| 1. |
- Björner, Sofie, et al.
(författare)
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Epithelial and Stromal MicroRNA Signatures of Columnar Cell Hyperplasia Linking Let-7c to Precancerous and Cancerous Breast Cancer Cell Proliferation
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:8
-
Tidskriftsartikel (refereegranskat)abstract
- Columnar cell hyperplasia (CCH) is the earliest histologically identifiable breast lesion linked to cancer progression and is characterized by increased proliferation, decreased apoptosis and elevated oestrogen receptor alpha (ER alpha) expression. The mechanisms underlying the initiation of these lesions have not been clarified but might involve early and fundamental changes in cancer progression. MiRNAs are key regulators of several biological processes, acting by influencing the post-transcriptional regulation of numerous targets, thus making miRNAs potential candidates in cancer initiation. Here we have defined novel epithelial as well as stromal miRNA signatures from columnar cell hyperplasia lesions compared to normal terminal duct lobular units by using microdissection and miRNA microarrays. Let-7c were among the identified downregulated epithelial miRNAs and its functions were delineated in unique CCH derived cells and breast cancer cell line MCF-7 suggesting anti-proliferative traits potentially due to effects on Myb and ER alpha. MiR-132 was upregulated in the stroma surrounding CCH compared to stoma surrounding normal terminal duct lobular units (TDLUs), and overexpression of miR-132 in immortalized fibroblasts and in fibroblasts co-cultured with epithelial CCH cells caused substantial expression changes of genes involved in metabolism, DNA damage and cell motility. The miRNA signatures identified in CCH indicate early changes in the epithelial and stromal compartment of CCH and could represent early key alterations in breast cancer progression that potentially could be targeted in novel prevention or treatment schedules.
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| 2. |
- Ekelund Axelson, Lena, et al.
(författare)
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Branschbeskrivning Trädgård : område hortikultur, utemiljö och fritidsodling
- 2012
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Det finns ett stort behov av att få kunskap om trädgårdsbranschens omfattning och betydelse.Här innefattas hortikulturell primärproduktion, utemiljöbranschen och fritidsodlingen. Branschen beskrivs bland annat i termer av arealer, antal företag, värdet i primärproduktionsledet, värdet i slutkonsumentledet, antal helårsanställda, antal säsongsanställda, forskningsvolym och utbildningsplatser. Hortikultur, trädgårdsodling karaktäriseras av ett stort antal trädgårdsväxtslag vilka intensivodlas till föda, för medicinskt eller industriellt bruk eller för estetisk användning i trädgård, park eller landskap (www.ne.se) och är också den interdisciplinära vetenskapliga plattform som är en nödvändig förutsättning för en kunskapsbaserad utveckling i trädgårdsbranschen. Den samlade produktionen av varor och tjänster inom trädgårdsbranschen, dvs. hortikulturell primärproduktion och utemiljötjänster, bedöms omfatta ca 30 miljarder kronor, fördelat på ca 7 miljarder i hortikulturell produktion av potatis, frukt, bär, grönsaker, svamp, prydnadsväxter och plantskoleväxter och ca 22 miljarder kronor av utemiljötjänster. Av värdet på hortikulturell primärproduktion, den första delen av trädgårdsbranschen, utgör ätliga produkter ungefär 70 % och prydnadsväxter samt småplantor/sticklingar 30 %. 70 % är fältodlade produkter och 30 % växthusodlade. Denna produktion sker på ca 50 000 hektar och sysselsätter motsvarande runt 8000 årsverken. Produktionen sker i ca 6000 företag. Ungefär 12 % av företagen har växthusproduktion och 90 % av antalet företag är inriktade på ätliga produkter. Trenden är att antalet företag minskar samtidigt som företagen blir allt större. Det finns samtidigt också små företag som i huvudsak odlar för den lokala marknaden. Södra Sverige och då framför allt Skåne, dominerar för flertalet produktionsinriktningar. Försäljningsvärdet i odlarledet av svensk produktion av kruk- och utplanteringsväxter, snittblommor, plantskoleväxter och liknande uppgick år 2010 till 1,6 miljarder kr. Importvärdet av växter var samtidigt ungefär 2,1 miljarder kr. Om man försöker basera konsumtionen på inhemsk produktion och import uppstår problem eftersom statistiken inte är jämförbar. Hushållens inköp av växter uppgick till ungefär 11 miljarder kr 2010. Utöver detta tillkommer en konsumtion utanför hushållen, exempelvis inköp till offentliga planteringar. Hushållens konsumtionsutgifter uppgick 2010 till knappt 19 miljarder kr för grönsaker och 14 miljarder för frukt. Enligt ett annat beräkningssätt uppgick hushållens totala inköp av frukt, grönsaker och potatis till drygt 31 miljarder kr. Av dessa utgjordes 12 miljarder av färska grönsaker och potatis och drygt 10 miljarder av färsk frukt medan resterande 9 miljarder bestod av bearbetade produkter. Utöver detta tillkommer den offentliga konsumtionen i måltider i skolor, dagis, vårdinrättningar och liknande. Den andra delen av trädgårdsbranschen, utemiljöbranschen, är det professionella arbetet med utemiljöer i form av parker, bostadsgårdar, kyrkogårdar, trädgårdar, golfbanor, dagistomter, sjukhusområden etc. Ett utmärkande drag är den starka uppsplittringen på många olika förvaltare och huvudmän. För många av dem är utemiljöverksamheten inte en huvudsyssla utan relativt marginell i förhållande till exempelvis fastighetsförvaltning i stort. Det samlade uppskattade värdet är minst 22 miljarder kronor och sysselsätter ca 33 000 personer i helårsarbeten. Enligt utredningens beräkningar är den totala omslutningen för skötsel av utemiljöer ca 17 miljarder kr, resterande 5 miljarder kr är således det samlade värdet för planering, projektering och anläggningsarbeten. Underlaget för den statistik som redovisas i denna sammanställning är inte fullständig, men bedömningen är att storleksordningarna bör stämma relativt väl. Utemiljötjänster som upplevelsetjänster (turism) och ”verksamhet inom trädgård och hälsa” har potentialen att med hortikulturen som grund omsätta mycket stora värden. Fritidsodlingen är den tredje stora delen av Trädgårdsbranschen. Det finns drygt 2,6 miljoner trädgårdar i Sverige, varav mer än 1,9 miljoner småhus, 675 000 fritidshus och över 50 000 kolonilotter. SCB uppskattar värdet av hushållens inköp av produkter för trädgården till 12,9 miljarder kr (2010). Ett fåtal universitet, institut och organisationer bedriver forskning inom hortikultur. SLU har både utbildningar, undervisning och forskning inom detta område. Tillhörigheten till landsbygdsdepartementet understryker denna profil i en jämförelse med andra lärosäten. SIK och JTI är exempel på institutsorganisationer med forskning inom området. Bedömning och beräkningar visar att hortikulturella forskningsprojekt vid LTJ- fakulteten, SLU i Alnarp i Skåne omsatte ca 22 miljoner kr (2011), såväl statsanslag som externa medel. Det utgör ca 20 % av fakultetens forskningsprojektsmedel och ca 3 % av bokförda forskningsprojektmedel inom SLU. Forskningen inom hortikultur motsvarar knappt 