| 1. |
- Hollander, Camilla, et al.
(författare)
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Human mast cells decrease SLPI levels in type II - like alveolar cell model, in vitro.
- 2003
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Mast cells are known to accumulate at sites of inflammation and upon activation to release their granule content, e.g. histamine, cytokines and proteases. The secretory leukocyte protease inhibitor (SLPI) is produced in the respiratory mucous and plays a role in regulating the activity of the proteases. Result We have used the HMC-1 cell line as a model for human mast cells to investigate their effect on SLPI expression and its levels in cell co-culture experiments, in vitro. In comparison with controls, we found a significant reduction in SLPI levels (by 2.35-fold, p < 0.01) in a SLPI-producing, type II-like alveolar cell line, (A549) when co-cultured with HMC-1 cells, but not in an HMC-1-conditioned medium, for 96 hours. By contrast, increased SLPI mRNA expression (by 1.58-fold, p < 0.05) was found under the same experimental conditions. Immunohistochemical analysis revealed mast cell transmigration in co-culture with SLPI-producing A549 cells for 72 and 96 hours. Conclusion These results indicate that SLPI-producing cells may assist mast cell migration and that the regulation of SLPI release and/or consumption by mast cells requires interaction between these cell types. Therefore, a "local relationship" between mast cells and airway epithelial cells might be an important step in the inflammatory response.
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| 2. |
- Kjellström, Johan, et al.
(författare)
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Increased toxicity of a trinuclear Pt-compound in a human squamous carcinoma cell line by polyamine depletion
- 2012
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mononuclear platinum anticancer agents hold a pivotal place in the treatment of many forms of cancers, however, there is a potential to improve response to evade resistance development and toxic side effects. BBR3464 is a promising trinuclear platinum anticancer agent, which is a polyamine mimic. The aim was to investigate the influence of polyamine pool reduction on the cytotoxic effects of the trinuclear platinum complex BBR3464 and cisplatin. Polyamine pool reduction was achieved by treating cells with either the polyamine biosynthesis inhibitor alpha-difluoromethylornithine (DFMO) or the polyamine analogue N-1,N-11-diethylnorspermine (DENSPM). Methods: A human squamous cell carcinoma cell line, LU-HNSCC-4, established from a primary head and neck tumour was used to evaluate cellular effects of each drug alone or combinations thereof. High-performance liquid-chromatography was used to quantify intracellular polyamine contents. Inductively coupled mass spectroscopy was used to quantify intracellular platinum uptake. Cells were exposed to DFMO or DENSPM during 48 h at concentrations ranging from 0 to 5 mM or 0 to 10 mu M, respectively. Thereafter, non-treated and treated cells were exposed to cisplatin or BBR3464 during 1 h at concentrations ranging from 0 to 100 mu M. A 96-well assay was used to determine cytotoxicity after five days after treatment. Results: The cytotoxic effect of BBR3464 on LU-HNSCC-4 cells was increased after cells were pre-treated with DENSPM or DFMO, and the interaction was found to be synergistic. In contrast, the interaction between cisplatin and DFMO or DENSPM was near-additive to antagonistic. The intracellular levels of the polyamines putrescine and spermidine were decreased after treatment with DFMO, and treatment with DENSPM resulted in an increase in putrescine level and concomitant decrease in spermidine and spermine levels. The uptake of BBR3464 was significantly increased after pre-treatment of the cells with DFMO, and varied dependent on the concentration of DENSPM. The uptake of cisplatin was unchanged. Conclusions: Taken together, these results demonstrate that combinations of polyamine synthesis inhibitors with BBR3464 appear to be a promising approach to enhance the anticancer activity against HSCC.
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| 3. |
- Zelvyte, Inga, et al.
(författare)
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αl-antitrypsin and its C-terminal fragment attenuate effects of degranulated neutrophil-conditioned medium on lung cancer HCC cells, in vitro
- 2004
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Tumor microenvironment, which is largely affected by inflammatory cells, is a crucial participant in the neoplastic process through promotion of cell proliferation, survival and migration. We measured the effects of polymorphonuclear neutrophil (PMN) conditioned medium alone, and supplemented with serine proteinase inhibitor α-1 antitrypsin (AAT) or its C-terminal fragment (C-36 peptide), on cultured lung cancer cells. Methods: Lung cancer HCC cells were grown in a regular medium or in a PMN-conditioned medium in the presence or absence of AAT (0.5 mg/ml) or its C-36 peptide (0.06 mg/ml) for 24 h. Cell proliferation, invasiveness and release of IL-8 and VEGF were analyzed by [ 3H]-thymidine incorporation, Matrigel invasion and ELISA methods, respectively. Results: Cells exposed to PMN-conditioned medium show decreased proliferation and IL-8 release by 3.9-fold, p < 0.001 and 1.3-fold, p < 0.05, respectively, and increased invasiveness by 2-fold (p < 0.001) compared to non-treated controls. In the presence of AAT, PMN-conditioned medium loses its effects on cell proliferation, invasiveness and IL-8 release, whereas VEGF is upregulated by 3.7-fold (p < 0.001) compared to controls. Similarly, C-36 peptide abolishes the effects of PMN-conditioned medium on cell invasiveness, but does not alter its effects on cell proliferation, IL-8 and VEGF release. Direct HCC cell exposure to AAT enhances VEGF, but inhibits IL-8 release by 1.7-fold (p < 0.001) and 1.4-fold (p < 0.01) respectively, and reduces proliferation 2.5-fold (p < 0.01). In contrast, C-36 peptide alone did not affect these parameters, but inhibited cell invasiveness by 51.4% (p < 0.001), when compared with non-treated controls. Conclusions: Our data provide evidence that neutrophil derived factors decrease lung cancer HCC cell proliferation and IL-8 release, but increase cell invasiveness. These effects were found to be modulated by exogenously present serine proteinase inhibitor, AAT, and its C-terminal fragment, which points to a complexity of the relationships between tumor cell biological activities and local microenvironment.
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| 4. |
- Abel, Frida, 1974, et al.
(författare)
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A 6-gene signature identifies four molecular subgroups of neuroblastoma
- 2011
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 11:9
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Background There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. Results The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p
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| 5. |
- Andersson, Mattias K, 1979, et al.
