| 1. |
- Augsten, Martin, et al.
(författare)
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CXCL14 is an autocrine growth factor for fibroblasts and acts as a multi-modal stimulator of prostate tumor growth
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 106:9, s. 3414-3419
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Tidskriftsartikel (refereegranskat)abstract
- This study explored the role of secreted fibroblast-derived factors in prostate cancer growth. Analyses of matched normal and tumor tissue revealed up-regulation of CXCL14 in cancer-associated fibroblasts of a majority of prostate cancer. Fibroblasts over-expressing CXCL14 promoted the growth of prostate cancer xenografts, and increased tumor angiogenesis and macrophage infiltration. Mechanistic studies demonstrated that autocrine CXCL14-stimulation of fibroblasts stimulate migration and ERK-dependent proliferation of fibroblasts. CXCL14-stimulation of monocyte migration was also demonstrated. Furthermore, CXCL14-producing fibroblasts, but not recombinant CXCL14, enhanced in vitro proliferation and migration of prostate cancer cells and in vivo angiogenesis. These studies thus identify CXCL14 as a novel autocrine stimulator of fibroblast growth and migration, with multi-modal tumor-stimulatory activities. In more general terms, our findings suggest autocrine stimulation of fibroblasts as a previously unrecognized mechanism for chemokine-mediated stimulation of tumor growth, and suggest a novel mechanism whereby cancer-associated fibroblasts achieve their pro-tumorigenic phenotype.
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| 2. |
- Borg, Daniel, et al.
(författare)
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Perinatal tissue distribution of perfluorooctane sulphonate (PFOS) in mice.
- 2009
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Ingår i: Abstracts of the 46th Congress of the European Societies of Toxicology. - : Elsevier BV. ; 189:SI, s. S147-S147
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Konferensbidrag (refereegranskat)abstract
- Perfluorooctane sulfonate (PFOS) is an industrial chemical that has been used as a surfactant and surface protector for more than fifty years. It has during the last decade emerged as an environmental contaminant due to its widespread presence in humans and wildlife and its persistant, bioaccumulative and toxic properties. PFOS is developmentally toxic and late in utero exposure in rodents affects neonatal survival and growth. Observed symptoms suggest impaired pulmonary function, but the cause of the mortality has not been clarified. The purpose of this study was to determine the perinatal tissue distribution of S35-labelled PFOS in mice using whole-body autoradiography (WBA) combined with liquid scintillation counting (LSC). Pregnant C57Bl/6 mice were dosed orally on gestation day (GD) 16 and sampled on GD18, GD20 and postnatal day (PND) 1 (dams + pups). The results from the WBA and the LSC were unequivocal. In dams, PFOS accumulated primarily in the liver, but also the lungs contained levels higher than the blood. PFOS was readily transferred to the fetus. At GD18 general PFOS levels were higher in the fetus than in the blood of the corresponding dam with accumulation in the liver. At GD20, general PFOS levels remained higher in the fetus than in the dam, with substantial accumulation also in the lung. The accumulation in the lung persisted at PND1. Our results show that the fetus is exposed to higher levels of PFOS than the dam and point towards the lung being the main perinatal target organ of PFOS.
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| 3. |
- Carneiro, Ana, et al.
(författare)
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Indistinguishable genomic profiles and shared prognostic markers in undifferentiated pleomorphic sarcoma and leiomyosarcoma: different sides of a single coin?
- 2009
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Ingår i: Laboratory Investigation. - : Elsevier BV. - 1530-0307 .- 0023-6837. ; 89, s. 668-675
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue sarcoma (STS) diagnostics and prognostics are challenging, particularly in highly malignant and pleomorphic subtypes such as undifferentiated pleomorphic sarcoma (UPS) and leiomyosarcoma (LMS). We applied 32K BAC arrays and gene expression profiling to 18 extremity soft tissue LMS and 31 extremity soft tissue UPS with the aim of identifying molecular subtype signatures and genomic prognostic markers. Both the gains/losses and gene expression signatures revealed striking similarities between UPS and LMS, which were indistinguishable using unsupervised hierarchical cluster analysis and significance analysis for microarrays. Gene expression analysis revealed just nine genes, among them tropomyosin beta, which were differentially expressed. Loss of 4q31 (encompassing the SMAD1 locus), loss of 18q22, and tumor necrosis were identified as independent predictors of metastasis in multivariate stepwise Cox regression analysis. Combined analysis applying loss of 4q31 and 18q22 and the presence of necrosis improved the area under receiver operating characteristic curve for metastasis prediction from 0.64 to 0.86. The extensive genetic similarities between extremity soft tissue UPS and LMS suggest a shared lineage of these STS subtypes and the new and independent genetic prognosticators identified hold promise for refined prognostic determination in high-grade, genetically complex STS.Laboratory Investigation advance online publication, 16 March 2009; doi:10.1038/labinvest.2009.18.
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| 4. |
- Carvalho, Marcelo, et al.