3 promille av branschens totala omsättning i primärproduktionsledet (ca 20 miljoner av 7 miljarder kr. Även forskning inom utemiljö bedrivs i första hand i Alnarp, men äve vis SLU iUltuna. Omfattningen var 2011 ca 32,5 miljoner kr varav hälften externa medel och hälften fakultetsmedel, vilket motsvarar 1,5 promille av utemiljöbranschens omsättning (ca 32 miljoner av 22 miljarder kr). Vid SLU finns ett flertal unika utbildningar inom hortikultur och inom utemiljöbranschen. De utbildningar som har fokus på hortikultur/trädgård är främst hortonom och trädgårdsingenjör. Andra utbildningar vid SLU som också har beröringspunkter med hortikultur är en kandidatutbildning inriktning livsmedel samt agronom utbildningen med inriktningarna landsbygdsutveckling och livsmedel i Ultuna. Landskapsarkitekter utbildas både i Uppsala och i Alnarp, landskapsingenjörer enbart i Alnarp. Om utbildningsvolymen motsvarar behovet har i dagsläget inte kunnat bedömas. Antalet utbildningsplatser på naturbruksskolor YH – utbildningar är däremot för låg. Antalet elever i årskurs 2 som har valt inriktning Trädgård på naturbruksprogrammet är 77 stycken i hela landet (våren 2012), en minskning med mer än hälften jämfört med år 2007. Elva naturbruksgymnasier har elever i årskurs 2 som valt inriktningen Trädgård. Några av skolorna har endast ett fåtal elever med denna inriktning. En konsekvens blir att antalet skolor som kan erbjuda inriktningen Trädgård inom gymnasieprogrammet kommer att minska. Yrkesvux är en nationell tidsbegränsad satsning på yrkesinriktad vuxenutbildning och en viktig rekryteringsbas för trädgårdsnäringen.
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| 3. |
- Glimelius, Bengt, et al.
(författare)
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U-CAN : a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.
- 2018
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Ingår i: Acta Oncologica. - : Taylor & Francis. - 0284-186X .- 1651-226X. ; 57:2, s. 187-194
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.
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| 4. |
- Lehn, Sophie, et al.
(författare)
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Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response
- 2014
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Ingår i: Bmc Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. Methods: YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. Results: In the ER+ (Estrogen Receptor a positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER-(Estrogen Receptor a negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p < 0.001) which includes low proliferating tumours of lower grade, usually associated with a good prognosis. This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies, such as tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Conclusions: Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation.
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| 5. |
- Agarwal, Prasoon
(författare)
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Regulation of Gene Expression in Multiple Myeloma Cells and Normal Fibroblasts : Integrative Bioinformatic and Experimental Approaches
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The work presented in this thesis applies integrative genomic and experimental approaches to investigate mechanisms involved in regulation of gene expression in the context of disease and normal cell biology.In papers I and II, we have explored the role of epigenetic regulation of gene expression in multiple myeloma (MM). By using a bioinformatic approach we identified the Polycomb repressive complex 2 (PRC2) to be a common denominator for the underexpressed gene signature in MM. By using inhibitors of the PRC2 we showed an activation of the genes silenced by H3K27me3 and a reduction in the tumor load and increased overall survival in the in vivo 5TMM model. Using ChIP-sequencing we defined the distribution of H3K27me3 and H3K4me3 marks in MM patients cells. In an integrated bioinformatic approach, the H3K27me3-associated genes significantly correlated to under-expression in patients with less favorable survival. Thus, our data indicates the presence of a common under-expressed gene profile and provides a rationale for implementing new therapies focusing on epigenetic alterations in MM.In paper III we address the existence of a small cell population in MM presenting with differential tumorigenic properties in the 5T33MM murine model. We report that the predominant population of CD138+ cells had higher engraftment potential, higher clonogenic growth, whereas the CD138- MM cells presented with less mature phenotype and higher drug resistance. Our findings suggest that while designing treatment regimes for MM, both the cellpopulations must be targeted.In paper IV we have studied the general mechanism of differential gene expression regulation by CGGBP1 in response to growth signals in normal human fibroblasts. We found that CGGBP1 binding affects global gene expression by RNA Polymerase II. This is mediated by Alu RNAdependentinhibition of RNA Polymerase II. In presence of growth signals CGGBP1 is retained in the nuclei and exhibits enhanced Alu binding thus inhibiting RNA Polymerase III binding on Alus. Hence we suggest a mechanism by which CGGBP1 orchestrates Alu RNA-mediated regulation of RNA Polymerase II. This thesis provides new insights for using integrative bioinformatic approaches to decipher gene expression regulation mechanisms in MM and in normal cells.
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| 6. |
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| 7. |
- Axelson, Håkan
(författare)
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Eyeing tumorigenesis: Notch signaling and epigenetic silencing of Rb in Drosophila.
- 2006
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Ingår i: BioEssays. - : Wiley. - 0265-9247 .- 1521-1878. ; 28:7, s. 692-695
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Tidskriftsartikel (refereegranskat)abstract
- Notch signaling plays an essential role in the processes of embryogenesis and cellular differentiation, and it is believed that the oncogenic effects of dysregulated Notch signaling are an anomalous reflection of the normal functions of this cascade. Nonetheless, the cellular events associated with oncogenic Notch signaling have thus far remained elusive. In a recent report, Ferres-Marco et al.((1)) described how they used the Drosphila eye as a model system and found that elevated Notch signaling in combination with activation of components of the Polycomb complex of transcriptional repressors led to metastatic growth of tumors through epigenetic silencing of the Rbf gene. Rbf is the Drosophila homologue of the retinoblastoma tumor-suppressor gene (Rb), thus it represents a novel link between Notch signaling, tumor growth and metastasis.
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| 8. |
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| 9. |
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| 10. |
- Axelson, Håkan, et al.
(författare)
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Renal stem cells and their implications for kidney cancer.
