| 1. |
- Chagtai, Tasnim, et al.
(författare)
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Gain of 1q as a prognostic biomarker in Wilms Tumors (WTs) treated with preoperative chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 trial : A SIOP renal tumours biology consortium study
- 2016
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 34:26, s. 3195-3203
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. Materials and Methods: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. Results: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. Conclusion: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
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| 2. |
- Andersson, Natalie, et al.
(författare)
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Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers
- 2020
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Ingår i: Cancer Research. - 1538-7445. ; 80:7, s. 1512-1523
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Tidskriftsartikel (refereegranskat)abstract
- Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors and 8 rhabdomyosarcomas. Whole genome copy number and whole exome mutational profiling of multiple regions per tumor was performed followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared to clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; p=0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.
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| 3. |
- 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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| 4. |
- Forslund, Ola, et al.
(författare)
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Regarding human cytomegalovirus in neuroblastoma.
- 2014
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 3:4, s. 1038-1040
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Wolmer-Solberg et al., reported that six human neuroblastoma cell lines and the vast majority of clinical neuroblastoma samples contained HCMV DNA and expressed HCMV proteins. We could not replicate the data and therefore remain skeptical towards the prevalence of HCMV DNA in neuroblastomas.
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| 5. |
- Gisselsson Nord, David, et al.
(författare)
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Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis.
- 2010
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:47, s. 20489-20493
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Tidskriftsartikel (refereegranskat)abstract
- One extra chromosome copy (i.e., trisomy) is the most common type of chromosome aberration in cancer cells. The mechanisms behind the generation of trisomies in tumor cells are largely unknown, although it has been suggested that dysfunction of the spindle assembly checkpoint (SAC) leads to an accumulation of trisomies through failure to correctly segregate sister chromatids in successive cell divisions. By using Wilms tumor as a model for cancers with trisomies, we now show that trisomic cells can form even in the presence of a functional SAC through tripolar cell divisions in which sister chromatid separation proceeds in a regular fashion, but cytokinesis failure nevertheless leads to an asymmetrical segregation of chromosomes into two daughter cells. A model for the generation of trisomies by such asymmetrical cell division accurately predicted several features of clones having extra chromosomes in vivo, including the ratio between trisomies and tetrasomies and the observation that different trisomies found in the same tumor occupy identical proportions of cells and colocalize in tumor tissue. Our findings provide an experimentally validated model explaining how multiple trisomies can occur in tumor cells that still maintain accurate sister chromatid separation at metaphase-anaphase transition and thereby physiologically satisfy the SAC.
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| 6. |
- Gisselsson Nord, David, et al.
(författare)
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Genetic bottlenecks and the hazardous game of population reduction in cell line based research.
- 2010
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 316, s. 3379-3386
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Tidskriftsartikel (refereegranskat)abstract
- Established tumour cell lines are ubiquitous tools in research, but their representativity is often debated. One possible caveat is that many cell lines are derived from cells with genomic instability, potentially leading to genotype changes in vitro. We applied SNP-array analysis to an established tumour cell line (WiT49). Even though WiT49 exhibited chromosome segregation errors in 30% of cell divisions, only a single chromosome segment exhibited a shift in copy number after 20 population doublings in culture. In contrast, sub-populations derived from single cells expanded for an equal number of population doublings showed on average 5.8 and 8.9 altered segments compared to the original culture and to each other, respectively. Most copy number variants differentiating these single cell clones corresponded to pre-existing variations in the original culture. Furthermore, no sub-clonal variation was detected in any of the populations derived from single cells. This indicates that genetic bottlenecks resulting from population reduction poses a higher threat to genetic representativity than prolonged culture per se, even in cell lines with a high rate of genomic instability. Genetic bottlenecks should therefore be considered a potential caveat in all studies involving sub-cloning, transfection and other conditions leading to a temporary reduction in cell number.
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| 7. |
- Helczynska, Karolina, et al.
(författare)
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Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer.
- 2008
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Ingår i: Cancer Research. - 1538-7445. ; 68:22, s. 9212-9220
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Tidskriftsartikel (refereegranskat)abstract
- Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.
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| 8. |
- Holmquist Mengelbier, Linda, et al.
(författare)
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Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster.
- 2010
-
Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 177:5, s. 2609-2621
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Tidskriftsartikel (refereegranskat)abstract
- Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.
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| 9. |
- Holmquist Mengelbier, Linda, et al.