(författare)
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Analysis of a set of missense, frameshift, and in-frame deletion variants of BRCA1
- 2009
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Ingår i: Mutation research. - : Elsevier BV. - 0027-5107 .- 1873-135X .- 1879-2871. ; 660:1-2, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations that inactivate BRCA1 are responsible for breast and ovarian cancer susceptibility. One possible outcome of genetic testing for BRCA1 is the finding of a genetic variant of uncertain significance for which there is no information regarding its cancer association. This outcome leads to problems in risk assessment, counseling and preventive care. The purpose of the present study was to functionally evaluate seven unclassified variants of BRCA1 including a genomic deletion that leads to the in-frame loss of exons 16/17 (Delta exons 16/17) in the mRNA, an insertion that leads to a frameshift and an extended carboxy-terminus (5673insC), and five missense variants (K1487R, S1613C, M1652I, Q1826H and V1833M). We analyzed the variants using a functional assay based on the transcription activation property of BRCA1 combined with supervised learning computational models. Functional analysis indicated that variants S1613C, Q1826H, and M1652I are likely to be neutral, whereas variants V1833M, Delta exons 16/17, and 5673insC are likely to represent deleterious variants. In agreement with the functional analysis, the results of the computational analysis also indicated that the latter three variants are likely to be deleterious. Taken together, a combined approach of functional and bioinformatics analysis, plus structural modeling, can be utilized to obtain valuable information pertaining to the effect of a rare variant on the structure and function of BRCA1. Such information can, in turn, aid in the classification of BRCA1 variants for which there is a lack of genetic information needed to provide reliable risk assessment.
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| 5. |
- Henriksson, Eva, et al.
(författare)
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Comparison of cisplatin sensitivity and the 18F fluoro-2-deoxy 2 glucose uptake with proliferation parameters and gene expression in squamous cell carcinoma cell lines of the head and neck
- 2009
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Ingår i: Journal of Experimental & Clinical Cancer Research. - : Springer Science and Business Media LLC. - 1756-9966. ; 28
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Tidskriftsartikel (refereegranskat)abstract
- Background: The survival of patients with locally advanced head and neck cancer is still poor, with 5-year survival rates of 24-35%. The identification of prognostic and predictive markers at the molecular and cellular level could make it possible to find new therapeutic targets and provide "taylor made" treatments. Established cell lines of human squamous cell carcinoma (HNSCC) are valuable models for identifying such markers. The aim of this study was to establish and characterize a series of cell lines and to compare the cisplatin sensitivity and 18F fluoro-2 deoxy 2 glucose (18F-FDG) uptake of these cell lines with other cellular characteristics, such as proliferation parameters and TP53 and CCND1 status. Methods: Explant cultures of fresh tumour tissue were cultivated, and six new permanent cell lines were established from 18 HNSCC cases. Successfully grown cell lines were analysed regarding clinical parameters, histological grade, karyotype, DNA ploidy, and index and S-phase fraction (Spf). The cell lines were further characterized with regard to their uptake of 18F-FDG, their sensitivity to cisplatin, as measured by a viability test ( crystal violet), and their TP53 and CCND1 status, by fluorescence in situ hybridization (FISH), polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) with DNA sequencing and, for cyclin D1, by immunohistochemistry. Results: Patients with tumours that could be cultured in vitro had shorter disease-free periods and overall survival time than those whose tumours did not grow in vitro, when analysed with the Kaplan-Meier method and the log-rank test. Their tumours also showed more complex karyotypes than tumours from which cell lines could not be established. No correlation was found between TP53 or CCND1 status and 18F-FDG uptake or cisplatin sensitivity. However, there was an inverse correlation between tumour cell doubling time and 18F-FDG uptake. Conclusion: In vitro growth of HNSCC cells seem to be an independent prognostic factor, with cell lines being more readily established from aggressive tumours, a phenomenon more dependent on the molecular genetic characteristics of the tumour cells than on tumour location or TNM status.
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| 6. |
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| 7. |
- Persson, Helena, et al.
(författare)
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The non-coding RNA of the multidrug resistance-linked vault particle encodes multiple regulatory small RNAs.
- 2009
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Ingår i: Nature Cell Biology. - : Springer Science and Business Media LLC. - 1465-7392 .- 1476-4679. ; 11:10, s. 1268-1271
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Tidskriftsartikel (refereegranskat)abstract
- Vault particles are conserved organelles implicated in multidrug resistance and intracellular transport. They contain three different proteins and non-coding vault RNAs (vRNAs). Here we show that human vRNAs produce several small RNAs (svRNAs) by mechanisms different from those in the canonical microRNA (miRNA) pathway. At least one of these svRNAs, svRNAb, associates with Argonaute proteins to guide sequence-specific cleavage and regulate gene expression similarly to miRNAs. We demonstrate that svRNAb downregulates CYP3A4, a key enzyme in drug metabolism. Our findings expand the repertoire of small regulatory RNAs and assign, for the first time, a function to vRNAs that may help explain the association between vault particles and drug resistance.
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| 8. |
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| 9. |
- Veerla, Srinivas, et al.
(författare)
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MiRNA expression in urothelial carcinomas: Important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31.
- 2009
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124, s. 2236-2242
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Tidskriftsartikel (refereegranskat)abstract
- We analyzed 34 cases of urothelial carcinomas by miRNA, mRNA and genomic profiling. Unsupervised hierarchical clustering using expression information for 300 miRNAs produced 3 major clusters of tumors corresponding to Ta, T1 and T2-T3 tumors, respectively. A subsequent SAM analysis identified 51 miRNAs that discriminated the 3 pathological subtypes. A score based on the expression levels of the 51 miRNAs, identified muscle invasive tumors with high precision and sensitivity. MiRNAs showing high expression in muscle invasive tumors included miR-222 and miR-125b and in Ta tumors miR-10a. A miRNA signature for FGFR3 mutated cases was also identified with miR-7 as an important member. MiR-31, located in 9p21, was found to be homozygously deleted in 3 cases and miR-452 and miR-452* were shown to be over expressed in node positive tumors. In addition, these latter miRNAs were shown to be excellent prognostic markers for death by disease as outcome. The presented data shows that pathological subtypes of urothelial carcinoma show distinct miRNA gene expression signatures. (c) 2009 Wiley-Liss, Inc.
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