| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
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| 6. |
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| 7. |
- Gurmu, Ambatchew, et al.
(författare)
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The inter-observer reliability is very low at clinical examination of parastomal hernia
- 2011
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Ingår i: International Journal of Colorectal Disease. - Heidelberg : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 26:1, s. 89-95
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Parastomal hernia in patients with a permanent colostomy is common. The aim of this study was to evaluate the reliability of the diagnosis based on clinical examination and to compare this examination with the result of a specially designed questionnaire and computerised tomography (CT) scan. METHODS: Forty-one patients operated upon with an abdominoperineal resection due to rectal cancer at three hospitals between 1996 and 2002 were included. At minimum of 4 years after the operation, they underwent clinical examination by two or three independent surgeons, answered a colostomy questionnaire and were offered a CT scan of the abdominal wall. RESULT: At Hospital I, 17 patients were examined by three surgeons, with inter-observer kappa values between 0.35 and 0.64. At Hospital II, 13 patients were examined by three surgeons, the kappa values ranged between 0.29 and 0.43. At Hospital III, 11 patients were examined by two surgeons, with kappa value of 0.73. The kappa value between CT scan and the colostomy questionnaire was 0.45. CONCLUSION: The inter-observer reliability was low, indicating that parastomal hernia is difficult to diagnose by patient history and clinical examination. Some herniae may not be detected by CT scan, and the correlation to patient-reported complaints is low. A more sensitive radiological method to detect parastomal hernia is needed.
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| 8. |
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| 9. |
- Hjelm, Barbara, et al.
(författare)
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High nuclear RBM3 expression is associated with an improved prognosis in colorectal cancer
- 2011
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Ingår i: Proteomics Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 5:11-12, s. 624-635
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In this study, we investigated the prognostic impact of human RBM3 expression in colorectal cancer using tissue microarray-based immunohistochemical analysis. Experimental design: One polyclonal antibody and four monoclonal anti-RBM3 antibodies were generated and epitope mapped using two different methods. Bacterial display revealed five distinct epitopes for the polydonal antibody, while the four mouse monoclonal antibodies were found to bind to three of the five epitopes. A peptide suspension bead array assay confirmed the five epitopes of the polydonal antibody, while only one of the monoclonal antibodies could be mapped using this approach. Antibody specificity was confirmed by Western blotting and immunohistochemistry, including siRNA-mediated knock-down. Two of the antibodies (polydonal and monoclonal) were subsequently used to analyze RBM3 expression in tumor samples from two independent colorectal cancer cohorts, one consecutive cohort (n = 270) and one prospectively collected cohort of patients with cancer of the sigmoid colon (n = 305). RBM3-expression was detected, with high correlation between both antibodies (R = 0.81, p < 0.001). Results: In both cohorts, tumors with high nuclear RBM3 staining had significantly prolonged the overall survival. This was also confirmed in multivariate analysis, adjusted for established prognostic factors. Conclusion and clinical relevance: These data demonstrate that high tumor-specific nuclear expression of RBM3 is an independent predictor of good prognosis in colorectal cancer.
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| 10. |
- Jögi, Annika, et al.
(författare)
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Cancer cell differentiation heterogeneity and aggressive behavior in solid tumors.
- 2012
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Ingår i: Uppsala Journal of Medical Sciences. - : Uppsala Medical Society. - 0300-9734 .- 2000-1967. ; 117:2, s. 217-224
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Tidskriftsartikel (refereegranskat)abstract
- The differentiation stage of tumors is a central aspect in the histopathological classification of solid malignancies. The differentiation stage is strongly associated with tumor behavior, and generally an immature tumor is more aggressive than the more differentiated counterpart. While this is common knowledge in surgical pathology, the contribution of differentiation-related gene expression and functions to tumor behavior is often overlooked in the experimental, tumor biological setting. The mechanisms by which tumor cell differentiation stages are perturbed or affected are poorly explored but have recently come into focus with the introduction.of the tumor stem cell concept. While developmental biologists view the differentiation as a unidirectional event, pathologists and tumor biologists have introduced the concept of dedifferentiation to explain phenotypic changes occurring in solid tumors. In this review we discuss the impact of the tumor cell differentiation stage as used in surgical pathology. We further discuss knowledge gained from exploring the molecular basis of the differentiation and dedifferentiation processes in neuroblastoma and breast cancer, two tumor forms where the tumor cell differentiation concept is used in the clinical diagnostic work and where the tumor stem cell theory has been applied.
