pinecone/core-2020-05-10-deduplication huggingface dataset:
Oncogenic role of miR-155 in anaplastic large cell lymphoma lacking the t(2;5) translocation

Anaplastic large cell lymphoma (ALCL) is a rare, aggressive non-Hodgkin lymphoma that is characterized by CD30 expression and disease onset in young patients. About half of ALCL patients bear the t(2;5)(p23;q35) translocation which results in the formation of the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion protein (ALCL, ALK+). However, little is known about the molecular features and tumor drivers in ALK negative ALCL (ALCL, ALK-), which is characterized by a worse prognosis. We show that ALCL, ALK- in contrast to ALK+ lymphomas display high miR-155 expression. In line, we observe an inverse correlation between miR-155 promoter methylation and miR-155 mRNA expression in ALCL. ALK kinase activity has no direct effect on miR-155 levels. Ago2 immunoprecipitation reveals miR-155 as the most abundant miRNA in the Ago2 complex in ALCL, ALK-. To investigate its function in T-cell lymphoma we have over-expressed miR-155 in ALCL, ALK+ cell lines and demonstrate reduced levels of the target protein C/EBPβ. In murine engraftment models of ALCL, ALK-, we show that anti-miR-155 mimics are able to reduce tumor growth. This goes hand in hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumors, which leads to suppression of STAT3 signaling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPβ target IL-8. These data suggest that miR-155 can act as a tumor driver in ALCL, ALK- and blocking miR-155 could be therapeutically relevant.This work was supported by the SCRI-LIMCR GmbH, the “Jubiläumsfond der Österreichischen Nationalbank” (grant-no. 14856 to O.M.), R.G. was supported by grant SFB P021 from the Austrian Science Funds (FWF), L.K. was supported by grant FWF, P26011, R.M. was supported by FWF grants SFB F28 and SFB F47. S.D.T. is a Senior Lecturer supported with funding from Leukemia and Lymphoma Research.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.453
A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: A role for Monocarboxylate Transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of prostate cancer, and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of Hypoxia Inducible Factor -target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCTs inhibitors.Pertega-Gomes N. and Sousa S. received fellowships from the Portuguese Foundation for Science and Technology (FCT), refs. SFRH/BD/61027/2009, and PTDC/SAU-MET/113415/2009, respectively. Felisbino S. received a fellowship from the Sao Paulo Research Foundation (FAPESP) ref. 2013/08830-2 and 2013/06802-1. We thank the core facilities at the Cancer Research UK Cambridge Institute led by James Hadfield (Genomics), Matt Eldridge (Bioinformatics) and Allen Hazelhurst (BRU). We also thank the support and critical advice on the project given by Christian Frezza and Marco Sciacovelli from The MRC Cancer Cell Unit and Professor Rui Henrique from Portuguese Institute of Oncology for providing samples from patients with metastatic prostate cancer.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.454
A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for Monocarboxylate Transporters as metabolic targets for therapy

Metabolic adaptation is considered an emerging hallmark of cancer, whereby cancer cells exhibit high rates of glucose consumption with consequent lactate production. To ensure rapid efflux of lactate, most cancer cells express high levels of monocarboxylate transporters (MCTs), which therefore may constitute suitable therapeutic targets. The impact of MCT inhibition, along with the clinical impact of altered cellular metabolism during prostate cancer (PCa) initiation and progression, has not been described. Using a large cohort of human prostate tissues of different grades, in silico data, in vitro and ex vivo studies, we demonstrate the metabolic heterogeneity of PCa and its clinical relevance. We show an increased glycolytic phenotype in advanced stages of PCa and its correlation with poor prognosis. Finally, we present evidence supporting MCTs as suitable targets in PCa, affecting not only cancer cell proliferation and survival but also the expression of a number of hypoxia-inducible factor target genes associated with poor prognosis. Herein, we suggest that patients with highly glycolytic tumours have poorer outcome, supporting the notion of targeting glycolytic tumour cells in prostate cancer through the use of MCT inhibitors.NPG and SSS received fellowships from the Portuguese Foundation for Science and Technology (FCT; Grant Nos SFRH/BD/61027/2009 and PTDC/SAU-MET/113415/2009, respectively). SF received a fellowship from the Sao Paulo Research Foundation (FAPESP; Grant Nos 2013/08830-2 and 2013/06802-1). We are grateful to the core facilities at the Cancer Research UK Cambridge Institute, led by James Hadfield (Genomics), Matt Eldridge (Bioinformatics) and Allen Hazelhurst (BRU). We are also grateful for support and critical advice on the project given by Christian Frezza and Marco Sciacovelli from the MRC Cancer Cell Unit, and Professor Rui Henrique from the Portuguese Institute of Oncology for providing samples from patients with metastatic prostate cancer
Defective erythropoiesis in a mouse model of reduced Fbxo7 expression due to decreased p27 expression