- 2013
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 23:1, s. 56-61
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Forskningsöversikt (refereegranskat)abstract
- The renal cell carcinomas (RCC) denote a diverse set of neoplasias with unique genetic and histological features. The RCCs emanate from the renal tubule, a highly heterogeneous epithelial structure, and depending on which cell is malignified the resulting cancer displays unique characteristics. Notwithstanding this, the cells of origin for the RCC forms are far from established, and only inferred by the accumulated weight of marker similarities, not always providing an unequivocal picture. The tubular epithelium is normally mitotically quiescent, but demonstrates a considerable regenerative capacity upon renal injury. Recently the hypothesis that regeneration is driven by adult stem cells has been added experimental support, providing further complexity to the issue of renal carcinogenesis. Whether these cells are linked to RCC is an open question. In the present review we therefore present the prevailing theories regarding kidney regeneration, since a better understanding of this process might be of relevance when considering the different malignancies that arise from kidney epithelium. Our own results show that papillary renal cell carcinoma displays considerable similarities to proximal tubular progenitor cells and we suggest that this tumor form may develop in a multi-step fashion via benign renal adenomas. The putative connection between renal stem cells and carcinomas is, however, not clarified, since the current understanding of the renal stem cell system is not complete. It is clear that the efforts to isolate and characterize renal progenitor/stem cells suffer from numerous technical limitations and that it remains likely that the kidney harbors different stem cell pools with a restricted differentiation potential.
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| 11. |
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| 12. |
- Axelson, Hans W, et al.
(författare)
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Microdialysis and electromyography of experimental muscle fatigue in healthy volunteers and patients with mitochondrial myopathy
- 2002
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Ingår i: Muscle and Nerve. - : Wiley. - 0148-639X .- 1097-4598. ; 26:4, s. 520-526
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Tidskriftsartikel (refereegranskat)abstract
- Consecutive 60-min microdialysis samples were taken from the tibial anterior muscle in 11 healthy subjects and 4 patients with mitochondrial myopathy before (2-3 samples) and after (3-4 samples, 2 controls and 1 patient excluded) sustained isometric foot dorsiflexions. Before exercise, mean concentrations of lactate, pyruvate, hypoxanthine, urate, aspartate, and glutamate did not significantly differ between controls and patients. After exercise, the controls showed significantly increased concentrations of lactate, pyruvate, and urate, decreased hypoxanthine, and no change in aspartate and glutamate. Similar findings were observed in the patients. Plasma lactate was unchanged. Exercise-induced increase in integrated electromyogram amplitude and rated subjective fatigue were correlated to increased post-exercise lactate concentrations, with no obvious difference between the groups. Microdialysis of skeletal muscle allows the detection and monitoring of biochemical changes in the interstitial space. With the exercise protocol used, however, it was not possible to demonstrate any biochemical difference between healthy controls and patients with mitochondrial myopathy.
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| 13. |
- Axelson, Hans W., et al.
(författare)
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No benefit of treatment with cyclophosphamide and autologous blood stem cell transplantation in multifocal motor neuropathy
- 2008
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Ingår i: Acta Neurologica Scandinavica. - : Hindawi Limited. - 0001-6314 .- 1600-0404. ; 117:6, s. 432-434
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Tidskriftsartikel (refereegranskat)abstract
- Introduction - Patients with multifocal motor neuropathy (MMN) usually respond to intravenous immunoglobulin (IVIG), but because of the short-lasting effect the treatment must be given repeatedly. Remission after treatment with high-dose cyclophosphamide has recently been reported in one patient refractory to IVIG. Case report - Here we report on a patient who responded to IVIG, but temporarily deteriorated dramatically after treatment with high-dose cyclophosphamide and autologous blood stem cell transplantation. Today the situation is the same as before the treatment with cyclophosphamide and blood stem cell transplantation, i.e. IVIG is given every 4 weeks. Conclusion - Our patient did not benefit from the treatment with high-dose cyclophosphamide and autologous blood stem cell transplantation. The effect of treatment with high-dose cyclophosphamide in MMN seems to be difficult to predict and that should be paid attention to if this type of treatment is considered.
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| 14. |
- Axelson, Hans W, et al.
(författare)
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Successful repeated treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP
- 2009
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Ingår i: BMJ Case Reports. - : BMJ. - 1757-790X.
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Tidskriftsartikel (refereegranskat)abstract
- Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterised by the occurrence of symmetrical weakness and sensory impairment in arms and legs. The course is relapsing or chronic and progressing. CIDP is considered to be an autoimmune disease, which is supported by the beneficial response to immunomodulating therapies in most patients. We report on a patient with CIDP who has been in remission for more than 3 years after treatment with high dose cyclophosphamide and autologous blood stem cell transplantation in CIDP on two occasions.
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| 15. |
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| 16. |
- Berg, Tracy J., et al.
(författare)
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The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 2
- 2021
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:8, s. 2101-2115
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Tidskriftsartikel (refereegranskat)abstract
- The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naive brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. Significance: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.
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| 17. |
- Boström, Anna-Karin, et al.
(författare)
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Effects of TGF-β signaling in Clear Cell Renal Cell Carcinoma cells.
- 2013
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 435:1, s. 126-133
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Tidskriftsartikel (refereegranskat)abstract
- Clear cell renal cell carcinoma (ccRCC) is by far the most common type of kidney cancer and is characterized by loss of the tumor suppressor gene von Hippel-Lindau (VHL). ccRCC patients with metastatic disease has poor prognosis and today's therapy is insufficient. The cytokine Transforming Growth Factor-β (TGF-β) has been extensively studied in tumor biology and is believed to serve a variety of functions in tumor progression. We have previously shown that inhibition of NOTCH signaling causes a reduced migratory and invasive capacity of ccRCC cells, at least partly by a cross-talk with the TGF-β pathway. In the present study we aimed to further clarify the role of TGF-β signaling in ccRCC. We investigated the effects of TGF-β pathway modulation and showed that TGF-β inhibition attenuates the invasive capacity of ccRCC cells. By performing expression profiling we obtained a gene signature of the TGF-β induced response in ccRCC cells. The expression analyses revealed an extensive overlap between the TGF-β response and genes regulated by the hypoxia inducible factor (HIF). The link between the hypoxic and the TGF-β pathways was further corroborated by functional experiments, which demonstrated that TGF-β pathway activity was attenuated upon reintroduction of functional VHL in ccRCC.
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| 18. |
- Boström, Anna-Karin, et al.
(författare)
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Sarcomatoid conversion of clear cell renal cell carcinoma in relation to epithelial-to-mesenchymal transition.