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| 11. |
- Kazi, Julhash U., et al.
(författare)
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The tyrosine kinase CSK associates with FLT3 and c-Kit receptors and regulates downstream signaling.
- 2013
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Ingår i: Cellular Signalling. - : Elsevier BV. - 1873-3913 .- 0898-6568. ; 25:9, s. 1852-1860
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Tidskriftsartikel (refereegranskat)abstract
- Type III receptor tyrosine kinases (RTKs), FLT3 and c-Kit play important roles in a variety of cellular processes. A number of SH2-domain containing proteins interact with FLT3 and c-Kit and regulate downstream signaling. The SH2-domain containing non-receptor protein tyrosine kinase CSK is mainly studied in context of regulating Src family kinases. Here we present an addition role of this kinase in RTK signaling. We show that CSK interacts with FLT3 and c-Kit in a phosphorylation dependent manner. This interaction is facilitated through the SH2-domain of CSK. Under basal conditions CSK is mainly localized throughout the cytosolic compartment but upon ligand stimulation it is recruited to the inner side of cell membrane. CSK association did not alter receptor ubiquitination or phosphorylation but disrupted downstream signaling. Selective depletion of CSK using siRNA, or inhibition with CSK inhibitor, led to increased phosphorylation of Akt and Erk, but not p38, upon FLT3 ligand (FL) stimulation. Stem cell factor (SCF)-mediated Akt and Erk activation was also elevated by CSK inhibition. However, siRNA mediated CSK knockdown increased SCF stimulated Akt phosphorylation but decreased Erk phosphorylation. CSK depletion also significantly increased both FL- and SCF-induced SHC, Gab2 and SHP2 phosphorylation. Furthermore, CSK depletion contributed to oncogenic FLT3- and c-Kit-mediated cell proliferation, but not to cell survival. Thus, the results indicate that CSK association with type III RTKs, FLT3 and c-Kit can have differential impact on receptor downstream signaling.
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| 12. |
- Lovén, Jakob, et al.
(författare)
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MYCN-regulated microRNAs repress estrogen receptor-alpha (ESR1) expression and neuronal differentiation in human neuroblastoma.
- 2010
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 107:4, s. 1553-8
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Tidskriftsartikel (refereegranskat)abstract
- MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17 approximately 92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-alpha (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.
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| 13. |
- Mohlin, Sofie, et al.
(författare)
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HIF2A and IGF2 Expression Correlates in Human Neuroblastoma Cells and Normal Immature Sympathetic Neuroblasts.
- 2013
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Ingår i: Neoplasia. - : Elsevier BV. - 1522-8002 .- 1476-5586. ; 15:3, s. 328-334
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Tidskriftsartikel (refereegranskat)abstract
- During normal sympathetic nervous system (SNS) development, cells of the ganglionic lineage can malignantly transform and develop into the childhood tumor neuroblastoma. Hypoxia-inducible transcription factors (HIFs) mediate cellular responses during normal development and are central in the adaptation to oxygen shortage. HIFs are also implicated in the progression of several cancer forms, and high HIF-2α expression correlates with disseminated disease and poor outcome in neuroblastoma. During normal SNS development, is transiently expressed in neuroblasts and chromaffin cells. SNS cells can, during development, be distinguished by distinct gene expression patterns, and () is a marker of sympathetic chromaffin cells, whereas sympathetic neuroblasts lack expression. Despite the neuronal derivation of neuroblastomas, we show that neuroblastoma cell lines and specimens express and that expression of and correlates, with the strongest correlation in high-stage tumors. In neuroblastoma, both and are hypoxia-driven and knocking down at hypoxia resulted in downregulated levels. HIF-2α and were strongly expressed in subsets of immature neuroblastoma cells, suggesting that these two genes could be co-expressed also at early stages of SNS development. We show that is indeed expressed in sympathetic chain ganglia at embryonic week 6.5, a developmental stage when HIF-2α is present. These findings provide a rationale for the unexpected expression in neuroblastomas and might suggest that and positive neuroblastoma cells are arrested at an embryonic differentiation stage corresponding to the stage when sympathetic chain ganglia begins to coalesce.
