979-986
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this study was to assess CT-colonography (CTC) in the follow-up of diverticulitis regarding patient acceptance and diagnostic accuracy for diverticular disease, adenomas and cancer, with colonoscopy as a reference standard. Methods. A prospective comparative study where half of the patients underwent colonoscopy first, followed immediately by CTC. The other half had the examinations in the reverse order. Patient experiences and findings were registered after every examination, blinded to the examiner. Results. Of a total of 110 consecutive patients, 108 were included in the study, with a median age of 56 years (range 27-84). The success rate was 91% for colonoscopy and 86% for CTC. Examination time was 25 mm for both methods. The mean time for CTC evaluation was 20 mm. Eighty-three per cent of the patients received sedation during colonoscopy. Despite this, patients experienced colonoscopy as more painful (p < 0.001) and uncomfortable (p < 0.001). Diverticulosis and polyps were detected in 94% and 20% with colonoscopy and in 94% and 29% with CTC, respectively. Sensitivity and specificity for CTC in the detection of diverticulosis was 99% and 67%, with a good agreement (kappa = 0.71). Regarding detection of polyps, the sensitivity and specificity were 47% and 75%, with a poor agreement (kappa = 0.17). No cancer was found. Conclusion. CTC was less painful and unpleasant and can be used for colonic investigation in the follow-up of diverticulitis. CTC detected diverticulosis with good accuracy while the detection accuracy of small polyps was poor. CTC is a viable alternative, especially in case of incomplete colonoscopy or in a situation with limited colonoscopy resources.
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| 17. |
- Chavali, Pavithra Lakshminarasimhan, et al.
(författare)
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TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival.
- 2014
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Ingår i: Cell Death & Disease. - : Springer Science and Business Media LLC. - 2041-4889. ; 449:5
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Tidskriftsartikel (refereegranskat)abstract
- Nuclear orphan receptor TLX (Drosophila tailless homolog) is essential for the maintenance of neural stem/progenitor cell self-renewal, but its role in neuroblastoma (NB) is not well understood. Here, we show that TLX is essential for the formation of tumor spheres in three different NB cell lines, when grown in neural stem cell media. We demonstrate that the knock down of TLX in IMR-32 cells diminishes its tumor sphere-forming capacity. In tumor spheres, TLX is coexpressed with the neural progenitor markers Nestin, CD133 and Oct-4. In addition, TLX is coexpressed with the migratory neural progenitor markers CD15 and matrix metalloproteinase-2 (MMP-2) in xenografts of primary NB cells from patients. Subsequently, we show the effect of TLX on the proliferative, invasive and migratory properties of IMR-32 cells. We attribute this to the recruitment of TLX to both MMP-2 and Oct-4 gene promoters, which resulted in the respective gene activation. In support of our findings, we found that TLX expression was high in NB patient tissues when compared with normal peripheral nervous system tissues. Further, the Kaplan-Meier estimator indicated a negative correlation between TLX expression and survival in 88 NB patients. Therefore, our results point at TLX being a crucial player in progression of NB, by promoting self-renewal of NB tumor-initiating cells and altering their migratory and invasive properties.
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| 18. |
- Cifani, Paolo, et al.
(författare)
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Hunting for Protein Markers of Hypoxia by Combining Plasma Membrane Enrichment with a New Approach to Membrane Protein Analysis
- 2011
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 10:4, s. 1645-1656
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Tidskriftsartikel (refereegranskat)abstract
- Nontransient hypoxia is strongly associated with malignant lesions, resulting in aggressive behavior and resistance to treatment. We present an analysis of mRNA and protein expression changes in neuroblastoma cell lines occurring upon the transition from normoxia to hypoxia. The correlation between mRNA and protein level changes was poor, although some known hypoxia-driven genes and proteins correlated well. We present previously undescribed membrane proteins expressed under hypoxic conditions that are candidates for evaluation as biomarkers.
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| 19. |
- Claeys, Shana, et al.