(författare)
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Proliferation of Ewing sarcoma cell lines is suppressed by the receptor tyrosine kinase inhibitors gefitinib and vandetanib
- 2008
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- ABSTRACT: BACKGROUND: Tyrosine kinase inhibitors (TKIs) have gained much attention in recent years as targeted agents for the treatment of a wide range of human cancers. We have investigated the effect of the TKIs gefitinib and vandetanib on tumor cell lines derived from Ewing sarcoma, a highly malignant tumor affecting bone and soft tissue in children and young adults. Gefitinib is an inhibitor of epidermal growth factor receptor tyrosine kinase activity (EGFR) and vandetanib selectively targets vascular endothelial growth factor receptor-2 (VEGFR-2) with additional activity against VEGFR-3, EGFR and RET kinase receptors. RESULTS: Two Ewing sarcoma cell lines investigated showed high levels of nuclear EGFR expression as well as moderate expression in plasma membrane and cytoplasm. When treated with concentrations of 5 muM and more of either gefitinib or vandetanib, we observed a significant decrease in cell proliferation. However, there were no detectable changes in p44/42 MAPK and Akt-1 phosphorylation, or in the expression of cyclin D1 or c-Myc following gefitinib or vandetanib treatment. CONCLUSION: We conclude that Ewing sarcoma tumor cell proliferation is not highly sensitive to inhibition of EGFR signaling alone or the simultaneous inhibition of VEGFR receptors, EGFR and RET kinase. Decreased tumor cell proliferation could be achieved with gefitinib and vandetanib, but only at higher doses where non-specific effects of the compounds may be overriding. As Ewing tumor cells do not seem to depend on EGFR and VEGFR pathways for survival, other key factors in the cellular signaling of Ewing sarcoma should be targeted in order to obtain a potent therapeutic response.
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| 6. |
- Carlsson, Jessica, 1984-, et al.
(författare)
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A miRNA expression signature that separates between normal and malignant prostate tissues
- 2011
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; :11, s. 14-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMicroRNAs (miRNAs) constitute a class of small non-coding RNAs that post-transcriptionally regulate genes involved in several key biological processes and thus are involved in various diseases, including cancer. In this study we aimed to identify a miRNA expression signature that could be used to separate between normal and malignant prostate tissues.ResultsNine miRNAs were found to be differentially expressed (p <0.00001). With the exception of two samples, this expression signature could be used to separate between the normal and malignant tissues. A cross-validation procedure confirmed the generality of this expression signature. We also identified 16 miRNAs that possibly could be used as a complement to current methods for grading of prostate tumor tissues.ConclusionsWe found an expression signature based on nine differentially expressed miRNAs that with high accuracy (85%) could classify the normal and malignant prostate tissues in patients from the Swedish Watchful Waiting cohort. The results show that there are significant differences in miRNA expression between normal and malignant prostate tissue, indicating that these small RNA molecules might be important in the biogenesis of prostate cancer and potentially useful for clinical diagnosis of the disease.
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| 7. |
- Falck, Eva, et al.
(författare)
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Expression patterns of PHF5A/Phf5a and GJa1/Gja1 in rat and human endometrial cancer
- 2013
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Endometrial adenocarcinoma is the most frequently diagnosed cancer of the female genital tract in the western world. Studies of complex diseases can be difficult to perform on human tumor samples due to the high genetic heterogeneity in human. The use of rat models is preferable since rat has similarities in pathogenesis and histopathological properties to that of human.A genomic region including the highly conserved Phf5a gene associated to development of EAC has previously been identified in an association study. PHF5A has been suggested to acts as a transcription factor or cofactor in the up regulation of expression of Gja1 gene in the presence of estrogen. It has earlier been shown that the Phf5a gene is down regulated in rat EAC derived cell lines by means of expression microarrays.We analyzed the expression of Phf5a and Gja1 by qPCR, and potential relations between the two genes in EAC tumors and non-malignant cell lines derived from the BDII rat model. In addition, the expression pattern of these genes was compared in rat and human EAC tumor samples.Changes in expression for Phf5a/PHF5A were found in tumors from both rat and human even though the observed pattern was not completely consistent between the two species. By separating rat EAC cell lines according to the genetic background, a significant lower expression of Phf5a in one of the two cross backgrounds was revealed, but not for the other. In contrast to other studies, Phf5a/PHF5A regulation of Gja1/GJA1 was not revealed in this study.
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| 8. |
- Falck, Eva, et al.
(författare)
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Loss of Glutathione peroxidase 3 expression is correlated with epigenetic mechanisms in endometrial adenocarcinoma
- 2010
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Glutathione peroxidase 3 (GPX3) is one of the key enzymes in the cellular defense against oxidative stress and the hepatocyte growth factor receptor, (MET) has been suggested to be influenced by the GPX3 gene expression. In a previous microarray study performed by our group, Gpx3 was identified as a potential biomarker for rat endometrial adenocarcinoma (EAC), since the expression was highly downregulated in rat EAC tumors. Herein, we have investigated the mRNA expression and Gpx3 and Met in rat EAC by real time quantitative PCR (qPCR), and the methylation status of Gpx3. In addition we have examined the expression of GPX3 and MET in 30 human EACs of different FIGO grades and 20 benign endometrial tissues. We found that the expression of GPX3 was uniformly down regulated in both rat and human EAC, regardless of tumor grade or histopathological subtype, implying that the down-regulation is an early event in EAC. The rate of Gpx3 promoter methylation reaches 91%, where biallelic methylation was present in 90% of the methylated tumors. The expression of the Met oncogene was slightly upregulated in EACs that showed loss of expression of Gpx3, but no tumor suppressor activity of Gpx3/GPX3 was detected. Preliminary results also suggest that the production of H2O2 is higher in rat endometrial tumors with down-regulated Gpx3 expression. A likely consequence of loss of GPX3 protein function would be a higher amount of ROS in the cancer cell environment. Thus, the results suggest important clinical implications of the GPX3 expression in EAC, both as a molecular biomarker for EAC and as a potential target for therapeutic interventions.
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| 9. |
- Falck, Eva, et al.