During the final stages of erythropoiesis, lineage-restricted progenitors mature over
three to five cell divisions culminating with withdrawal from the cell cycle and the loss of
most organelles, including mitochondria and nuclei. Recent genome wide association
studies to associate haematological parameters with SNPs in human populations have
identified several SNPs near or within FBXO7 with erythrocyte phenotypes. Fbxo7 encodes a
multi-functional F-box protein known to bind p27 and participate in selective mitophagy.
One SNP causes an amino acid substitution (Met115Ile) and is associated with smaller RBC
size. We find the less common IIe115 allele of Fbxo7 binds less efficiently to p27, and cells
expressing this allele proliferate faster than cells expressing Met115. We show an
erythroleukemic cell line with reduced Fbxo7 expression fails to stabilize p27 levels, exit the
cell cycle and produce haemoglobin. In addition, mice deficient for Fbxo7 expression are
anaemic due to a reduction in erythrocyte numbers, and this is associated with lower p27
levels, increased numbers of late-stage erythroblasts with >2N DNA content, and delayed
mitophagy during terminal differentiation. Collectively, these data support an important
physiological, cell cycle regulatory role for Fbxo7 during erythropoiesis.This work was supported by the BBSRC (BB/J007846/1), and the
Cambridge Fund for the Prevention of Disease.This is the final version of the article. It first appeared from Wiley at http://dx.doi.org/10.1002/path.457
Serotonin promotes acinar dedifferentiation following pancreatitis-induced regeneration in the adult pancreas

The exocrine pancreas exhibits a distinctive capacity for tissue regeneration and renewal following injury. This regenerative ability has important implications for a variety of disorders, including pancreatitis and pancreatic cancer, diseases associated with high morbidity and mortality. Thus, understanding its underlying mechanisms may help develop therapeutic interventions. Serotonin (5-hydroxytryptamine, 5-HT) has been recognized as a potent mitogen for a variety of cells and tissues. Here we investigated whether serotonin exerts a mitogenic effect in pancreatic acinar cells in three regenerative models, namely inflammatory tissue injury following pancreatitis, tissue loss following partial pancreatectomy and thyroid hormone-stimulated acinar proliferation. Genetic and pharmacological techniques were used to modulate serotonin levels in vivo. Acinar de-differentiation and cell cycle progression during the regenerative phase were investigated over the course of two weeks. By comparing acinar proliferation in the different murine models of regeneration, we found that serotonin did not affect clonal regeneration of mature acinar cells. Serotonin was however required for acinar de-differentiation following inflammation-mediated tissue injury. Specifically, lack of serotonin resulted in delayed up-regulation of progenitor genes, delayed formation of acinar-to-ductal metaplasia and defective acinar cell proliferation. We identified serotonin-dependent acinar secretion as a key step in the progenitor-based regeneration, as it promoted acinar cell de-differentiation and the recruitment of type 2 macrophages. Finally, we identified a regulatory Hes1-Ptfa axis in the uninjured adult pancreas activated by zymogen secretion. Our findings indicate that serotonin plays a critical role in the regeneration of the adult pancreas following pancreatitis by promoting de-differentiation of acinar cells
Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcaemic type

Small cell carcinoma of the ovary, hypercalcaemic type () is a lethal and sometimes familial ovarian tumour of young women and children. We and others recently discovered that over 90% of harbour inactivating mutations in the chromatin remodelling gene with concomitant loss of its encoded protein (), one of two mutually exclusive of the / chromatin remodelling complex. To determine the specificity of loss for , we examined the expression of by immunohistochemistry in more than 3000 primary gynaecological tumours. Among ovarian tumours, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high‐grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that (), the other mutually exclusive of the / complex, is necessary for survival of tumour cells lacking . Therefore, we examined expression and discovered that all ‐negative also lacked protein by , including the cell lines and . Among ovarian tumours, the / dual loss phenotype appears completely specific for . loss was not due to mutation but rather from an absence of expression, which was restored by treatment with the histone deacetylase inhibitor trichostatin A. Re‐expression of or inhibited the growth of and cell lines. Our results indicate that loss, either alone or with , is highly sensitive and specific for and that restoration of either / can inhibit the growth of cell lines. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland
Animal modelling for inherited central vision loss.