- 2012
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Ingår i: Human Pathology. - : Elsevier BV. - 1532-8392 .- 0046-8177. ; 43, s. 708-719
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 8% of clear cell renal cell carcinoma cases contain regions of radically different morphology, demonstrating a mesenchymal appearance histologically resembling sarcomas. These biphasic neoplasms are called sarcomatoid clear cell renal cell carcinoma. Patients diagnosed with sarcomatoid clear cell renal cell carcinoma face a considerably worse prognosis due to an increased propensity for metastasis. In the present study we investigate whether the sarcomatoid conversion of clear cell renal cell carcinoma could be interpreted as linked to the process of epithelial-mesenchymal transition. Using 6 biphasic clear cell renal cell carcinoma cases we show that sarcomatoid clear cell renal cell carcinoma shares characteristic markers associated with loss of von Hippel-Lindau tumor suppressor with conventional clear cell renal cell carcinoma and also exhibits a markedly higher proliferative index. Furthermore the sarcomatoid elements demonstrate an enhanced expression of epithelial-mesenchymal transition related mesenchymal markers as compared with the clear cell renal cell carcinoma counterparts. We further selected a representative case, clinically demonstrating direct overgrowth of the sarcomatoid component into the liver and colon, for extended immunohistochemical characterization, resulting in a further set of positive and negative epithelial-mesenchymal transition markers as well as pronounced transforming growth factor β positivity, indicating that sarcomatoid clear cell renal cell carcinoma may be associated to epithelial-mesenchymal transition. Transforming growth factor β1 exposure of in vitro cultured primary clear cell renal cell carcinoma cells resulted in cells adopting a mesenchymal morphology similar to sarcomatoid clear cell renal cell carcinoma. Corresponding changes in RNA levels for key epithelial-mesenchymal transition markers were also seen. We therefore suggest that sarcomatoid clear cell renal cell carcinoma morphologically and immunohistochemically may represent a completed epithelial-mesenchymal transition and that transforming growth factor β1 could be an important driving force during the sarcomatoid transdifferentiation of clear cell renal cell carcinoma.
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| 19. |
- Braekeveldt, Noémie, et al.
(författare)
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Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
- 2018
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Ingår i: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
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Tidskriftsartikel (refereegranskat)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
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| 20. |
- de Alwis, Roger, et al.
(författare)
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Identification and validation of NFIA as a novel prognostic marker in renal cell carcinoma
- 2023
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Ingår i: The journal of pathology. Clinical research. - : John Wiley & Sons. - 2056-4538. ; 9:4, s. 261-272
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Tidskriftsartikel (refereegranskat)abstract
- Prognostic tools are an essential component of the clinical management of patients with renal cell carcinoma (RCC). Although tumour stage and grade can provide important information, they fail to consider patient- and tumour-specific biology. In this study, we set out to find a novel molecular marker of RCC by using hepatocyte nuclear factor 4A (HNF4A), a transcription factor implicated in RCC progression and malignancy, as a blueprint. Through transcriptomic analyses, we show that the nuclear factor I A (NFIA)-driven transcription network is active in primary RCC and that higher levels of NFIA confer a survival benefit. We validate our findings using immunohistochemical staining and analysis of a 363-patient tissue microarray (TMA), showing for the first time that NFIA can independently predict poor cancer-specific survival in clear cell RCC (ccRCC) patients (hazard ratio = 0.46, 95% CI = 0.24–0.85, p value = 0.014). Furthermore, we confirm the association of HNF4A with higher grades and stages in ccRCC in our TMA cohort. We present novel data that show HNF4A protein expression does not confer favourable prognosis in papillary RCC, confirming our survival analysis with publicly available HNF4A RNA expression data. Further work is required to elucidate the functional role of NFIA in RCC as well as the testing of these markers on patient material from diverse multi-centre cohorts, to establish their value for the prognostication of RCC.
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| 21. |
- De Alwis, Roger, et al.
(författare)
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Size-based isolation and detection of renal carcinoma cells from whole blood
- 2022
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Ingår i: Molecular and clinical oncology. - : Spandidos Publications. - 2049-9450 .- 2049-9469. ; 16:5
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Tidskriftsartikel (refereegranskat)abstract
- Renal cell carcinoma (RCC) is a tumour type with an indolent growth pattern and rather vague symptoms. The present study developed a platform for liquid biopsy of RCC based upon the isolation of circulating tumour cells (CTCs). Founded on the observation that RCC tumour cells are considerably larger than leucocytes, the present study employed a microfluidics-based system for isolation of RCC CTCs from whole blood. Using this system, it was revealed that 66% of spiked-in RCC tumour cells could be retrieved using this approach. Furthermore, it was demonstrated that these cells could be molecularly detected with digital PCR using RCC-specific genes down to one tumour cell, whilst avoiding detection in samples lacking tumour cells. Finally, subtype specific transcripts were identified to distinguish the different subtypes of RCC, which were then validated in patient tumours. The present study established a novel workflow for the isolation of RCC CTCs from whole blood, with the potential to detect these cells irrespective of subtype.
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| 22. |
- Edsjö, Anders, et al.
(författare)
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Differences in early and late responses between neurotrophin-stimulated trkA- and trkC-transfected SH-SY5Y neuroblastoma cells
- 2001
-
Ingår i: Cell Growth & Differentiation. - 1044-9523. ; 12:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Despite their sympathetic neuroblast origin, highly malignant neuroblastoma tumors and derived cell lines have no or low expression of the neurotrophin receptor genes, trkA and trkC. Expression of exogenous trkA in neuroblastoma cells restores their ability to differentiate in response to nerve growth factor (NGF). Here we show that stable expression of trkC in SH-SY5Y neuroblastoma cells resulted in morphological and biochemical differentiation upon treatment with neurotrophin-3 (NT-3). To some extent, trkA- and trkC-transfected SH-SY5Y (SH-SY5Y/trkA and SH-SY5Y/trkC) cells resembled one another in terms of early signaling events and neuronal marker gene expression, but important differences were observed. Although induced Erk 1/2 and Akt/PKB phosphorylation was stronger in NT-3-stimulated SH-Y5Y/trkC cells, activation of the immediate-early genes tested was more prominent in NGF-treated SH-SY5Y/ trkA cells. In particular, c-fos was not induced in the SH-SY5Y/trkC cells. There were also phenotypic differences. The concentrations of norepinephrine, the major sympathetic neurotransmitter, and growth cone-located synaptophysin, a neurosecretory granule protein, were increased in NGF-treated SH-SY5Y/trkA but not in NT-3-treated SH-SY5Y/trkC cells. Our data suggest that NT-3/p145trkC and NGF/p140trkA signaling differ in some aspects in neuroblasoma cells, and that this may explain the phenotypic differences seen in the long-term neurotrophin-treated cells.
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| 23. |
- Ekelund Axelson, Lena, et al.
(författare)
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How does Modernity Taste? Tomatoes in the Societal Change from Modernity to Late Modernity
- 2011
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Ingår i: Culture Unbound. Journal of Current Cultural Research. - : Linkoping University Electronic Press. - 2000-1525. ; 3, s. 439-454
-
Tidskriftsartikel (refereegranskat)abstract
- The aim of this article is to discuss how changes in tomato food regulation, production and consumption, can be seen as part of a broader societal change from Modernity to Late Modernity. Based on evidence from the Swedish and European food systems we demonstrate how a system, which has been successfully managing development in food production for several decades by stressing rationality, homogeneity and standardization, is being challenged by a system that has adapted to, and also exploited, consumer preferences such as heterogeneity, diversity and authenticity. The article shows how tomato growers develop differentiation strategies, adapting to and cultivating this new consumer interest, and how authorities responsible for regulations of trade and quality struggle to adapt to the new situation. As the products become more diversified, taste becomes an important issue and is associated with a view that traditional and natural are superior to standardized and homogeneous products. The analytical approaches for the discussion come from two study areas: ethnological, and marketing and policy perspective, thus showing a multidimensional picture of a changing food system.