(författare)
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SKY analysis revealed recurrent numerical and structural chromosome changes in BDII rat endometrial carcinomas
- 2011
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genomic alterations are common features of cancer cells, and some of these changes are proven to be neoplastic-specific. Such alterations may serve as valuable tools for diagnosis and classification of tumors, prediction of clinical outcome, disease monitoring, and choice of therapy as well as for providing clues to the location of crucial cancer-related genes. Endometrial carcinoma (EC) is the most frequently diagnosed malignancy of the female genital tract, ranking fourth among all invasive tumors affecting women. Cytogenetic studies of human ECs have not produced very conclusive data, since many of these studies are based on karyotyping of limited number of cases and no really specific karyotypic changes have yet been identified. As the majority of the genes are conserved among mammals, the use of inbred animal model systems may serve as a tool for identification of underlying genes and pathways involved in tumorigenesis in humans. In the present work we used spectral karyotyping (SKY) to identify cancer-related aberrations in a well-characterized experimental model for spontaneous endometrial carcinoma in the BDII rat tumor model. Results: Analysis of 21 experimental ECs revealed specific nonrandom numerical and structural chromosomal changes. The most recurrent numerical alterations were gains in rat chromosome 4 (RNO4) and losses in RNO15. The most commonly structural changes were mainly in form of chromosomal translocations and were detected in RNO3, RNO6, RNO10, RNO11, RNO12, and RNO20. Unbalanced chromosomal translocations involving RNO3p was the most commonly observed structural changes in this material followed by RNO11p and RNO10 translocations. Conclusion: The non-random nature of these events, as documented by their high frequencies of incidence, is suggesting for dynamic selection of these changes during experimental EC tumorigenesis and therefore for their potential contribution into development of this malignancy. Comparative molecular analysis of the identified genetic changes in this tumor model with those reported in the human ECs may provide new insights into underlying genetic changes involved in EC development and tumorigenesis.
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| 10. |
- Jurcevic, Sanja, et al.
(författare)
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Validation of Suitable Endogenous Control Genes for Quantitative PCR Analysis of microRNA gene expression in a rat model of endometrial cancer
- 2013
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundMicroRNAs are small RNA molecules that negatively regulate gene expression by translational inhibition or mRNA cleavage. The discovery that abnormal expression of particular miRNAs contributes to human disease, including cancer, has spurred growing interest in analysing expression profiles of these molecules. Quantitative polymerase chain reaction is frequently used for quantification of miRNA expression due to its sensitivity and specificity. To minimize experimental error in this system an appropriate endogenous control gene must be chosen. An ideal endogenous control gene should be expressed at a constant level across all samples and its expression stability should be unaffected by the experimental procedure.ResultsThe expression and validation of candidate control genes (4.5S RNA(H) A, Y1, 4.5S RNA(H) B, snoRNA, U87 and U6) was examined in 21 rat cell lines to establish the most suitable endogenous control for miRNA analysis in a rat model of cancer. The stability of these genes was analysed using geNorm and NormFinder algorithms. U87 and snoRNA were identified as the most stable control genes, while Y1 was least stable.ConclusionThis study identified the control gene that is most suitable for normalizing the miRNA expression data in rat. That reference gene will be useful when miRNAs expression are analyzed in order to find new miRNA markers for endometrial cancer in rat.
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| 11. |
- Karlsson, Sandra, et al.
(författare)
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Gene expression profiling predicts a three-gene expression signature of endometrial adenocarcinoma in a rat model
- 2009
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 9, s. Article Number: 12-
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the Western world, endometrial cancers are the most common gynaecological neoplastic disorders among women. Initial symptoms are often vague and may be confused with several other conditions or disorders. Thus, there is a need for an easy and reliable diagnostic tool. The objective of this work was to identify a gene expression signature specific for endometrial adenocarcinomas to be used for testing potential endometrial biomarkers.Results: Changes in expression between endometrial adenocarcinomas and non-/pre-malignant endometrium from the BDII EAC rat model were compared in cDNA microarray assays. By employing classification analysis (Weka) on the expression data from approximately 5600 cDNA clones and TDT analysis on genotype data, we identified a three-gene signature (Gpx3, Bgn and Tgfb3). An independent analysis of differential expression, revealed a total of 354 cDNA clones with significant changes in expression. Among the 10 best ranked clones, Gpx3, Bgn and Tgfb3 were found. Conclusion: Taken together, we present a unique data set of genes with different expression patterns between EACs and non-/pre-malignant endometrium, and specifically we found three genes that were confirmed in two independent analyses. These three genes are candidates for an EAC signature and further evaluations of their involvement in EAC tumorigenesis will be undertaken.
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| 12. |
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| 13. |
- Monazzam, Azita, et al.
(författare)
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A new, fast and semi-automated size determination method (SASDM) for studying multicellular tumor spheroids
- 2005
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; :5, s. 32-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Considering the width and importance of using Multicellular Tumor Spheroids (MTS) in oncology research, size determination of MTSs by an accurate and fast method is essential. In the present study an effective, fast and semi-automated method, SASDM, was developed to determinate the size of MTSs. The method was applied and tested in MTSs of three different cell-lines. Frozen section autoradiography and Hemotoxylin Eosin (H&E) staining was used for further confirmation.RESULTS:SASDM was shown to be effective, user-friendly, and time efficient, and to be more precise than the traditional methods and it was applicable for MTSs of different cell-lines. Furthermore, the results of image analysis showed high correspondence to the results of autoradiography and staining.CONCLUSION:The combination of assessment of metabolic condition and image analysis in MTSs provides a good model to evaluate the effect of various anti-cancer treatments.
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| 14. |
- Monazzma, Azita, et al.
(författare)
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Multicellular Tumour Spheroid as a model for evaluation of [18F]FDG as biomarker for breast cancer treatment monitoring
- 2006
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 6, s. 6-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn order to explore a pre-clinical method to evaluate if [18F]FDG is valid for monitoring early response, we investigated the uptake of FDG in Multicellular tumour spheroids (MTS) without and with treatment with five routinely used chemotherapy agents in breast cancer.MethodsThe response to each anticancer treatment was evaluated by measurement of the [18F]FDG uptake and viable volume of the MTSs after 2 and 3 days of treatment.ResultsThe effect of Paclitaxel and Docetaxel on [18F]FDG uptake per viable volume was more evident in BT474 (up to 55% decrease) than in MCF-7 (up to 25% decrease).Doxorubicin reduced the [18F]FDG uptake per viable volume more noticeable in MCF-7 (25%) than in BT474 MTSs.Tamoxifen reduced the [18F]FDG uptake per viable volume only in MCF-7 at the highest dose of 1 μM.No effect of Imatinib was observed.ConclusionMTS was shown to be appropriate to investigate the potential of FDG-PET for early breast cancer treatment monitoring; the treatment effect can be observed before any tumour size changes occur.The combination of PET radiotracers and image analysis in MTS provides a good model to evaluate the relationship between tumour volume and the uptake of metabolic tracer before and after chemotherapy. This feature could be used for screening and selecting PET-tracers for early assessment of treatment response.In addition, this new method gives a possibility to assess quickly, and in vitro, a good preclinical profile of existing and newly developed anti-cancer drugs.