(författare)
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Effect of hypoxia on the tumor phenotype: the neuroblastoma and breast cancer models
- 2006
-
Ingår i: Advances in experimental medicine and biology. - 0065-2598. ; 587, s. 179-193
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Konferensbidrag (refereegranskat)abstract
- The tumor oxygenation status associates with aggressive behavior. Oxygen shortage, hypoxia, is a major driving force behind tumor vascularization, and hypoxia enhances mutational rate, metastatic spread, and resistance to radiation and chemotherapy. We recently discovered that hypoxia promotes dedifferentiation of neuroblastoma and breast carcinoma cells and development of stem cell-like features. In both these tumor forms there is a correlation between low differentiation stage and poor outcome, and we conclude that the dedifferentiating effect of lowered oxygen adds to the aggressive phenotype induced by hypoxia. With neuroblastoma and breast carcinoma as human tumor model systems, we have addressed questions related to hypoxia-induced molecular mechanisms governing malignant behavior of tumor cells, with emphasis on differentiation and growth control. By global gene expression analyses we are currently screening for gene products exclusively expressed or modified in hypoxic cells with the aim to use them as targets for treatment.
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| 10. |
- Holmquist Mengelbier, Linda
(författare)
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Hypoxia-induced phenotypic modulation of human neuroblastoma cells
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma is a childhood tumour derived from cells of the sympathetic nervous system, which are arrested at low differentiation stages. Low differentiation stage and high tumour stage correlate to poor outcome. In earlier studies we have found that hypoxia induces dedifferentiation of neuroblastoma cells, which implies that hypoxia evokes a more aggressive phenotype. Here we employ microarray analysis to investigate the hypoxic effects, in neuroblastoma cells, on the expression of a larger set of genes. Genes involved in survival and treatment resistance were upregulated, which support the concept of an aggressive hypoxic phenotype. The microarray results further strengthened the concept of hypoxia-induced dedifferentiation of neuroblastoma cells. Hypoxia-treated neuroblastoma cells were reoxygenated to determine the persistence of the hypoxic phenotype. Based on neuronal- and neural crest marker gene expression analysis, we conclude that the hypoxic phenotype persisted for at least 24 h upon reoxygenation. Hence, there was no selection for dedifferentiated cells; instead the hypoxic phenotype appears adaptable and dynamically reversible. Major transcription factors that act in response to hypoxia are the hypoxia-inducible factors HIF-1a and HIF-2a. Intriguingly, HIF-2a, but not HIF-1a, was detected adjacent to blood vessels in neuroblastoma specimen, indicating a role for HIF-2a at more physiological oxygen levels. Analysis of HIF-protein levels in neuroblastoma cells exposed to hypoxia (1% O2) or 5% O2 (mimicking a more physiological oxygen level) revealed that HIF-1a is primarily and only transiently induced at 1% O2. HIF-2a, on the other hand, is induced at both 1 and 5% O2 and its protein levels increase over time. In a microarray analysis we extracted a set of genes with regulation patterns similar to that of the HIF-protein patterns seen in neuroblastoma cells grown at either 1 or 5% O2. We propose that the differences in HIF target gene utilization are dependent on time and oxygen conditions, rather than on target gene specificity. According to that concept, we propose that HIF-1a primarily drives gene transcription at acute hypoxia, while HIF-2a is active at prolonged hypoxia and at 5% O2, conclusions supported by HIF-1a and HIF-2a siRNA analyses and expression of the HIF-driven genes VEGF and DEC1/BHLB2. Evaluation of a clinical neuroblastoma material showed correlation between HIF-2a immunostaining and poor patient outcome. Our results further implicate HIF-2a as a possible individual prognostic marker for neuroblastoma patients. Tumour growth of neuroblastoma cells knocked down for HIF-2a in nude mice was slower than neuroblastoma cells transfected with a scramble siRNA sequence. These observations support a role for HIF-2a in neuroblastoma progression. Immunostaining of neuroblastoma specimen revealed co-localization of VEGF and HIF-2a, suggesting a putative mechanism for neuroblastoma tumour growth due to HIF-2a-induced VEGF expression. Our results implicate an oncogenic role for HIF-2a in neuroblastoma aggressiveness, which might be exploited in the treatment of aggressive neuroblastomas.
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| 11. |
- Holmquist Mengelbier, Linda, et al.
(författare)
-
Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P=0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.
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| 12. |
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| 13. |
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| 14. |
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| 15. |
- Holmquist Mengelbier, Linda, et al.