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| 24. |
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| 25. |
- Fritz, Helena, et al.
(författare)
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The Axl-Regulating Tumor Suppressor miR-34a Is Increased in ccRCC but Does Not Correlate with Axl mRNA or Axl Protein Levels.
- 2015
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- High expression of the receptor tyrosine kinase Axl is associated with poor prognosis in patients with Renal Cell Carcinoma (RCC), the most common malignancy of the kidney. The miR-34a has been shown to directly regulate Axl in cancer cells. The miR-34a is a mediator of p53-dependent tumor suppression, and low expression of miR-34a has been associated with worse prognosis in several cancers. Our aim was to elucidate whether miR-34a or the other members of the miR-34 family (miR-34b/c) regulate Axl in RCC.
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| 26. |
- Fritz, Helena, et al.
(författare)
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The miR(21/10b) ratio as a prognostic marker in clear cell renal cell carcinoma
- 2014
-
Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:10, s. 1758-1765
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common type of cancer in the adult kidney, and the prognosis of metastatic ccRCC remains poor with high mortality. In ccRCC, microRNAs (miRs) differentially expressed in tumour tissue have been identified and have been proposed to predict prognosis. The purpose of this study was to evaluate candidate miR markers identified from analysis of The Cancer Genome Atlas (TCGA) datasets in a large RCC cohort and to elucidate whether a ratio of miRs provided additional prognostic information. Experimental design: Deep sequencing data from TCGA datasets were analysed using biostatistical methods to identify candidate miRs that correlate with factors such as survival and stage of disease. Candidate miRs were analysed by reverse transcription and quantitative polymerase chain reaction (RT-qPCR) in a cohort of 198 RCC tumours (ccRCC, n = 152) and 50 normal kidney samples. Results: Four candidate miRs (miR-10b, miR-21, miR-101 and miR-223) were selected from the TCGA analysis and analysed in our cohort. Of these, miR-21 and miR-10b were differentially expressed in RCC subtypes and in ccRCC nuclear grades. Individually, the two miRs demonstrated a non-significant trend to correlate with survival. Importantly, the ratio of miR-21/miR10b (miR(21/10b),) correlated significantly with disease severity and survival, a high miR(21/10b) being associated with poor prognosis (P = 0.0095). In particular, the miR(21/10b) was found to be an independent prognostic factor in metastasis-free patients (P = 0.016; confidence interval (CI) 1.201-5.736). Conclusions: We have shown that the miR(21/10b) ratio is an independent prognostic factor for M0 ccRCC patients, which could be useful to identify high-risk M0 patients who could benefit from increased surveillance.
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| 27. |
- Gestblom, C, et al.
(författare)
-
The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas
- 1999
-
Ingår i: Laboratory Investigation. - 1530-0307 .- 0023-6837. ; 79, s. 67-
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Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is derived from the sympathetic nervous system and might arise as a result of impaired differentiation, retaining the neuroblastic tumor cells in the cell cycle. Thus, to understand the genesis of neuroblastoma, the study of mechanisms and genes regulating normal sympathetic development is of potential interest. The basic helix-loop-helix transcription factors human achaete-scute homolog-1 (HASH-1) and deciduum, heart, autonomic nervous system, and neural crest derivatives (dHAND) are expressed in the sympathetic nervous system of embryonic mice and chicken, with undetectable postnatal expression. By in situ hybridization technique, we show that dHAND was expressed by human sympathetic neuronal and extra-adrenal chromaffin cells throughout embryonic and fetal life, and was initially expressed in immature chromaffin cells of the adrenal gland. With overt chromaffin differentiation, dHAND was down-regulated. HASH-1, in contrast, was expressed in human sympathetic cells only at the earliest embryonic ages examined (Week 6.5 to 7). All examined neuroblastoma specimens (25/25) and all cell lines (5/5) had detectable dHAND mRNA levels. HASH-1 expression in tumor specimens was more restricted, although all cell lines (5/5) were HASH-1-positive. These results show that neuroblastoma tumors have retained embryonic features, suggesting that many neuroblastomas are blocked at an early stage of normal development when HASH-1 and dHAND are expressed. dHAND also appears to be a reliable and potentially useful clinical diagnostic marker for neuroblastoma, because expression was not dependent on tumor or differentiation stages and other pediatric tumors were dHAND-negative.
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| 28. |
- Gustafsson, Anna, et al.
(författare)
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Gas6 and the receptor tyrosine kinase Axl in clear cell renal cell carcinoma.
- 2009
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:10, s. e7575-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The molecular biology of renal cell carcinoma (RCC) is complex and not fully understood. We have recently found that the expression of the receptor tyrosine kinase Axl in the RCC tumors independently correlates with survival of the patients. PRINCIPAL FINDINGS: Here, we have investigated the role of Axl and its ligand Gas6, the vitamin-K dependent protein product of the growth arrest-specific gene 6, in clear cell RCC (ccRCC) derived cells. The Axl protein was highly expressed in ccRCC cells deficient in functional von Hippel-Lindau (VHL) protein, a tumor suppressor gene often inactivated in ccRCC. VHL reconstituted cells expressed decreased levels of Axl protein, but not Axl mRNA, suggesting VHL to regulate Axl expression. Gas6-mediated activation of Axl in ccRCC cells resulted in Axl phosphorylation, receptor down-regulation, decreased cell-viability and migratory capacity. No effects of the Gas6/Axl system could be detected on invasion. Moreover, in ccRCC tumor tissues, Axl was phosphorylated and Gas6 gamma-carboxylated, suggesting these molecules to be active in vivo. SIGNIFICANCE: These results provide novel information regarding the complex function of the Gas6/Axl system in ccRCC.
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| 29. |
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| 30. |
- Hansson, Anders, et al.
(författare)
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The Lim-only protein LMO2 acts as a positive regulator of erythroid differentiation
- 2007
-
Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 364:3, s. 675-681
-
Tidskriftsartikel (refereegranskat)abstract
- LMO2, a member of the LIM-only protein family, is essential for the regulation of hematopoietic stem cells and formation of erythroid cells. It is found in a transcriptional complex comprising LMO2, TAL1, E47, GATA-1, and LDB1 which regulates erythroid genes. While TAL1 has been shown to induce erythroid differentiation, LMO2 appears to suppress fetal erythropoiesis. In addition to LMO2, the closely related LMO4 gene is expressed in hematopoietic cells, but has unknown functions. Here we demonstrate that LMO2 and LMO4 are expressed at the same level in erythroid colonies from mouse bone marrow, implying a function in erythroid differentiation. However, while LMO2 induced erythroid differentiation, LMO4 had no such effect. Interestingly, both LMO2 and TAL1 were able to partially suppress myeloid differentiation, implying that they activate erythroid differentiation in uncommitted bone marrow progenitors. Both LMO2 and LMO4 interacted strongly to LDB1, which was required for their localization to the nucleus. © 2007 Elsevier Inc. All rights reserved.