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| 15. |
- Turk, Casey M., et al.
(författare)
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Paralemmin-1 is over-expressed in estrogen-receptor positive breast cancers
- 2012
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 12, s. 17-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Paralemmin-1 is a phosphoprotein lipid-anchored to the cytoplasmic face of membranes where it functions in membrane dynamics, maintenance of cell shape, and process formation. Expression of paralemmin-1 and its major splice variant (Delta exon 8) as well as the extent of posttranslational modifications are tissue-and development-specific. Paralemmin-1 expression in normal breast and breast cancer tissue has not been described previously. Results: Paralemmin-1 mRNA and protein expression was evaluated in ten breast cell lines, 26 primary tumors, and 10 reduction mammoplasty (RM) tissues using real time RT-PCR. Paralemmin-1 splice variants were assessed in tumor and RM tissues using a series of primers and RT-PCR. Paralemmin-1 protein expression was examined in cell lines using Western Blots and in 31 ductal carcinomas in situ, 65 infiltrating ductal carcinomas, and 40 RM tissues using immunohistochemistry. Paralemmin-1 mRNA levels were higher in breast cancers than in RM tissue and estrogen receptor (ER)-positive tumors had higher transcript levels than ER-negative tumors. The Delta exon 8 splice variant was detected more frequently in tumor than in RM tissues. Protein expression was consistent with mRNA results showing higher paralemmin-1 expression in ER-positive tumors. Conclusions: The differential expression of paralemmin-1 in a subset of breast cancers suggests the existence of variation in membrane dynamics that may be exploited to improve diagnosis or provide a therapeutic target.
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| 16. |
- Deicher, Anton, et al.
(författare)
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Targeting dendritic cells in pancreatic ductal adenocarcinoma
- 2018
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 18:1
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Forskningsöversikt (refereegranskat)abstract
- Dendritic cells (DC) are an integral part of the tumor microenvironment. Pancreatic cancer is characterized by reduced number and function of DCs, which impacts antigen presentation and contributes to immune tolerance. Recent data suggest that exosomes can mediate communication between pancreatic cancer cells and DCs. Furthermore, levels of DCs may serve as prognostic factors. There is also growing evidence for the effectiveness of vaccination with DCs pulsed with tumor antigens to initiate adaptive cytolytic immune responses via T cells. Most experience with DC-based vaccination has been gathered for MUC1 and WT1 antigens, where clinical studies in advanced pancreatic cancer have provided encouraging results. In this review, we highlight the role of DC in the course, prognosis and treatment of pancreatic cancer.
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| 17. |
- Fath, MK, et al.
(författare)
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Current understanding of epigenetics role in melanoma treatment and resistance
- 2022
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Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 22:1, s. 313-
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Tidskriftsartikel (refereegranskat)abstract
- Melanoma is the most aggressive form of skin cancer resulting from genetic mutations in melanocytes. Several factors have been considered to be involved in melanoma progression, including genetic alteration, processes of damaged DNA repair, and changes in mechanisms of cell growth and proliferation. Epigenetics is the other factor with a crucial role in melanoma development. Epigenetic changes have become novel targets for treating patients suffering from melanoma. These changes can alter the expression of microRNAs and their interaction with target genes, which involves cell growth, differentiation, or even death. Given these circumstances, we conducted the present review to discuss the melanoma risk factors and represent the current knowledge about the factors related to its etiopathogenesis. Moreover, various epigenetic pathways, which are involved in melanoma progression, treatment, and chemo-resistance, as well as employed epigenetic factors as a solution to the problems, will be discussed in detail.
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| 18. |
- Fath, MK, et al.
(författare)
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Exosome-based strategies for diagnosis and therapy of glioma cancer
- 2022
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Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 22:1, s. 262-
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Tidskriftsartikel (refereegranskat)abstract
- Glioblastoma belongs to the most aggressive type of cancer with a low survival rate that is characterized by the ability in forming a highly immunosuppressive tumor microenvironment. Intercellular communication are created via exosomes in the tumor microenvironment through the transport of various biomolecules. They are primarily involved in tumor growth, differentiation, metastasis, and chemotherapy or radiation resistance. Recently several studies have highlighted the critical role of tumor-derived exosomes against immune cells. According to the structural and functional properties, exosomes could be essential instruments to gain a better molecular mechanism for tumor understanding. Additionally, they are qualified as diagnostic/prognostic markers and therapeutic tools for specific targeting of invasive tumor cells such as glioblastomas. Due to the strong dependency of exosome features on the original cells and their developmental status, it is essential to review their critical modulating molecules, clinical relevance to glioma, and associated signaling pathways. This review is a non-clinical study, as the possible role of exosomes and exosomal microRNAs in glioma cancer are reported. In addition, their content to overcome cancer resistance and their potential as diagnostic biomarkers are analyzed.
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| 19. |
- Fath, MK, et al.
(författare)
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Revisiting characteristics of oncogenic extrachromosomal DNA as mobile enhancers on neuroblastoma and glioma cancers
- 2022
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Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 22:1, s. 200-
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Tidskriftsartikel (refereegranskat)abstract
- Cancer can be induced by a variety of possible causes, including tumor suppressor gene failure and proto-oncogene hyperactivation. Tumor-associated extrachromosomal circular DNA has been proposed to endanger human health and speed up the progression of cancer. The amplification of ecDNA has raised the oncogene copy number in numerous malignancies according to whole-genome sequencing on distinct cancer types. The unusual structure and function of ecDNA, and its potential role in understanding current cancer genome maps, make it a hotspot to study tumor pathogenesis and evolution. The discovery of the basic mechanisms of ecDNA in the emergence and growth of malignancies could lead researchers to develop new cancer therapies. Despite recent progress, different aspects of ecDNA require more investigation. We focused on the features, and analyzed the bio-genesis, and origin of ecDNA in this review, as well as its functions in neuroblastoma and glioma cancers.
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| 20. |
- Gao, Jingfang, et al.