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| 14. |
- Mohlin, Sofie, et al.
(författare)
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Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage.
- 2011
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 21:4, s. 276-282
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is a childhood malignancy of the sympathetic neuronal lineage. It is a rare disease, but since it is frequently diagnosed during infancy, neuroblastoma causes life-long medical follow up of those children that survive the disease. It was early recognized that a high tumor cell differentiation stage correlates to favorable clinical stage and positive clinical outcome. Today, highly differentiated tumors are surgically removed and not further treated. Cells of many established human neuroblastoma cell lines have the capacity to differentiate when stimulated properly, and these cell lines have been used as models for studying and understanding central concepts of tumor cell differentiation. One recent aspect of this issue is the observation that tumor cells can dedifferentiate and gain a stem cell-like phenotype during hypoxic conditions, which was first shown in neuroblastoma. Aberrant or blocked differentiation is a central aspect of neuroblastoma genesis. In this review we summarize known genetic and non-genetic events in neuroblastoma that might be coupled to an aberrant sympathetic neuronal differentiation and thereby indirectly influencing tumorigenesis and/or aggressive neuroblastoma behavior.
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| 15. |
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| 16. |
- Munksgaard Persson, Matilda, et al.
(författare)
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HIF-2 alpha Expression Is Suppressed in SCLC Cells, Which Survive in Moderate and Severe Hypoxia When HIF-1 alpha Is Repressed
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier. - 0002-9440 .- 1525-2191. ; 180:2, s. 494-504
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Tidskriftsartikel (refereegranskat)abstract
- Small cell lung carcinoma (SCLC) is extremely aggressive and frequently metastasizes widely in its early stage. Because tumor hypoxia is related to aggressive tumor behavior and the hypoxic adaptation of SCLC is poorly documented, we stained SCLC tumors arranged in a tissue microarray for hypoxia-inducible factor (HIF)-1 alpha and HIF-2 alpha proteins. We found an overall lack of HIF-2 alpha protein expression, which was confirmed in large tumor sections. HIF-1 alpha protein was strongly expressed in most tumors, frequently adjacent to necrotic regions. In concordance, cultured SCLC but not non-small cell lung carcinoma cells showed no or extremely low levels of HIF-2 alpha mRNA and no HIF-2 alpha protein at hypoxia. HIF-1 alpha was stabilized after 4 hours at hypoxia, and its accumulation increased up to 96 hours. SCLC cells survived well and showed net proliferation and low cell death in modest (1% oxygen) and severe (0.1% oxygen) hypoxia. HIF-1 alpha repression virtually did not influence cell death or viability despite reduced levels of hypoxia-inducible genes, such as BNIP3 and BNIP3L. At 1% oxygen no increased autophagy (LC3B-II activation) or NF-kappa B signaling were detected, whereas the unfolded protein response was activated at severe hypoxia. Our data indicate that HIFs are not exclusively required for SCLC cell survival at modest or severe hypoxia and that additional, yet uncharacterized, hypoxia-driven adaptation pathways may become activated.
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| 17. |
- Pernemalm, Maria, et al.