Disease-causing variants of a large number of genes trigger inherited retinal degeneration leading to photoreceptor loss. Because cones are essential for daylight and central vision such as reading, mobility, and face recognition, this review focuses on a variety of animal models for cone diseases. The pertinence of using these models to reveal genotype/phenotype correlations and to evaluate new therapeutic strategies is discussed. Interestingly, several large animal models recapitulate human diseases and can serve as a strong base from which to study the biology of disease and to assess the scale-up of new therapies. Examples of innovative approaches will be presented such as lentiviral-based transgenesis in pigs and adeno-associated virus (AAV)-gene transfer into the monkey eye to investigate the neural circuitry plasticity of the visual system. The models reported herein permit the exploration of common mechanisms that exist between different species and the identification and highlighting of pathways that may be specific to primates, including humans
Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.

Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterised by pain – frequently debilitating.  Although the exact prevalence is unknown the economic burden is substantial (~$50B a year in the USA alone) and it is associated with considerable morbidity.  The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates.  However, the use of these animals is ethically challenging and very expensive.  A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal.  These models are genetically manipulable and facilitate precise mechanistic studies.  In addition these models can be used to study malignant transformation in epithelial ovarian carcinoma.  Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA respectively).  While this progression is rare understanding the underlying mechanisms of transformation may offer new prevention and therapeutic strategies.  Our ability to do this is highly dependent on improved animal models but the current transgenic models that genetically modify the ovarian surface epithelium and oviduct are poor models of ectopic endometrial tissue.  In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.CMK was funded by a grant from CRUK (A13095).  Part of the research work disclosed in this publication is funded by the Strategic Educational Pathways Scholarship (Malta) to CB. The scholarship is part-financed by the European Union-European Social Fund (ESF) under Operational Programme II-Cohesion Policy 2007-2013, "Empowering People for More Jobs and a Better Quality of Life”.  JDB is supported by CRUK (A15601).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.465
Placental endoplasmic reticulum stress negatively regulates transcription of placental growth factor via ATF4 and ATF6 β: implications for the pathophysiology of human pregnancy complications

Low maternal circulating concentrations of placental growth factor (PlGF) are one of the hallmarks of human pregnancy complications, including fetal growth restriction (FGR) and early-onset pre-eclampsia (PE). Currently, PlGF is used clinically with other biomarkers to screen for high-risk cases, although the mechanisms underlying its regulation are largely unknown. Placental endoplasmic reticulum (ER) stress has recently been found to be elevated in cases of FGR, and to an even greater extent in early-onset PE complicated with FGR. ER stress activates the unfolded protein response (UPR); attenuation of protein translation and a reduction in cell growth and proliferation play crucial roles in the pathophysiology of these complications of pregnancy. In this study, we further identified that ER stress regulates release of PlGF. We first observed that down-regulation of PlGF protein was associated with nuclear localization of ATF4, ATF6α and ATF6β in the syncytiotrophoblast of placentas from PE patients. Transcript analysis showed a decrease of PlGF  mRNA, and an increase from genes encoding those UPR transcription factors, in placentas from cases of early-onset PE, but not in the late-onset (>34 weeks) PE, compared to term controls. Further investigations indicated a strong correlation between ATF4 and PlGF mRNA levels only (r = -0.73, p<0.05). These results could be recapitulated in trophoblast-like cells exposed to chemical inducers of ER stress or hypoxia/reoxygenation. The stability of PlGF transcripts was unchanged. The use of small interfering RNA specific for transcription factors in the UPR pathways revealed that ATF4 and ATF6β, but not ATF6α, modulate PlGF transcription. To conclude, ATF4 and ATF6β act synergistically in the negative regulation of PlGF mRNA expression, resulting in reduced PlGF secretion by the trophoblast in response to stress. Therefore, these results further support targeting of placental ER stress as a potential new therapeutic intervention for these pregnancy complications.This study was supported by a grant from The Wellcome Trust (084804/2/08/Z).This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/path.467
Tumour stroma-derived lipocalin-2 promotes breast cancer metastasis