(författare)
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ALK positively regulates MYCN activity through repression of HBP1 expression
- 2019
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 38:15, s. 2690-2705
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Tidskriftsartikel (refereegranskat)abstract
- ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI3K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI3K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.
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| 20. |
- De Preter, Katleen, et al.
(författare)
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Human fetal neuroblast and neuroblastoma transcriptome analysis confirms neuroblast origin and highlights neuroblastoma candidate genes
- 2006
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1474-7596 .- 1465-6906. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroblastoma tumor cells are assumed to originate from primitive neuroblasts giving rise to the sympathetic nervous system. Because these precursor cells are not detectable in postnatal life, their transcription profile has remained inaccessible for comparative data mining strategies in neuroblastoma. This study provides the first genome-wide mRNA expression profile of these human fetal sympathetic neuroblasts. To this purpose, small islets of normal neuroblasts were isolated by laser microdissection from human fetal adrenal glands. Results: Expression of catecholamine metabolism genes, and neuronal and neuroendocrine markers in the neuroblasts indicated that the proper cells were microdissected. The similarities in expression profile between normal neuroblasts and malignant neuroblastomas provided strong evidence for the neuroblast origin hypothesis of neuroblastoma. Next, supervised feature selection was used to identify the genes that are differentially expressed in normal neuroblasts versus neuroblastoma tumors. This approach efficiently sifted out genes previously reported in neuroblastoma expression profiling studies; most importantly, it also highlighted a series of genes and pathways previously not mentioned in neuroblastoma biology but that were assumed to be involved in neuroblastoma pathogenesis. Conclusion: This unique dataset adds power to ongoing and future gene expression studies in neuroblastoma and will facilitate the identification of molecular targets for novel therapies. In addition, this neuroblast transcriptome resource could prove useful for the further study of human sympathoadrenal biogenesis.
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| 21. |
- De Preter, K, et al.
(författare)
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Positional and functional mapping of a neuroblastoma differentiation gene on chromosome 11
- 2005
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Loss of chromosome 11q defines a subset of high-stage aggressive neuroblastomas. Deletions are typically large and mapping efforts have thus far not lead to a well defined consensus region, which hampers the identification of positional candidate tumour suppressor genes. In a previous study, functional evidence for a neuroblastoma suppressor gene on chromosome 11 was obtained through microcell mediated chromosome transfer, indicated by differentiation of neuroblastoma cells with loss of distal 11q upon introduction of chromosome 11. Interestingly, some of these microcell hybrid clones were shown to harbour deletions in the transferred chromosome 11. We decided to further exploit this model system as a means to identify candidate tumour suppressor or differentiation genes located on chromosome 11. Results: In a first step, we performed high-resolution arrayCGH DNA copy-number analysis in order to evaluate the chromosome 11 status in the hybrids. Several deletions in both parental and transferred chromosomes in the investigated microcell hybrids were observed. Subsequent correlation of these deletion events with the observed morphological changes lead to the delineation of three putative regions on chromosome 11: 11q25, 11p13-> 11p15.1 and 11p15.3, that may harbour the responsible differentiation gene. Conclusion: Using an available model system, we were able to put forward some candidate regions that may be involved in neuroblastoma. Additional studies will be required to clarify the putative role of the genes located in these chromosomal segments in the observed differentiation phenotype specifically or in neuroblastoma pathogenesis in general.
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| 22. |
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| 23. |
- Edsjö, Anders, et al.