(författare)
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The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis
- 2019
-
Ingår i: Journal of Pathology. - : Wiley. - 0022-3417. ; 247:1
-
Tidskriftsartikel (refereegranskat)abstract
- Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3−/Irx5− mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3−/− cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/β-catenin-signalling. In contrast, IRX5−/− cells displayed activation of Hippo and non-canonical WNT-signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation.
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| 16. |
- Jansson, Caroline, et al.
(författare)
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Retinoic acid promotes differentiation of WiT49- but not of CCG99-11 Wilms tumour cells
- 2023
-
Ingår i: Cancer Reports. - 2573-8348. ; 6:6
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Most children with Wilms tumour are successfully treated with multidrug chemotherapy and surgery. These treatments cause severe side effects for the patients, an issue that needs to be addressed by exploring other treatment options with less or no side effects. One option is to complement current therapies with agents that could potentially induce tumour cell differentiation, for example retinoic acid (RA). Aims: To facilitate quick assessment of an agent's effect on Wilms tumour differentiation by a rapid in vitro model system. Methods and Results: Here WiT49 and CCG99-11 Wilms tumour cells were treated with 10 μM RA for 72 h or 9 days. Cultured cells were scraped off from Petri dishes, pelleted and embedded in paraffin in the same way as clinical tumour specimens are preserved. Cell morphology and differentiation were evaluated by analyses of haematoxylin eosin (H&E) and immunohistochemical stainings. Based on H&E, WT1 and CKAE1/3 stainings, RA treatment induced further epithelial differentiation of WiT49 cells, whereas there was no sign of induced maturation in CCG99-11 cells. Ki67 staining showed that RA inhibited cell proliferation in both cell lines. Conclusions: Our study shows that in vitro culturing of WiT49 and CCG99-11 cells, followed by pelleting and paraffin embedding of cell pellets, could aid in a quick evaluation of potential differentiating agents against Wilms tumour. In addition, our results strengthen previous results that retinoic acid could be a potential complement to regular Wilms tumour treatment.
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| 17. |
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| 18. |
- Karlsson, Jenny, et al.
(författare)
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Aberrant epigenetic regulation in clear cell sarcoma of the kidney featuring distinct DNA hypermethylation and EZH2 overexpression.
- 2016
-
Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:10, s. 36-11127
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Tidskriftsartikel (refereegranskat)abstract
- The global methylation profile and the mutational status of 633 specific epigenetic regulators were analyzed in the pediatric tumor clear cell sarcoma of the kidney (CCSK). Methylation array analyses of 30 CCSKs revealed CCSK tumor DNA to be globally hypermethylated compared to Wilms tumor, normal fetal kidney, and adult kidney. The aberrant methylation pattern of CCSKs was associated with activation of genes involved in embryonic processes and with silencing of genes linked to normal kidney function. No epigenetic regulator was recurrently mutated in our cohort, but a mutation in the key epigenetic regulator EZH2 was discovered in one case. EZH2 mRNA was significantly higher in CCSK compared to Wilms tumor and normal kidney, and the EZH2 protein was strongly expressed in more than 90 % of CCSK tumor cells in 9/9 tumors analyzed. This was in striking contrast to the lack of EZH2 protein expression in Wilms tumor stromal elements, indicating that EZH2 could be explored further as a diagnostic marker and a potential drug target for CCSK.
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| 19. |
- Karlsson, Jenny, et al.
(författare)
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Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney.
- 2015
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Ingår i: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 357:2, s. 498-501
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Tidskriftsartikel (refereegranskat)abstract
- Clear cell sarcoma of the kidney (CCSK) is a rare tumor type affecting infants and young children. Most CCSKs display few genomic aberrations, and no general underlying mechanism for tumor initiation has yet been identified, although a YWHAE-NUTM2B/NUTM2E fusion gene has been observed in a minority of cases. We performed RNA-sequencing of 22 CCSKs to investigate the presence of additional fusion transcripts. The presence of the YWHAE-NUTM2B/NUTM2E fusion was confirmed in two cases. In addition, a novel IRX2-TERT fusion transcript was identified in one case. SNP-array analyses revealed the underlying event to be an interstitial deletion in the short arm of chromosome 5 (5p15.33). TERT was dramatically upregulated under the influence of the IRX2 promoter. In line with TERT expression being driven by active IRX2 regulatory elements, we found a high expression of IRX2 in CCSKs irrespective of fusion gene status. IRX2 was also expressed in human fetal kidney - the presumed tissue of origin for CCSK. We conclude that in addition to promoter mutations and epigenetic events, TERT can also be activated in tumors via formation of fusion transcripts.