(författare)
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Quantitative Proteomics Profiling of Primary Lung Adenocarcinoma Tumors Reveals Functional Perturbations in Tumor Metabolism
- 2013
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Ingår i: Journal of Proteome Research. - : American Chemical Society (ACS). - 1535-3893 .- 1535-3907. ; 12:9, s. 3934-3943
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have analyzed human primary lung adenocarcinoma tumors using global mass spectrometry to elucidate the biological mechanisms behind relapse post surgery. In total, we identified over 3000 proteins with high confidence. Supervised multivariate analysis was used to select 132 proteins separating the prognostic groups. Based on in-depth bioinformatics analysis, we hypothesized that the tumors with poor prognosis had a higher glycolytic activity and HIF activation. By measuring the bioenergetic cellular index of the tumors, we could detect a higher dependency of glycolysis among the tumors with poor prognosis. Further, we could also detect an up-regulation of HIF1 alpha mRNA expression in tumors with early relapse. Finally, we selected three proteins that were upregulated in the poor prognosis group (cathepsin D, ENO1, and VDAC1) to confirm that the proteins indeed originated from the tumor and not from a stromal or inflammatory component. Overall, these findings show how in-depth analysis of clinical material can lead to an increased understanding of the molecular mechanisms behind tumor progression.
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| 18. |
- 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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| 19. |
- Pietras, Alexander, et al.
(författare)
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The HIF-2alpha-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization.
- 2010
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Ingår i: Diverse Effects of Hypoxia on Tumor Progression. - Berlin, Heidelberg : Springer Berlin Heidelberg. - 0070-217X. - 9783642133299 - 9783642133282 ; 345, s. 1-20
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Bokkapitel (refereegranskat)abstract
- Cellular adaptation to diminished tissue oxygen tensions, hypoxia, is largely governed by the hypoxia inducible transcription factors, HIF-1 and HIF-2. Tumor hypoxia and high HIF protein levels are frequently associated with aggressive disease. In recent years, high tumor cell levels of HIF-2 and the oxygen sensitive subunit HIF-2alpha have been associated with unfavorable disease and shown to be highly expressed in tumor stem/initiating cells originating from neuroblastoma and glioma, respectively. In these cells, HIF-2 is active under nonhypoxic conditions as well, creating a pseudo-hypoxic phenotype with clear influence on tumor behavior. Neuroblastoma tumor initiating cells are immature with a neural crest-like phenotype and downregulation of HIF-2alpha in these cells results in neuronal sympathetic differentiation and the cells become phenotypically similar to the bulk of neuroblastoma cells found in clinical specimens. Knockdown of HIF-2alpha in neuroblastoma and glioma tumor stem/initiating cells leads to reduced levels of VEGF and poorly vascularized, highly necrotic tumors. As high HIF-2alpha expression further correlates with disseminated disease as demonstrated in neuroblastoma, glioma, and breast carcinoma, we propose that targeting HIF-2alpha and/or the pseudo-hypoxic phenotype induced by HIF-2 under normoxic conditions has great clinical potential.
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| 20. |
- Reinbothe, Susann, et al.
(författare)
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EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation.
- 2014
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 445:1, s. 163-169
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Tidskriftsartikel (refereegranskat)abstract
- The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα(+)) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.
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| 21. |
- Sun, Jianmin, et al.
(författare)
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The PI3-kinase isoform p110 delta is essential for cell transformation induced by the D816V mutant of c-Kit in a lipid-kinase-independent manner
- 2014
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 33:46, s. 5360-5369
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Tidskriftsartikel (refereegranskat)abstract
- PI3-kinase has a crucial role in transformation mediated by the oncogenic c-Kit mutant D816V. In this study, we demonstrate that the c-Kit/D816V-mediated cell survival is dependent on an intact direct binding of PI3-kinase to c-Kit. However, mutation of this binding site had little effect on the PI3-kinase activity in the cells, suggesting that c-Kit/D816V-mediated cell survival is dependent on PI3-kinase but not its kinase activity. Furthermore, inhibition of the lipid kinase activity of PI3-kinase led only to a slight inhibition of cell survival. Knockdown of the predominant PI3-kinase isoform p110 delta in c-Kit/D816V-expressing Ba/F3 cells led to reduced cell transformation both in vitro and in vivo without affecting the overall PI3-kinase activity. This suggests that p110 delta has a lipid-kinaseindependent role in c-Kit/D816V-mediated cell transformation. We furthermore demonstrate that p110 delta is phosphorylated at residues Y524 and S1039 and that phosphorylation requires an intact binding site for PI3-kinase in c-Kit/D816V. Overexpression of p110 delta carrying the Y523F and S1038A mutations significantly reduced c-Kit/D816V-mediated cell survival and proliferation. Taken together, our results demonstrate an important lipid-kinase-independent role of p110 delta in c-Kit/D816V-mediated cell transformation. This furthermore suggests that p110 delta could be a potential diagnostic factor and selective therapeutic target for c-Kit/D816V-expressing malignancies.