(författare)
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TGF-β isoforms induce EMT independent migration of ovarian cancer cells.
- 2014
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Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor beta (TGF-β) plays major roles in tumorigenesis by regulating cell growth, epithelial-to-mesenchymal transition (EMT), migration/invasion and metastasis. The epithelial markers E-cadherin, claudin-3 and claudin-4, commonly decreased in human adenocarcinomas are actually up regulated during ovarian carcinogenesis. In human ovarian cancer TGF-β1 may either suppress or promote tumor progression, but whether other TGF-β isoforms (TGF-β2 and TGF-β3) exert similar effects is not known.
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| 21. |
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| 22. |
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| 23. |
- Jurcevic, Sanja, 1971-, et al.
(författare)
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MicroRNA expression in human endometrial adenocarcinoma
- 2014
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Ingår i: Cancer Cell International. - London : BioMed Central (BMC). - 1475-2867. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: MicroRNAs are small non-coding RNAs that play crucial roles in the pathogenesis of different cancer types. The aim of this study was to identify miRNAs that are differentially expressed in endometrial adenocarcinoma compared to healthy endometrium. These miRNAs can potentially be used to develop a panel for classification and prognosis in order to better predict the progression of the disease and facilitate the choice of treatment strategy.METHODS: Formalin fixed paraffin embedded endometrial tissue samples were collected from the Örebro university hospital. QPCR was used to quantify the expression levels of 742 miRNAs in 30 malignant and 20 normal endometrium samples. After normalization of the qPCR data, miRNAs differing significantly in expression between normal and cancer samples were identified, and hierarchical clustering analysis was used to identify groups of miRNAs with coordinated expression profiles.RESULTS: In comparisons between endometrial adenocarcinoma and normal endometrium samples 138 miRNAs were found to be significantly differentially expressed (p < 0.001) among which 112 miRNAs have not been previous reported for endometrial adenocarcinoma.CONCLUSION: Our study shows that several miRNAs are differentially expressed in endometrial adenocarcinoma. These identified miRNA hold great potential as target for classification and prognosis of this disease. Further analysis of the differentially expressed miRNA and their target genes will help to derive new biomarkers that can be used for classification and prognosis of endometrial adenocarcinoma.
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| 24. |
- Kamat, Nasir, et al.
(författare)
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Chemotherapy induced microsatellite instability and loss of heterozygosity in chromosomes 2, 5, 10, and 17 in solid tumor patients
- 2014
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 14, s. 118-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The inevitable side effects of the currently used chemotherapy are associated with serious syndromes. Genotoxic effects and consequent genetic instability may play an important role in these syndromes. The aim of the study was to evaluate chemotherapy-related microsatellite instability (MSI), loss of heterozygosity (LOH), and loss of mismatch repair (MMR) expression in solid tumor patients. Methods: Samples were collected from 117 de novo patients with solid tumors of different origins. Specimens, taken pre- and post-treatment, were screened for MSI and LOH in 10 microsatellite sequences in blood, and expression of five MMR proteins were analyzed in cancer tissues using immunohistochemistry. Statistical analysis included the use of; Fisher's exact test, Chi Square, and an inter-rater reliability test using Cohen's kappa coefficient. Results: Microsatellite analysis showed that 66.7% of the patients had MSI, including 23.1% high-positive MSI and 43.6% low-positive MSI. A large portion (41%) of the patients exhibited LOH in addition to MSI. MSI and LOH were detected in seven loci in which incidence rates ranged from 3.8% positive for Bat-26 to 34.6% positive for Tp53-Alu. Immunohistochemistry revealed that human mutL homolog 1 (hMLH1) expression was deficient in 29.1% of the patients, whereas 18.8%, 23.9%, 13.4%, and 9.7% were deficient for human mutS homolog 2 (hMSH2), P53, human mutS homolog 6 (hMSH6) and human post-meiotic segregation increased 2 (hPMS2), respectively. There was a significant correlation between MSI and LOH incidence in Tp53-Alu, Mfd41, and APC with low or deficient expression of hMLH1, hMSH2, and P53. A significant association between MSI and LOH, and incidence of secondary tumors was also evident. Conclusions: The negative correlation between MMR expression, MSI, and LOH and increased resistance to anti-cancer drugs and development of secondary cancers demonstrates a useful aid in early detection of potential chemotherapy-related side-effects. The diagnostic value demonstrated in our earlier study on breast cancer patients was confirmed for other solid tumors.
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| 25. |
- Keane, Simon, et al.
(författare)
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The loss of DLG2 isoform 7/8, but not isoform 2, is critical in advanced staged neuroblastoma
- 2021
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Ingår i: Cancer Cell International. - : Springer Nature. - 1475-2867. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuroblastoma is a childhood neural crest tumor showing large clinical and genetic heterogeneity, one form displaying 11q-deletion is very aggressive. It has been shown that 11q-deletion results in decreased expression of DLG2, a gene residing in the deleted region. DLG2 has a number of different isoforms with the main difference is the presence or absence of a L27 domain. The L27 domain containing DLG proteins can form complexes with CASK/MPP and LIN7 protein family members, which will control cell polarity and signaling. Methods: We evaluated the DLG gene family and the LIN7 gene family for their expression in differently INSS staged neuroblastoma from publically available data and primary tumors, we included two distinct DLG1 and DLG2 N-terminal transcript isoforms encoding L27 domains for their expression. Functionality of DLG2 isoforms and of LIN7A were evaluated in the 11q-deleted neuroblastoma cell line SKNAS. Results: In neuroblastoma only two DLG2 isoforms were expressed: isoform 2 and isoform 7/8. Using the array data we could determine that higher expression of DLG members that contain L27 domains correlated to better survival and prognosis. Whilst DLG1 showed a decrease in both isoforms with increased INSS stage, only the full length L27 containing DLG2 transcripts DLG2-isoform 7/8 showed a decrease in expression in high stage neuroblastoma. We could show that the protein encoded by DLG2-isoform 7 could bind to LIN7A, and increased DLG2-isoform 7 gene expression increased the expression of LIN7A, this reduced neuroblastoma cell proliferation and viability, with increased BAX/BCL2 ratio indicating increased apoptosis. Conclusion: We have provided evidence that gene expression of the L27 domain containing DLG2-isoform 7/8 but not L27 domain lacking DLG2-isoform 2 is disrupted in neuroblastoma, in particular in the aggressive subsets of tumors. The presence of the complete L27 domain allows for the binding to LIN7A, which will control cell polarity and signaling, thus affecting cancer cell viability.