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| 31. |
- Hansson, Jennifer, et al.
(författare)
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Evidence for a morphologically distinct and functionally robust cell type in the proximal tubules of human kidney
- 2014
-
Ingår i: Human Pathology. - : Elsevier BV. - 0046-8177 .- 1532-8392. ; 45:2, s. 382-393
-
Tidskriftsartikel (refereegranskat)abstract
- Acute tubular necrosis (ATN), elicited by ischemia and/or toxicity, is a potentially life-threatening condition. Histologically, ATN corresponds to necrosis and detachment of renal tubular epithelial cells. However, the tubules possess a considerable regenerative capacity and may be restored. We have previously identified a scattered population of progenitor-like cells within the proximal tubules, sharing marker expression with the parietal epithelial cells of Bowman's capsule as well as with renal tubules regenerating after ATN. In the present analysis, we use transmission electron microscopy, immunoelectron microscopy and immunofluorescence of human kidney cortex to further explore these cells. We demonstrate that the cells are smaller and have drastically fewer mitochondria than the surrounding proximal tubule cells. They also display strong expression of several structural proteins such as vimentin, collagen-7A1 and the tight junction protein claudin-1. To functionally assess these cells, we also developed a novel human kidney explant model of ATN demonstrating that the cells are more resilient to injury than the surrounding proximal tubular cells. Taken together the results suggest a novel robust cell type with a contrasting biological role to that of the bulk of proximal tubular epithelium.
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| 32. |
- Hansson, Jennifer, et al.
(författare)
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Overexpression of functional SLC6A3 in clear cell renal cell carcinoma
- 2017
-
Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:8, s. 2105-2115
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Renal cell carcinoma (RCC) is derived from a tissue with a remarkable capacity for vectorial transport. We therefore performed an unbiased exploration of transporter proteins in normal kidney and kidney cancer in order to discover novel clinical targets.EXPERIMENTAL DESIGN: Using the TCGA database we investigated differences in membrane transporter expression in ccRCC and normal kidney. We identified the dopamine transporter SLC6A3 as a specific biomarker for ccRCC. To investigate the functionality of SLC6A3 we used a [3H]-dopamine uptake assay on ccRCC cells. We further explored the effect of HIF proteins on SLC6A3 expression by introducing siRNA in ccRCC cells and by hypoxic treatment of non-malignant cells.RESULTS: We show that ccRCC express very high transcript levels of SLC6A3 in contrast to normal kidney tissue and other tumor types, which do not express appreciable levels of this transporter. Importantly, we demonstrate that the elevated expression of SLC6A3 in ccRCC cells is associated with specific uptake of dopamine. By targeting the expression of HIF-1α and HIF-2α we could show that SLC6A3 expression is primarily influenced by HIF-2α, and that hypoxia can induce SLC6A3 expression in normal renal cells.CONCLUSIONS: We conclude that the dopamine transporter SLC6A3 constitute a novel biomarker that is highly specific for ccRCC. We further postulate that the protein can be exploited for diagnostic or therapeutic purposes for detection or treatment of ccRCC.
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| 33. |
- Hansson, J, et al.
(författare)
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Species diversity regarding the presence of proximal tubular progenitor cells of the kidney
- 2016
-
Ingår i: European Journal of Histochemistry. - : PAGEPress Publications. - 2038-8306 .- 1121-760X. ; 60:1, s. 2567-2567
-
Tidskriftsartikel (refereegranskat)abstract
- The cellular source for tubular regeneration following kidney injury is a matter of dispute, with reports suggesting a stem or progenitor cells as the regeneration source while linage tracing studies in mice seemingly favor the classical theory, where regeneration is performed by randomly surviving cells. We, and others have previously described a scattered cell population localized to the tubules of human kidney, which increases in number following injury. Here we have characterized the species distribution of these proximal tubular progenitor cells (PTPCs) in kidney tissue from chimpanzee, pig, rat and mouse using a set of human PTPC markers. We detected PTPCs in chimpanzee and pig kidneys, but not in mouse tissue. Also, subjecting mice to the unilateral urethral obstruction model, caused clear signs of tubular injury, but failed to induce the PTPC phenotype in renal tubules.
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| 34. |
- Heath, Alicia K, et al.
(författare)
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Soft Drink and Juice Consumption and Renal Cell Carcinoma Incidence and Mortality in the European Prospective Investigation into Cancer and Nutrition
- 2021
-
Ingår i: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - : American Association for Cancer Research. - 1538-7755 .- 1055-9965. ; 30:6, s. 1270-1274
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Renal cell carcinoma (RCC) accounts for more than 80% of kidney cancers in adults, and obesity is a known risk factor. Regular consumption of sweetened beverages has been linked to obesity and several chronic diseases, including some types of cancer. It is uncertain whether soft drink and juice consumption is associated with risk of RCC. We investigated the associations of soft drink and juice consumption with RCC incidence and mortality in the European Prospective Investigation into Cancer and Nutrition (EPIC).METHODS: A total of 389,220 EPIC participants with median age of 52 years at recruitment (1991-2000) were included. Cox regression yielded adjusted HRs and 95% confidence intervals (CI) for RCC incidence and mortality in relation to intakes of juices and total, sugar-sweetened, and artificially sweetened soft drinks.RESULTS: A total of 888 incident RCCs and 356 RCC deaths were identified. In models including adjustment for body mass index and energy intake, there was no higher risk of incident RCC associated with consumption of juices (HR per 100 g/day increment = 1.03; 95% CI, 0.97-1.09), total soft drinks (HR = 1.01; 95% CI, 0.98-1.05), sugar-sweetened soft drinks (HR = 0.99; 95% CI, 0.94-1.05), or artificially sweetened soft drinks (HR = 1.02; 95% CI, 0.96-1.08). In these fully adjusted models, none of the beverages was associated with RCC mortality (HR, 95% CI per 100 g/day increment 1.06, 0.97-1.16; 1.03, 0.98-1.09; 0.97, 0.89-1.07; and 1.06, 0.99-1.14, respectively).CONCLUSIONS: Consumption of juices or soft drinks was not associated with RCC incidence or mortality after adjusting for obesity.IMPACT: Soft drink and juice intakes are unlikely to play an independent role in RCC development or mortality.
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| 35. |
- Hobro, Sture, et al.