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| 22. |
- Vaapil, Marica, et al.
(författare)
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Hypoxic conditions induce a cancer-like phenotype in human breast epithelial cells.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:9
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Tidskriftsartikel (refereegranskat)abstract
- Solid tumors are less oxygenated than their tissue of origin. Low intra-tumor oxygen levels are associated with worse outcome, increased metastatic potential and immature phenotype in breast cancer. We have reported that tumor hypoxia correlates to low differentiation status in breast cancer. Less is known about effects of hypoxia on non-malignant cells. Here we address whether hypoxia influences the differentiation stage of non-malignant breast epithelial cells and potentially have bearing on early stages of tumorigenesis.
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| 23. |
- von Stedingk, Kristoffer, et al.
(författare)
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snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis.
- 2013
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Ingår i: Translational Oncology. - : Elsevier BV. - 1936-5233. ; 6:4, s. 447-457
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Tidskriftsartikel (refereegranskat)abstract
- Amplification of the MYCN oncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCN amplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance, most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue micro-arrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability.
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| 24. |
- Zhang, Xiaonan, et al.
(författare)
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Induction of mitochondrial dysfunction as a strategy for targeting tumour cells in metabolically compromised microenvironments
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5, s. 3295-
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal vascularization of solid tumours results in the development of microenvironments deprived of oxygen and nutrients that harbour slowly growing and metabolically stressed cells. Such cells display enhanced resistance to standard chemotherapeutic agents and repopulate tumours after therapy. Here we identify the small molecule VLX600 as a drug that is preferentially active against quiescent cells in colon cancer 3-D microtissues. The anticancer activity is associated with reduced mitochondrial respiration, leading to bioenergetic catastrophe and tumour cell death. VLX600 shows enhanced cytotoxic activity under conditions of nutrient starvation. Importantly, VLX600 displays tumour growth inhibition in vivo. Our findings suggest that tumour cells in metabolically compromised microenvironments have a limited ability to respond to decreased mitochondrial function, and suggest a strategy for targeting the quiescent populations of tumour cells for improved cancer treatment.
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| 25. |
- Zirath, Hanna, et al.
(författare)
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MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells
- 2013
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 110:25, s. 10258-10263
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Tidskriftsartikel (refereegranskat)abstract
- The MYC genes are the most frequently activated oncogenes in human tumors and are hence attractive therapeutic targets. MYCN amplification leads to poor clinical outcome in childhood neuroblastoma, yet strategies to modulate the function of MYCN do not exist. Here we show that 10058-F4, a characterized c-MYC/Max inhibitor, also targets the MYCN/Max interaction, leading to cell cycle arrest, apoptosis, and neuronal differentiation in MYCN-amplified neuroblastoma cells and to increased survival of MYCN transgenic mice. We also report the discovery that inhibition of MYC is accompanied by accumulation of intracellular lipid droplets in tumor cells as a direct consequence of mitochondrial dysfunction. This study expands on the current knowledge of how MYC proteins control the metabolic reprogramming of cancer cells, especially highlighting lipid metabolism and the respiratory chain as important pathways involved in neuroblastoma pathogenesis. Together our data support direct MYC inhibition as a promising strategy for the treatment of MYC-driven tumors.
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