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| 26. |
- Khodakarami, A, et al.
(författare)
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The molecular biology and therapeutic potential of Nrf2 in leukemia
- 2022
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Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 22:1, s. 241-
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Tidskriftsartikel (refereegranskat)abstract
- NF-E2-related factor 2 (Nrf2) transcription factor has contradictory roles in cancer, which can act as a tumor suppressor or a proto-oncogene in different cell conditions (depending on the cell type and the conditions of the cell environment). Nrf2 pathway regulates several cellular processes, including signaling, energy metabolism, autophagy, inflammation, redox homeostasis, and antioxidant regulation. As a result, it plays a crucial role in cell survival. Conversely, Nrf2 protects cancerous cells from apoptosis and increases proliferation, angiogenesis, and metastasis. It promotes resistance to chemotherapy and radiotherapy in various solid tumors and hematological malignancies, so we want to elucidate the role of Nrf2 in cancer and the positive point of its targeting. Also, in the past few years, many studies have shown that Nrf2 protects cancer cells, especially leukemic cells, from the effects of chemotherapeutic drugs. The present paper summarizes these studies to scrutinize whether targeting Nrf2 combined with chemotherapy would be a therapeutic approach for leukemia treatment. Also, we discussed how Nrf2 and NF-κB work together to control the cellular redox pathway. The role of these two factors in inflammation (antagonistic) and leukemia (synergistic) is also summarized.
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| 27. |
- Kopsida, Maria, et al.
(författare)
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RhoB expression associated with chemotherapy response and prognosis in colorectal cancer
- 2024
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To examine the role of RhoB expression in relation to chemotherapy response, clinical outcomes and associated signaling pathways in colorectal cancer patients.Materials and methods: The study included 5 colon cancer cell lines, zebrafish embryos and 260 colorectal cancer patients treated with 5-fluorouracil (5-FU) and oxaliplatin (OXL). The methods consisted of CRISPR/Cas9, reactive oxygen species (ROS), caspase-3 activity, autophagy flux, in-silico RNA sequencing and immunohistochemistry. Gene expression analysis and pathway analysis were conducted using RNA-seq data.Results: All cancer lines tested, including SW480, SW480-KO13 (RhoB knockout), SW480-KO55 (RhoB knockout), HCT116 and HCT116-OE (RhoB overexpressed), exhibited cytotoxicity to 5-FU and OXL. RhoB knockout cell lines demonstrated significantly reduced migration compared to the control cell lines. Furthermore, RhoB played a role in caspase-3-dependent apoptosis, regulation of ROS production and autophagic flux. The mRNA sequencing data indicated lower expression levels of oncogenes in RhoB knockout cell lines. The zebrafish model bearing SW480-KO showed a light trend toward tumor regression. RhoB expression by immunohistochemistry in patients was increased from normal mucosa to tumor samples. In patients who received chemotherapy, high RhoB expression was related to worse survival compared to low RhoB expression. Furthermore, the molecular docking analysis revealed that OXL had a higher binding affinity for RhoB than 5-FU, with a binding affinity of -7.8 kcal/mol and HADDOCK predicted molecular interactions between RhoB and caspase 3 protein. Gene-set enrichment analysis supported these findings, showing that enrichment of DNA damage response pathway and p53 signaling in RhoB overexpression treatment group, while the RhoB knockout treatment group exhibited enrichment in the negative regulation pathway of cell migration.Conclusion: RhoB was negatively associated with chemotherapy response and survival in colorectal cancers. Therefore, RhoB inhibition may enhance chemotherapeutic responses and patient survival.
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| 28. |
- Magan Barre, Mustafa, et al.
(författare)
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CAFs affect the proliferation and treatment response of head and neck cancer spheroids during co-culturing in a unique in vitro model
- 2020
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Ingår i: Cancer Cell International. - : BMC. - 1475-2867. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors for which the overall survival rate worldwide is around 60%. The tumor microenvironment, including cancer-associated fibroblasts (CAFs), is believed to affect the treatment response and migration of HNSCC. The aim of this study was to create a biologically relevant HNSCC in vitro model consisting of both tumor cells and CAFs cultured in 3D to establish predictive biomarkers for treatment response, as well as to investigate the impact of CAFs on phenotype, proliferation and treatment response in HNSCC cells. Methods Three different HNSCC patient-derived tumor cell lines were cultured with and without CAFs in a 3D model. Immunohistochemistry of the proliferation marker Ki67, epidermal growth factor receptor (EGFR) and fibronectin and a TUNEL-assay were performed to analyze the effect of CAFs on both tumor cell proliferation and response to cisplatin and cetuximab treatment in tumor spheroids (3D). mRNA expression of epithelial-mesenchymal transition (EMT) and cancer stem cells markers were analyzed using qRT-PCR. Results The results demonstrated increased cell proliferation within the tumor spheroids in the presence of CAFs, correlating with increased expression of EGFR. In spheroids with increased expression of EGFR, a potentiated response to cetuximab treatment was observed. Surprisingly, an increase in Ki67 expressing tumor cells were observed in spheroids treated with cisplatin for 3 days, correlating with increased expression of EGFR. Furthermore, tumor cells co-cultured with CAFs presented an increased EMT phenotype compared to tumor cells cultured alone in 3D. Conclusion Taken together, our results reveal increased cell proliferation and elevated expression of EGFR in HNSCC tumor spheroids in the presence of CAFs. These results, together with the altered EMT phenotype, may influence the response to cetuximab or cisplatin treatment.
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| 29. |
- Melissaridou, Styliani, et al.