(författare)
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Dialysis as a Novel Adjuvant Treatment for Malignant Cancers
- 2022
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 14:20
-
Forskningsöversikt (refereegranskat)abstract
- Cancer metabolism is characterized by an increased utilization of fermentable fuels, such as glucose and glutamine, which support cancer cell survival by increasing resistance to both oxidative stress and the inherent immune system in humans. Dialysis has the power to shift the patient from a state dependent on glucose and glutamine to a ketogenic condition (KC) combined with low glutamine levels—thereby forcing ATP production through the Krebs cycle. By the force of dialysis, the cancer cells will be deprived of their preferred fermentable fuels, disrupting major metabolic pathways important for the ability of the cancer cells to survive. Dialysis has the potential to reduce glucose levels below physiological levels, concurrently increase blood ketone body levels and reduce glutamine levels, which may further reinforce the impact of the KC. Importantly, ketones also induce epigenetic changes imposed by histone deacetylates (HDAC) activity (Class I and Class IIa) known to play an important role in cancer metabolism. Thus, dialysis could be an impactful and safe adjuvant treatment, sensitizing cancer cells to traditional cancer treatments (TCTs), potentially making these significantly more efficient.
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| 36. |
- Höglund, Mattias, et al.
(författare)
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The Lund taxonomy for bladder cancer classification – from gene expression clustering to cancer cell molecular phenotypes, and back again
- 2023
-
Ingår i: Journal of Pathology. - : Wiley. - 0022-3417 .- 1096-9896. ; 259:4, s. 369-375
-
Forskningsöversikt (refereegranskat)abstract
- Treatment of bladder cancer patients depends on precise diagnosis. Molecular subtyping by gene expression profiling may contribute substantially to subclassification of bladder cancer. Several classification systems have been proposed. Most of these base their classification on whole biopsy features, and molecular subtypes are therefore often defined by a combination of features from the cancer cells as well as infiltrating noncancer cells. This makes the link to what is seen at the cancer cell level unclear. The aim of the Lund taxonomy (LundTax) has been to align gene expression-level classification with immunohistochemical classification to identify cancer cell phenotypes independent of infiltration and proliferation. A systematic approach was used in which gene expression clusters were validated and adjusted by immunohistochemistry using markers expressed only by the cancer cells. This review provides a rationale for defining molecular subtypes and a step-by-step description of the development of the LundTax with motivations for each modification and extension. As the cancer cell phenotype defined by gene expression profiling corresponds with the immunohistochemistry of cancer cells, the LundTax represents a harmonization of the gene expression and immunohistochemical levels. Furthermore, the classification system is independent of pathological stage and is, thus, applicable to all urothelial carcinomas. A unified classification system relevant for both the molecular biologist and pathologist will facilitate systematization of current treatment practices, as well as the development of new treatments.
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| 37. |
- Johansson, Elinn, et al.
(författare)
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CD44 interacts with HIF-2α to modulate the hypoxic phenotype of perinecrotic and perivascular glioma cells
- 2017
-
Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:7, s. 1641-1653
-
Tidskriftsartikel (refereegranskat)abstract
- Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic phenotype of stem-like glioma cells is achieved by stabilization of HIF-2α through interaction with CD44, independently of oxygen.
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| 38. |
- Johansson, Elinn, et al.
(författare)
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Simultaneous targeted activation of Notch1 and Vhl-disruption in the kidney proximal epithelial tubular cells in mice
- 2016
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, representing approximately 75% of all renal neoplasms. ccRCC is known to be strongly associated with silencing of the von Hippel Lindau (VHL) tumor suppressor gene, yet VHL deficiency alone does not seem to be sufficient to drive the oncogenic transformation of normal renal epithelium and induce renal tumorigenesis. We, and others, have previously suggested that constitutive activation of the Notch signaling pathway, alongside with VHL loss, contribute to the oncogenic features of ccRCC. Here we report a prevailing hyperactivation of the Notch1 receptor in human ccRCC relative to the healthy counterpart. To explore the consequences of the elevated Notch1 signaling observed in ccRCC patient material, we made use of a conditional mouse model based on concurrent ectopic expression of constitutively active Notch1 (NICD1) and deletion of the Vhl gene. Histological examination of the kidneys of the conditional mice demonstrate the existence of nests of dysplastic cells with a clear cytoplasm as a consequence of lipid accumulation, thus displaying a one important hallmark of human ccRCC.
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| 39. |
- Johansson, Martin, et al.
(författare)
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Kidney cancer.
- 2013
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Ingår i: Seminars in Cancer Biology. - : Elsevier BV. - 1096-3650 .- 1044-579X. ; 23:1, s. 1-2
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Tidskriftsartikel (refereegranskat)
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| 40. |
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| 41. |
- Jögi, Annika, et al.
(författare)
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Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype.
- 2002
-
Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 99:10, s. 7021-7026
-
Tidskriftsartikel (refereegranskat)abstract
- Insufficient oxygen and nutrient supply often restrain solid tumor growth, and the hypoxia-inducible factors (HIF) 1 alpha and HIF-2 alpha are key transcription regulators of phenotypic adaptation to low oxygen levels. Moreover, mouse gene disruption studies have implicated HIF-2 alpha in embryonic regulation of tyrosine hydroxylase, a hallmark gene of the sympathetic nervous system. Neuroblastoma tumors originate from immature sympathetic cells, and therefore we investigated the effect of hypoxia on the differentiation status of human neuroblastoma cells. Hypoxia stabilized HIF-1 alpha and HIF-2 alpha proteins and activated the expression of known hypoxia-induced genes, such as vascular endothelial growth factor and tyrosine hydroxylase. These changes in gene expression also occurred in hypoxic regions of experimental neuroblastoma xenografts grown in mice. In contrast, hypoxia decreased the expression of several neuronal/neuroendocrine marker genes but induced genes expressed in neural crest sympathetic progenitors, for instance c-kit and Notch-1. Thus, hypoxia apparently causes dedifferentiation both in vitro and in vivo. These findings suggest a novel mechanism for selection of highly malignant tumor cells with stem-cell characteristics.
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| 42. |
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| 43. |
- Jögi, Annika, et al.
(författare)
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Modulation of Basic Helix-Loop-Helix Transcription Complex Formation by Id Proteins during Neuronal Differentiation.
- 2002
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 277:11, s. 9118-9126
-
Tidskriftsartikel (refereegranskat)abstract
- It is assumed that the Id helix-loop-helix (HLH) proteins act by associating with ubiquitously expressed basic HLH (bHLH) transcription factors, such as E47 and E2-2, which prevents these factors from forming functional hetero- or homodimeric DNA binding complexes. Several tissue-specific bHLH proteins, including HASH-1, dHAND, and HES-1, are important for development of the nervous system. Neuroblastoma tumors are derived from the sympathetic nervous system and exhibit neural crest features. In differentiating neuroblastoma cells, HASH-1 is down-regulated, and there is coincident up-regulation of the transcriptional repressor HES-1, which is known to bind the HASH-1 promoter. We found that the three Id proteins expressed in neuroblastoma cells (Id1, Id2, and Id3) were down-regulated during induced differentiation, indicating that Id proteins help keep the tumor cells in an undifferentiated state. Studying interactions, we noted that all four Id proteins could dimerize with E47 or E2-2, but not with HASH-1 or dHAND. However, the Id proteins did complex with HES-1, and increased levels of Id2 reduced the DNA binding activity of HES-1. Furthermore, HES-1 interfered with Id2/E2-2 complex formation. The ability of Id proteins to affect HES-1 activity is of particular interest in neuronal cells, where regulation of HES-1 is essential for the timing of neuronal differentiation.