(författare)
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Differences in early and late responses between neurotrophin-stimulated trkA- and trkC-transfected SH-SY5Y neuroblastoma cells
- 2001
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Ingår i: Cell Growth & Differentiation. - 1044-9523. ; 12:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Despite their sympathetic neuroblast origin, highly malignant neuroblastoma tumors and derived cell lines have no or low expression of the neurotrophin receptor genes, trkA and trkC. Expression of exogenous trkA in neuroblastoma cells restores their ability to differentiate in response to nerve growth factor (NGF). Here we show that stable expression of trkC in SH-SY5Y neuroblastoma cells resulted in morphological and biochemical differentiation upon treatment with neurotrophin-3 (NT-3). To some extent, trkA- and trkC-transfected SH-SY5Y (SH-SY5Y/trkA and SH-SY5Y/trkC) cells resembled one another in terms of early signaling events and neuronal marker gene expression, but important differences were observed. Although induced Erk 1/2 and Akt/PKB phosphorylation was stronger in NT-3-stimulated SH-Y5Y/trkC cells, activation of the immediate-early genes tested was more prominent in NGF-treated SH-SY5Y/ trkA cells. In particular, c-fos was not induced in the SH-SY5Y/trkC cells. There were also phenotypic differences. The concentrations of norepinephrine, the major sympathetic neurotransmitter, and growth cone-located synaptophysin, a neurosecretory granule protein, were increased in NGF-treated SH-SY5Y/trkA but not in NT-3-treated SH-SY5Y/trkC cells. Our data suggest that NT-3/p145trkC and NGF/p140trkA signaling differ in some aspects in neuroblasoma cells, and that this may explain the phenotypic differences seen in the long-term neurotrophin-treated cells.
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| 24. |
- Edsjö, Anders, et al.
(författare)
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Expression of trkB in Human Neuroblastoma in Relation to MYCN Expression and Retinoic Acid Treatment.
- 2003
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Ingår i: Laboratory Investigation. - 1530-0307. ; 83:6, s. 813-823
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Tidskriftsartikel (refereegranskat)abstract
- Expression of full-length trkB can be found in some highly malignant neuroblastoma tumors with an amplified MYCN gene. This contrasts sympathetic neuroblasts, from which neuroblastomas are thought to arise, which neither express trkB nor are dependent on the p145trkB ligands, brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5, for their normal development. In this study we show that trkB was expressed in two out of five neuroblastoma tumors with amplified MYCN, while no trkB expression was observed when the MYCN gene was overexpressed in a non–MYCN-amplified neuroblastoma cell line. This shows that MYCN overexpression per se is not sufficient to induce trkB expression. trkB expression and BDNF responsiveness in neuroblastoma cells can be induced by all-trans-retinoic acid (RA). When SH-SY5Y cells were stimulated with a combination of RA and BDNF, norepinephrine and tyrosine hydroxylase levels were unaltered, showing that the cells did not change toward a more catecholaminergic sympathetic phenotype. However, expression of growth-associated protein 43, indicative of a neuronal phenotype, was elevated. Vesicular acetylcholine transporter, choline acetyl transferase, and neuropeptide tyrosine mRNA levels also increased in RA-BDNF–treated cells, which could suggest that these cells develop into a sympathetic cholinergic phenotype. In addition, treatment with RA-induced expression of the platelet-derived growth factor receptor-alpha. As previously shown for BDNF, platelet-derived growth factor stimulated growth of the RA-treated cells, findings that could have clinical relevance. If these receptors mediate a mitogenic signal in vivo also, this might limit the effect of RA treatment on neuroblastoma patients.
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| 25. |
- Edsjö, Anders, et al.
(författare)
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Neuroblastoma as an experimental model for neuronal differentiation and hypoxia-induced tumor cell dedifferentiation.
- 2007
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 17:3, s. 248-256
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Forskningsöversikt (refereegranskat)abstract
- Neuroblastoma is a childhood tumor derived from precursor or immature cells of the sympathetic nervous system. Neuroblastomas show a tremendous clinical heterogeneity, encompassing truly benign as well as extremely aggressive forms. In vivo as well as in vitro data have shown that the degree of sympathetic neuronal tumor cell differentiation influences patient outcome. Unraveling mechanisms governing neuroblastoma cell differentiation is therefore a central issue in the neuroblastoma research field. In this communication, we discuss some of the in vitro models frequently used to study human neuroblastoma cell differentiation. We also review recent data demonstrating that oxygen shortage, hypoxia, shifts neuroblastoma cells toward an immature, stem cell-like phenotype and discuss the potential clinical impact of hypoxia on neuroblastoma behavior.
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