(författare)
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The effect of 2D and 3D cell cultures on treatment response, EMT profile and stem cell features in head and neck cancer 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis
- 2019
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Head and Neck Squamous Cell Carcinoma (HNSCC) tumors are often resistant to therapies. Therefore searching for predictive markers and new targets for treatment in clinically relevant in vitro tumor models is essential. Five HNSCC-derived cell lines were used to assess the effect of 3D culturing compared to 2D monolayers in terms of cell proliferation, response to anti-cancer therapy as well as expression of EMT and CSC genes. Methods: The viability and proliferation capacity of HNSCC cells as well as induction of apoptosis in tumor spheroids cells after treatment was assessed by MTT assay, crystal violet- and TUNEL assay respectively. Expression of EMT and CSC markers was analyzed on mRNA (RT-qPCR) and protein (Western blot) level. Results: We showed that HNSCC cells from different tumors formed spheroids that differed in size and density in regard to EMT-associated protein expression and culturing time. In all spheroids, an up regulation of CDH1, NANOG and SOX2 was observed in comparison to 2D but changes in the expression of EGFR and EMT markers varied among the cell lines. Moreover, most HNSCC cells grown in 3D showed decreased sensitivity to cisplatin and cetuximab (anti-EGFR) treatment. Conclusions: Taken together, our study points at notable differences between these two cellular systems in terms of EMT-associated gene expression profile and drug response. As the 3D cell cultures imitate the in vivo behaviour of neoplastic cells within the tumor, our study suggest that 3D culture model is superior to 2D monolayers in the search for new therapeutic targets.
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| 30. |
- Pellegrini, Paola, et al.
(författare)
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A drug screening assay on cancer cells chronically adapted to acidosis
- 2018
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Ingår i: Cancer Cell International. - : BMC. - 1475-2867. ; 18
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Tidskriftsartikel (refereegranskat)abstract
- Background: Drug screening for the identification of compounds with anticancer activity is commonly performed using cell lines cultured under normal oxygen pressure and physiological pH. However, solid tumors are characterized by a microenvironment with limited access to nutrients, reduced oxygen supply and acidosis. Tumor hypoxia and acidosis have been identified as important drivers of malignant progression and contribute to multicellular resistance to different forms of therapy. Tumor acidosis represents an important mechanism mediating drug resistance thus the identification of drugs active on acid-adapted cells may improve the efficacy of cancer therapy. Methods: Here, we characterized human colon carcinoma cells (HCT116) chronically adapted to grow at pH 6.8 and used them to screen the Prestwick drug library for cytotoxic compounds. Analysis of gene expression profiles in parental and low pH-adapted cells showed several differences relating to cell cycle, metabolism and autophagy. Results: The screen led to the identification of several compounds which were further selected for their preferential cytotoxicity towards acid-adapted cells. Amongst 11 confirmed hits, we primarily focused our investigation on the benzoporphyrin derivative Verteporfin (VP). VP significantly reduced viability in low pH-adapted HCT116 cells as compared to parental HCT116 cells and normal immortalized epithelial cells. The cytotoxic activity of VP was enhanced by light activation and acidic pH culture conditions, likely via increased acid-dependent drug uptake. VP displayed the unique property to cause light-dependent cross-linking of proteins and resulted in accumulation of polyubiquitinated proteins without inducing inhibition of the proteasome. Conclusions: Our study provides an example and a tool to identify anticancer drugs targeting acid-adapted cancer cells.
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| 31. |
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| 32. |
- Torén, William, et al.
(författare)
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Immunohistochemical investigation of prognostic biomarkers in resected colorectal liver metastases : A systematic review and meta-analysis
- 2018
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Ingår i: Cancer Cell International. - : Springer Science and Business Media LLC. - 1475-2867. ; 18:1
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Forskningsöversikt (refereegranskat)abstract
- Background: Many studies have investigated the prognostic role of biomarkers in colorectal liver metastases (CRLM). However, no biomarker has been established in routine clinical practice. The aim of this study was to scrutinize the current literature for biomarkers evaluated by immunohistochemistry as prognostic markers in patients with resected CRLM. Methods: A systematic review was performed according to the PRISMA guidelines. Articles were identified in the PubMed database with selected search terms and by cross-references search. The REMARK quality criteria were applied. Markers were included if they reported the prognostic impact of immunohistochemical markers in a multivariable setting in relation to overall survival (OS). A meta-analysis was conducted when more than one original article provided survival data of a marker. Results: In total, 26 biomarkers were identified as independent significant markers for OS in resected CRLM. These biomarkers were found to be involved in multiple oncogenic signalling pathways that control cell growth, apoptosis, angiogenesis and evasion of immune detection. Among these biomarker candidates were Ki-67, EGFR, p53, hTERT, CD34, TSP-1, KISS1, Aurora kinase A and CDX2. CD34 and TSP-1 were reported as significantly associated with survival by more than one study and where therefore pooled in a meta-analysis. Conclusion: A number of independent prognostic biomarkers for resected CRLM were identified. However, most markers were evaluated in a retrospective setting with small patient cohorts, without external validation. Large, prospective, multicentre studies with standardised methods are needed before biomarkers can translated into the clinic.
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| 33. |
- Xu, Cheng, et al.
(författare)
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Prognostic value and biological function of LRRN4 in colorectal cancer
- 2022
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Ingår i: Cancer Cell International. - : BMC. - 1475-2867. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Several nervous and nerve-related biomarkers have been detected in colorectal cancer (CRC) and can contribute to the progression of CRC. However, the role of leucine-rich repeat neuronal 4 (LRRN4), a recently identified neurogenic marker, in CRC remains unclear. Methods We examined the expression and clinical outcomes of LRRN4 in CRC from TCGA-COREAD mRNA-sequencing datasets and immunohistochemistry in a Chinese cohort. Furthermore, colony formation, flow cytometry, wound healing assays and mouse xenograft models were used to investigate the biological significance of LRRN4 in CRC cell lines with LRRN4 knockdown or overexpression in vitro and in vivo. In addition, weighted coexpression network analysis, DAVID and western blot analysis were used to explore the potential molecular mechanism. Results We provide the first evidence that LRRN4 expression, at both the mRNA and protein levels, was remarkably high in CRC compared to controls and positively correlated with the clinical outcome of CRC patients. Specifically, LRRN4 was an independent prognostic factor for progression-free survival and overall survival in CRC patients. Further functional experiments showed that LRRN4 promoted cell proliferation, cell DNA synthesis and cell migration and inhibited apoptosis. Knockdown of LRRN4 can correspondingly decrease these effects in vitro and can significantly suppress the growth of xenografts. Several biological functions and signaling pathways were regulated by LRRN4, including proteoglycans in cancer, glutamatergic synapse, Ras, MAPK and PI3K. LRRN4 knockdown resulted in downregulation of Akt, p-Akt, ERK1/2 and p-ERK1/2, the downstream of the Ras/MAPK signaling pathway, overexpression of LRRN4 leaded to the upregulation of these proteins. Conclusions Our results suggest that LRRN4 could be a biological and molecular determinant to stratify CRC patients into distinct risk categories, and mechanistically, this is likely attributable to LRRN4 regulating several malignant phenotypes of neoplastic cells via RAS/MAPK signal pathways.