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| 44. |
- Jögi, Annika, et al.
(författare)
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Patched 2, located in 1p32-34, is not mutated in high stage neuroblastoma tumors
- 2000
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Ingår i: International Journal of Oncology. - : Spandidos Publications. - 1019-6439 .- 1791-2423. ; 16:5, s. 943-949
-
Tidskriftsartikel (refereegranskat)abstract
- Neuroblastoma is a childhood malignancy originating from cells of the sympathetic nervous system, exhibiting a marked diversity in outcome, with spontaneous regression at one end of the spectrum and severe disease and death at the other end. Features associated with frequent recurrence, a poor prognosis, and high tumor stage are loss of heterozygosity in the distal region of chromosome 1p and amplification of the N-myc gene. Patched 2 is a novel homologue to the tumor suppressor gene Patched 1, and has been mapped to 1p32-34, a part of chromosome 1 frequently deleted in high stage neuroblastoma tumors. RT-PCR analysis of 9 neuroblastoma cell lines showed expression of both Patched 1 and 2. We analyzed 14, mainly high stage, neuroblastoma tumors for mutations in the Patched 2 gene with denaturing HPLC using the Wave DNA fragment analysis system. In four tumor samples variations were detected within the coding sequence, and two of them gave rise to amino-acid substitutions. These variations were, however, also detected in normal DNA from the respective patients. We conclude that Patched 2 is expressed, but not frequently mutated, in high stage neuroblastomas and is therefore not likely to be involved in the genesis of this tumor.
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| 45. |
- Lagergren, Anna, et al.
(författare)
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Neuroblastoma and pre-B lymphoma cells share expression of key transcription factors but display tissue restricted target gene expression
- 2004
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407. ; 4:80
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Tidskriftsartikel (refereegranskat)abstract
- Background: Transcription factors are frequently involved in the process of cellular transformation, and many malignancies are characterized by a distinct genetic event affecting a specific transcription factor. This probably reflects a tissue specific ability of transcription factors to contribute to the generation of cancer but very little is known about the precise mechanisms that governs these restricted effects. Methods: To investigate this selectivity in target gene activation we compared the overall gene expression patterns by micro-array analysis and expression of target genes for the transcription factor EBF in lymphoma and neuroblastoma cells by RT-PCR. The presence of transcription factors in the different model cell lines was further investigated by EMSA analysis. Results: In pre-B cells mb-1 and CD19 are regulate by EBF-1 in collaboration with Pax-5 and E-proteins. We here show that neuroblastoma cells express these three, for B cell development crucial transcription factors, but nevertheless fail to express detectable levels of their known target genes. Expression of mb-1 could, however, be induced in neuroblastoma cells after disruption of the chromatin structure by treatment with 5-azacytidine and Trichostatin A. Conclusion: These data suggest that transcription factors are able to selectively activate target genes in different tissues and that chromatin structure plays a key role in the regulation of this activity.
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| 46. |
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| 47. |
- Lindgren, David, et al.
(författare)
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Cell-Type-Specific Gene Programs of the Normal Human Nephron Define Kidney Cancer Subtypes
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 20:6, s. 1476-1489
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Tidskriftsartikel (refereegranskat)abstract
- Comprehensive transcriptome studies of cancers often rely on corresponding normal tissue samples to serve as a transcriptional reference. In this study, we performed in-depth analyses of normal kidney tissue transcriptomes from the TCGA and demonstrate that the histological variability in cellularity, inherent in the kidney architecture, lead to considerable transcriptional differences between samples. This should be considered when comparing expression profiles of normal and cancerous kidney tissues. We exploited these differences to define renal-cell-specific gene signatures and used these as a framework to analyze renal cell carcinoma (RCC) ontogeny. Chromophobe RCCs express FOXI1-driven genes that define collecting duct intercalated cells, whereas HNF-regulated genes, specific for proximal tubule cells, are an integral part of clear cell and papillary RCC transcriptomes. These networks may be used as a framework for understanding the interplay between genomic changes in RCC subtypes and the lineage-defining regulatory machinery of their non-neoplastic counterparts.
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| 48. |
- Lindgren, David, et al.
(författare)
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Isolation and characterization of progenitor-like cells from human renal proximal tubules.
- 2011
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 178:2, s. 828-837
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Tidskriftsartikel (refereegranskat)abstract
- The tubules of the kidney display a remarkable capacity for self-renewal on damage. Whether this regeneration is mediated by dedifferentiating surviving cells or, as recently suggested, by stem cells has not been unequivocally settled. Herein, we demonstrate that aldehyde dehydrogenase (ALDH) activity may be used for isolation of cells with progenitor characteristics from adult human renal cortical tissue. Gene expression profiling of the isolated ALDH(high) and ALDH(low) cell fractions followed by immunohistochemical interrogation of renal tissues enabled us to delineate a tentative progenitor cell population scattered through the proximal tubules (PTs). These cells expressed CD24 and CD133, previously described markers for renal progenitors of Bowman's capsule. Furthermore, we show that the PT cells, and the glomerular progenitors, are positive for KRT7, KRT19, BCL2, and vimentin. In addition, tubular epithelium regenerating on acute tubular necrosis displayed long stretches of CD133(+)/VIM(+) cells, further substantiating that these cells may represent a progenitor cell population. Furthermore, a potential association of these progenitor cells with papillary renal cell carcinoma was discovered. Taken together, our data demonstrate the presence of a previously unappreciated subset of the PT cells that may be endowed with a more robust phenotype, allowing increased resistance to acute renal injury, enabling rapid repopulation of the tubules.
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| 49. |
- Lindgren, David, et al.
(författare)
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Tracing Renal Cell Carcinomas back to the Nephron
- 2018
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Ingår i: Trends in Cancer. - : Elsevier BV. - 2405-8033. ; 4:7, s. 472-484
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Tidskriftsartikel (refereegranskat)abstract
- Renal cell carcinomas (RCCs) are a heterogeneous group of tumors derived from the epithelial cells of the nephron. In recent years the genetic landscape of these tumors has been detailed, leading to progress in mouse modeling of the human disease. In parallel, substantial advancements have been made in describing the transcriptional programs of normal nephron cell types and how they respond to renal insults. Integrating these research fields may provide a deeper understanding of renal tumor initiation and progression, and provide leads that can be conveyed into mouse models that faithfully recapitulate the different RCC subtypes. We summarize here the genetic lesions and molecular pathways that define RCC subtypes and discuss how these relate to cell-of-origin and renal repair programs.
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| 50. |
- 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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