Tumour cell-secreted factors skew infiltrating immune cells towards a tumour-supporting phenotype, expressing pro-tumourigenic mediators. However, the influence of lipocalin-2 (Lcn2) on the metastatic cascade in the tumour micro-environment is still not clearly defined. Here, we explored the role of stroma-derived, especially macrophage-released, Lcn2 in breast cancer progression. Knockdown studies and neutralizing antibody approaches showed that Lcn2 contributes to the early events of metastasis in vitro. The release of Lcn2 from macrophages induced an epithelial–mesenchymal transition programme in MCF-7 breast cancer cells and enhanced local migration as well as invasion into the extracellular matrix, using a three-dimensioanl (3D) spheroid model. Moreover, a global Lcn2 deficiency attenuated breast cancer metastasis in both the MMTV–PyMT breast cancer model and a xenograft model inoculating MCF-7 cells pretreated with supernatants from wild-type and Lcn2-knockdown macrophages. To dissect the role of stroma-derived Lcn2, we employed an orthotopic mammary tumour mouse model. Implantation of wild-type PyMT tumour cells into Lcn2-deficient mice left primary mammary tumour formation unaltered, but specifically reduced tumour cell dissemination into the lung. We conclude that stroma-secreted Lcn2 promotes metastasis in vitro and in vivo, thereby contributing to tumour progression. Our study highlights the tumourigenic potential of stroma-released Lcn2 and suggests Lcn2 as a putative therapeutic target
Anti-stromal treatment together with chemotherapy targets multiple signalling pathways in pancreatic adenocarcinoma

Stromal targeting for pancreatic ductal adenocarcinoma (PDAC) is rapidly becoming an attractive option, due to lack of efficacy of standard chemotherapy and increased knowledge about PDAC stroma. We postulated that the addition of stromal therapy may enhance the anti-tumour efficacy of chemotherapy. Gemcitabine and all-trans retinoic acid (ATRA) were combined in a clinically applicable regimen, to target cancer cells and pancreatic stellate cells (PSC) respectively, in 3D organotypic culture models and genetically engineered mice (LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre: KPC mice) representing the spectrum of PDAC. In two distinct sets of organotypic models as well as KPC mice, we demonstrate a reduction in cancer cell proliferation and invasion together with enhanced cancer cell apoptosis when ATRA is combined with gemcitabine, compared to vehicle or either agent alone. Simultaneously, PSC activity (as measured by deposition of extra-cellular matrix proteins such as collagen and fibronectin), and PSC invasive ability were both diminished in response to combination therapy. These effects were mediated through a range of signalling cascades (Wnt, hedgehog, retinoid and FGF) in cancer as well as stellate cells, affecting epithelial cellular functions such as epithelial-mesenchymal transition, cellular polarity and lumen formation. At the tissue level, this resulted in enhanced tumour necrosis, increased vascularity, and diminished hypoxia. Consequently, there was an overall reduction in tumour size. The enhanced effect of stromal co-targeting (ATRA) alongside chemotherapy (gemcitabine) appears to be mediated by dampening multiple signalling cascades in the tumour-stroma cross-talk, rather than ablating stroma or targeting a single pathway.This work was supported by project grants from the Knowledge Transfer Network (Engineering and Physical Sciences Research Committee) and Pancreatic Cancer Research Fund (UK) to HMK. CF was supported by an EMBO long term fellowship and by a Marie Curie Intra8European Fellowship within the 7th European Community Framework Programme. TB and FR were supported by Cancer Research UK (grant C14303/A17197). Other grant funding includes project grants from Pancreatic Cancer Research Fund, Cancer Research UK and Barts Charity.This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/path.472
Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions

The von Hippel-Lindau (VHL) tumour suppressor gene is biallelically inactivated in the majority of cases of clear cell renal cell carcinoma (ccRCC), however Vhl knockout mouse models do not recapitulate human ccRCC, implying that additional mutations are required for tumour formation. Mutational inactivation of VHL sensitises renal epithelial cells to lose the primary cilium in response to other mutations or extracellular stimuli. Cilia loss is believed to represent a second hit in VHL mutant cells that causes the development of cystic lesions that in some cases can progress to ccRCC. Supporting this idea, genetic ablation of the primary cilium by deletion of the kinesin family member 3A (Kif3a) gene cooperates with loss of Vhl to accelerate cyst formation in mouse kidneys. Additionally, aged Vhl/Trp53 double mutant mice develop renal cysts and tumours at a relatively low incidence, suggesting that there is a genetic cooperation between VHL and TP53 mutation in the development of ccRCC. Here we generated renal epithelium-specific Kif3a/Trp53 and Vhl/Kif3a/Trp53 mutant mice to investigate whether primary cilium deletion would accelerate the development of cystic precursor lesions or cause their progression to ccRCC. Longitudinal microcomputed tomography imaging and histopathological analyses revealed an increased rate of cyst formation, increased proportion of cysts with proliferating cells, higher frequency of atypical cysts as well as the development of neoplasms in Vhl/Kif3a/Trp53 mutant kidneys compared to Kif3a/Trp53 or Vhl/Kif3a mutant kidneys. These findings demonstrate that primary cilium loss in addition to Vhl and Trp53 losses promotes the transition towards malignancy and provide further evidence that the primary cilium functions as a tumour suppressor organelle in the kidney