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| 34. |
- Yang, Jingmei, et al.
(författare)
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Combating drug resistance in acute myeloid leukaemia by drug rotations : the effects of quizartinib and pexidartinib
- 2021
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Acute myeloid leukaemia (AML) is an aggressive blood cancer. In approximately 30% of the cases, driver mutations in the FLT3 gene are identified. FLT3 inhibitors are used in treatment of such patients together with cytotoxic drugs or (in refractory AML) as single agents. Unfortunately, resistance to FLT3 inhibitors limits their efficacy. Resistance is often due to secondary mutations in the gene encoding the molecular target. The gatekeeper mutation F691L confers resistance to specific FLT3 inhibitors such as quizartinib, but pexidartinib is much less resistance to this mutation. Pexidartinib alone is however sensitive to many other resistance mutations. In chronic myeloid leukaemia (CML), it has been suggested that rotation between drugs with a different landscape of resistance mutations might postpone the emergence of resistance. Methods We studied the effect of quizartinib and pexidartinib in AML cell lines that express FLT3 (MOLM-14 and MV4-11). Using a rotation protocol, we further examined whether the emergence of resistance could be postponed. Computational modelling was used to analyse the onset of resistance and suggest which mutations are most likely to occur in a quantitative fashion. Results The cells were sensitive to both inhibitors but quickly developed resistance that could be inherited, suggesting a genetic origin. Rotation protocols were not useful to postpone the emergence of resistance, which implies that such protocols, or changing from pexidartinib to quizartinib (or vice-versa) should not be used in patients. The computational modelling led to similar conclusions and suggested that F691L is the most common mutation to occur with quizartinib, and also when both drugs are used in rotation. Conclusions AML patients are not likely to benefit from a quizartinib/pexidartinib rotation protocol. A combination of tyrosine kinase inhibitors (with different molecular targets) might be more useful in the future. Development of specific FLT3 inhibitors that are less sensitive to resistance mutations might also lead to a better outcome.
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| 35. |
- Yang, Jingmei, et al.
(författare)
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Combination strategies to overcome drug resistance in FLT+ acute myeloid leukaemia
- 2023
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Ingår i: Cancer Cell International. - : BioMed Central (BMC). - 1475-2867. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAcute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly.MethodsWe examined combination therapies aimed at FLT3(+)-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism.ResultsWe show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance.ConclusionsThis study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.
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| 36. |
- Zheng, TY, et al.
(författare)
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Systematical analysis reveals a strong cancer relevance of CREB1-regulated genes
- 2021
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Ingår i: Cancer cell international. - : Springer Science and Business Media LLC. - 1475-2867. ; 21:1, s. 530-
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor cyclic-AMP response element-binding protein 1 (CREB1) responds to cAMP level and controls the expression of target genes, which regulates nutrition partitioning. The promoters of CREB1-targeted genes responsive to cAMP have been extensively investigated and characterized with the presence of both cAMP response element and TATA box. Compelling evidence demonstrates that CREB1 also plays an essential role in promoting tumor development. However, only very few genes required for cell survival, proliferation and migration are known to be constitutively regulated by CREB1 in tumors. Their promoters mostly do not harbor any cAMP response element. Thus, it is very likely that CREB1 regulates the expressions of distinct sets of target genes in normal tissues and tumors. The whole gene network constitutively regulated by CREB1 in tumors has remained unrevealed. Here, we employ a systematical and integrative approach to decipher this gene network in the context of both tissue cultured cancer cells and patient samples. We combine transcriptomic, Rank-Rank Hypergeometric Overlap, and Chipseq analysis, to define and characterize CREB1-regulated genes in a multidimensional fashion. A strong cancer relevance of those top-ranked targets, which meet the most stringent criteria, is eventually verified by overall survival analysis of cancer patients. These findings strongly suggest the importance of genes constitutively regulated by CREB1 for their implicative involvement in promoting tumorigenesis.
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| 37. |
- Lindmark, Ulrika, et al.
(författare)
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Food selection associated with sense of coherence in adults.
- 2005
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Ingår i: Nutrition Journal. - : Springer Science and Business Media LLC. - 1475-2891. ; 28:4, s. 9-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Favorable dietary habits promote health, whereas unfavorable habits link to various chronic diseases. An individual's "sense of coherence" (SOC) is reported to correlate with prevalence of some diseases to which dietary habits are linked. However, understanding what determines an individual's dietary preferences and how to change his/her behavior remains limited. The aim of the present study was to evaluate associations between dietary intake and SOC in adults. METHODS: Diet intake was recorded by an 84-item semi-quantitative food frequency questionnaire and SOC was measured by the 13-item Antonovsky questionnaire in 2,446 men and 2,545 women (25-74 years old) from the population based northern Sweden MONICA screening in 1999. RESULTS: Intakes of energy, total and saturated fat, ascorbic acid, sucrose, and servings of fruits, vegetables, cereals, and sweets correlated with SOC among women, whereas intakes of total and saturated fat, ascorbic acid, fiber, and alcohol, and servings of fruits, vegetables, bread, bread and cereals, fish, and potatoes correlated with SOC among men. With a few exceptions, intakes of these nutrients/foods were significantly explained by SOC quartile scores in linear GLM models. Both women and men classified into the highest SOC quartile had significantly higher age-BMI-education standardized mean intakes of vegetables than those in the lowest quartiles. Women in the highest SOC quartile also had higher intake of fruits but lower intakes of energy, total and saturated fat, sucrose, and sweets. Projection to latent structures (PLS) multivariate modeling of intakes of the 84 food items and food aggregates simultaneously on SOC scores supported low SOC to coincide with a presumably less health promoting dietary preference, e.g. intake of pizza, soft drinks, candies, sausages for main course, hamburgers, mashed potato, chips and other snacks, potato salad, French fries, whereas men and women with high SOC scores were characterized by e.g. high intake of rye crisp whole meal bread, boiled potato, vegetables, berries, and fruits. CONCLUSION: Both men and women in the highest, as compared with the lowest, SOC score quartile reported more "healthy" food choices. Dietary habits for individuals in the lowest SOC quartile therefore may render a higher risk for various endemic diseases.
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