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| 20. |
- Karlsson, Jenny, et al.
(författare)
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Clear cell sarcoma of the kidney demonstrates an embryonic signature indicative of a primitive nephrogenic origin.
- 2014
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 53:5, s. 381-391
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Tidskriftsartikel (refereegranskat)abstract
- Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High-resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state. © 2014 Wiley Periodicals, Inc.
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| 21. |
- Karlsson, Jenny, et al.
(författare)
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Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 944-950
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored1–5. We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.
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| 22. |
- Karlsson, Jenny, et al.
(författare)
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High-resolution genomic profiling of an adult Wilms' tumor: evidence for a pathogenesis distinct from corresponding pediatric tumors.
- 2011
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Ingår i: Virchows Archiv: an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 459, s. 547-553
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Tidskriftsartikel (refereegranskat)abstract
- Wilms' tumor (WT), the most common kidney tumor among children, is characterized by a triphasic morphology consisting of blastemal, epithelial, and stromal components. Adult WT is a rare malignancy displaying similar histological features. We here present the first published high-resolution genomic analysis of a mixed-type adult WT. This revealed a more pronounced genetic complexity than usually observed in children with mixed-type WT. The majority of chromosomes displayed uniparental disomies, and microdeletions were present in genes with known importance for tumor formation (LRP1B, FHIT, and WWOX) or organogenesis (NEGR1 and ZFPM2), abnormalities not previously reported for pediatric WT. Our results indicate that adult WT is a biological entity distinct from the corresponding pediatric tumor type.
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| 23. |
- Löfstedt, Tobias, et al.
(författare)
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HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells.
- 2009
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 315:11, s. 1924-1936
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Tidskriftsartikel (refereegranskat)abstract
- Adaptation to low oxygen conditions is essential for maintaining homeostasis and viability in oxygen-consuming multi-cellular tissues, including solid tumors. Central in these processes are the hypoxia-inducible transcription factors, HIF-1 and HIF-2, controlling genes involved in e.g. glucose metabolism and neovascularization. Tumor hypoxia and HIF expression have also been associated with a dedifferentiated phenotype and increased aggressiveness. In this report we show that the MAX interactor-1 (MXI1) gene is directly regulated by HIF proteins in neuroblastoma and breast cancer cells. HIF-binding and transactivation were detected within MXI1 gene regulatory sequences in the vicinity of the MXI1-0 promoter, leading to rapid induction of the alternate MXI1-0 isoform followed by a long-term induction of both the MXI1-0 and MXI1 isoforms. Importantly, knock-down of MXI1 had limited effect on MYC/MYCN activity under hypoxia, an observation that might be related to the different functional attributes of the two MXI1 isoforms.
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| 24. |
- Löfstedt, Tobias, et al.
(författare)
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Hypoxia inducible factor-2alpha in cancer.
- 2007
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Ingår i: Cell Cycle. - 1551-4005. ; 6:8, s. 919-926
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Tidskriftsartikel (refereegranskat)abstract
- Poorly oxygenated ( hypoxic) tumors are frequently more aggressive compared to corresponding tumors that are better oxygenated. Adaptation to hypoxia is primarily mediated by two closely related hypoxia inducible transcription factor complexes, HIF-1 and HIF-2, which become stabilized and activated at low oxygen levels. Whether HIF-1 and HIF-2 have different roles in tumorigenesis is an open question and an issue we discuss. With focus on HIF-2, we summarize reported phenotypical changes of HIF genetic models and HIF expression patterns during normal development, in adult non - malignant tissues and in tumors. We further address the much - discussed subject of target gene preferences between HIF-1 and HIF-2, given that both transcription factors bind to the same DNA motif. Finally, we also discuss the observations that the oxygen - sensitive HIF-2 alpha subunit is accumulated and active under non - hypoxic conditions as exemplified by HIF-2 alpha expressing tumor macrophages and neuroblastoma cells located in seemingly well - vascularized tumor regions and how this phenomenon is related to tumor aggressiveness.
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| 25. |
- Pedersen, Malin, et al.
(författare)
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Stem cell factor induces HIF-1alpha at normoxia in hematopoietic cells.
- 2008
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 98:103, s. 98-103
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Tidskriftsartikel (refereegranskat)abstract
- Signaling by the receptor for stem cell factor (SCF), c-Kit, is of major importance for hematopoiesis, melanogenesis and reproduction, and the biological responses are commonly proliferation and cell survival. Thus, constitutive activation due to c-Kit mutations is involved in the pathogenesis of several forms of cancer, e.g. leukemias, gastrointestinal stromal tumors and testicular tumors. Tumor survival requires oxygen supply through induced neovascularization, a process largely mediated by the vascular endothelial growth factor (VEGF), a prominent target of the transcription factors hypoxia-inducible factor-1 (HIF-1) and HIF-2. Using Affymetrix microarrays we have identified genes that are upregulated following SCF stimulation. Interestingly, many of the genes induced were found to be related to a hypoxic response. These findings were corroborated by our observation that SCF stimulation of the hematopoietic cell lines M-07e induces HIF-1alpha and HIF-2alpha protein accumulation at normoxia. In addition, SCF-induced HIF-1alpha was transcriptionally active, and transcribed HIF-1 target genes such as VEGF, BNIP3, GLUT1 and DEC1, an effect that could be reversed by siRNA against HIF-1alpha. We also show that SCF-induced accumulation of HIF-1alpha is dependent on both the PI-3-kinase and Ras/MEK/Erk pathways. Our data suggest a novel mechanism of SCF/c-Kit signaling in angiogenesis and tumor progression.
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| 26. |
- Rastegar, Bahar, et al.
(författare)
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Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution
- 2023
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 29:14, s. 2668-2677
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors.EXPERIMENTAL DESIGN: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments.RESULTS: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments.CONCLUSIONS: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics.
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| 27. |
- Sehic, Daniel, et al.
(författare)
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Absence of Epstein-Barr and Cytomegalovirus Infection in Neuroblastoma Cells by Standard Detection Methodologies.
- 2013
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 60:9, s. 91-93
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Tidskriftsartikel (refereegranskat)abstract
- Indications exist in the scientific literature that infection with human herpes family viruses may contribute to the pathogenesis of neuroblastoma (NB). However, systematic investigations regarding viral presence in NB cells have been scarcely reported. Here, the presence of DNA from Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) was assessed by PCR in 12 NBs, supplemented with RNA in situ hybridization, immunohistochemical detection, and high-throughput DNA sequencing. These standard methods did not detect infection by EBV or HCMV in NB cells in any tumor, while occasional immune cells were positive for EBV RNA or HCMV protein in four cases. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
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| 28. |
- Uno, Kaname, et al.
(författare)
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A Gradual Transition Toward Anaplasia in Wilms Tumor Through Tolerance to Genetic Damage
- 2024
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Ingår i: Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. - 1530-0285. ; 37:1, s. 100382-100382
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Tidskriftsartikel (refereegranskat)abstract
- Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT.
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| 29. |
- Valind, Anders, et al.
(författare)
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Confined trisomy 8 mosaicism of meiotic origin: A rare cause of aneuploidy in childhood cancer.
- 2014
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 53:7, s. 634-638
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Tidskriftsartikel (refereegranskat)abstract
- Whether chromosome abnormalities observed in tumor cells may in some cases reflect low-grade somatic mosaicism for anomalies present already at zygote formation, rather than acquired somatic mutations, has for long remained a speculation. We here report a patient with Wilms tumor, where constitutional somatic mosaicism of trisomy 8 was detected in a previously healthy 2 ½-year-old boy. Single Nucleotide Polymorphism (SNP) array analysis of tumor tissue revealed a complex distribution of allele frequencies for chromosome 8 that could not be explained solely by mitotic events. Combined analysis of allele frequencies, chromosome banding, and fluorescence in situ hybridization revealed that the majority of tumor cells contained four copies of chromosome 8, with three distinct haplotypes at a 2:1:1 ratio. Because the patient had not been subject to organ transplantation, these findings indicated that the tumor karyotype evolved from a cell with trisomy 8 of meiotic origin, with subsequent somatic gain of one additional chromosome copy. Haplotype analysis was consistent with trisomy 8 through nondisjunction at meiosis I. Matched normal renal tissue or peripheral blood did not contain detectable amounts of cells with trisomy 8, consistent with the complete lack of mosaic trisomy 8 syndrome features in the patient. This case provides proof of principle for the hypothesis that tumor genotypes may in rare cases reflect meiotic rather than mitotic events, also in patients lacking syndromic features. © 2014 Wiley Periodicals, Inc.
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