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  • 1
    Keywords: LUNG-CANCER ; HIGH-DOSE CHEMOTHERAPY ; ANAPLASTIC LYMPHOMA ; NON-HODGKIN-LYMPHOMA ; SMALL-MOLECULE INHIBITOR ; PROTEASOME INHIBITOR BORTEZOMIB ; MULTICENTER PHASE-II ; MONOCLONAL-ANTIBODY KW-0761 ; BRENTUXIMAB VEDOTIN SGN-35 ; PROLYMPHOCYTIC LEUKEMIA
    Abstract: ntroduction: Peripheral T-cell lymphomas (PTCLs) and natural killer (NK) or T-cell non-Hodgkin's lymphomas (NHLs) are a rare and heterogeneous class of diseases with generally poor prognosis. This work intends to provide a focused primer on clinical diagnosis, current treatment regimens, and novel therapeutic approaches. The recent WHO classification has defined 18 different subtypes of PTCL and NK T-cell lymphomas. Diagnosis is mainly based on histology, flow-cytometric analysis of surface molecules in the blood and bone marrow, cytogenetics/fluorescence in situ hybridization (FISH), and T-cell receptor (TCR) rearrangement. Staging as well as follow-up diagnostic procedures rely on imaging techniques such as computerized tomography (CT) and positron emission tomography (PET). Current chemotherapeutic regimens such as CHOP result in a 60 - 70% response rate; however, 5-year survival is only around 30%. Therefore, new treatment strategies are urgently needed. Currently, different drug classes are under scrutiny. Areas covered: The authors discuss substances that directly target the tumor cells. The article includes such substances as antimetabolites, antibodies, histone deacetylase inhibitors, tyrosine kinase inhibitors, and immunomodulatory substances such as lenalidomide. Expert opinion: In the future a close collaboration of geneticists, biochemists, and clinicians together with new technologies such as deep sequencing will allow the refinement of treatment strategies in many diseases including PTCLs and NHLs. This refinement will allow treatments to be prepared according to the need of the individual patient.
    Type of Publication: Journal article published
    PubMed ID: 22998641
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  • 2
    Keywords: TYROSINE KINASE ; GENE-EXPRESSION ; TRANSGENIC MICE ; IDENTIFICATION ; PROMOTER ; leukemia ; PATHOGENESIS ; NPM-ALK ; HODGKIN LYMPHOMA ; MICRORNA-155
    Abstract: Anaplastic large cell lymphoma (ALCL) is a rare, aggressive, non-Hodgkin's 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 tumour drivers in ALK-negative ALCL (ALCL ALK(-) ), which is characterized by a worse prognosis. We found that ALCL ALK(-) , in contrast to ALCL ALK(+) , lymphomas display high miR-155 expression. Consistent with this, we observed an inverse correlation between miR-155 promoter methylation and miR-155 expression in ALCL. However, no direct effect of the ALK kinase on miR-155 levels was observed. Ago2 immunoprecipitation revealed miR-155 as the most abundant miRNA, and enrichment of target mRNAs C/EBPbeta and SOCS1. To investigate its function, we over-expressed miR-155 in ALCL ALK(+) cell lines and demonstrated reduced levels of C/EBPbeta and SOCS1. In murine engraftment models of ALCL ALK(-) , we showed that anti-miR-155 mimics are able to reduce tumour growth. This goes hand-in-hand with increased levels of cleaved caspase-3 and high SOCS1 in these tumours, which leads to suppression of STAT3 signalling. Moreover, miR-155 induces IL-22 expression and suppresses the C/EBPbeta target IL-8. These data suggest that miR-155 can act as a tumour driver in ALCL ALK(-) and blocking miR-155 could be therapeutically relevant. Original miRNA array data are to be found in the supplementary material (Table S1). Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Publication: Journal article published
    PubMed ID: 25820993
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  • 3
    Abstract: Loss of tumor suppressor adenomatous polyposis coli (APC) activates beta-catenin to initiate colorectal tumorigenesis. However, beta-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.
    Type of Publication: Journal article published
    PubMed ID: 28130546
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  • 4
    Keywords: EXPRESSION ; IN-VITRO ; proliferation ; CELL ; IN-VIVO ; VITRO ; VIVO ; SUPPORT ; DISEASE ; NEW-YORK ; GENE ; DIFFERENTIATION ; MICE ; AP-1 ; C-JUN ; TRANSGENIC MICE ; NUMBER ; MARKERS ; PHENOTYPE ; BONE-FORMATION ; REGULATOR ; MOUSE DEVELOPMENT ; AP-1,conditional gene targeting,osteoblasts,osteopenia,osteopetrosis ; TARGETED DISRUPTION
    Abstract: Because JunB is an essential gene for placentation, it was conditionally deleted in the embryo proper. junB(Delta/Delta) mice are born viable, but develop severe low turnover osteopenia caused by apparent cell-autonomous osteoblast and osteoclast defects before a chronic myeloid leukemia-like disease. Although JunB was reported to be a negative regulator of cell proliferation, junB(Delta/Delta) osteoclast precursors and osteoblasts show reduced proliferation along with a differentiation defect in vivo and in vitro. Mutant osteoblasts express elevated p16(INK4a) levels, but exhibit decreased cyclin D1 and cyclin A expression. Runx2 is transiently increased during osteoblast differentiation in vitro, whereas mature osteoblast markers such as osteocalcin and bone sialoprotein are strongly reduced. To support a cell-autonomous function of JunB in osteoclasts, junB was inactivated specifically in the macrophage-osteoclast lineage. Mutant mice develop an osteopetrosis-like phenotype with increased bone mass and reduced numbers of osteoclasts. Thus, these data reveal a novel function of JunB as a positive regulator controlling primarily osteoblast as well as osteoclast activity
    Type of Publication: Journal article published
    PubMed ID: 14769860
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  • 5
    Keywords: EXPRESSION ; DISEASE ; transcription ; ACTIVATION ; STAT5B ; CANCER DEVELOPMENT ; INSULIN-RESISTANCE ; NONALCOHOLIC STEATOHEPATITIS ; FATTY LIVER-DISEASE ; LIPID-METABOLISM ; CORTICOSTEROID-BINDING GLOBULIN
    Abstract: Growth hormone (GH)-activated signal transducer and activator of transcription 5 (STAT5) and the glucocorticoid (GC)-responsive glucocorticoid receptor (GR) are important signal integrators in the liver during metabolic and physiologic stress. Their deregulation has been implicated in the development of metabolic liver diseases, such as steatosis and progression to fibrosis. Using liver-specific STAT5 and GR knockout mice, we addressed their role in metabolism and liver cancer onset. STAT5 single and STAT5/GR double mutants developed steatosis, but only double-mutant mice progressed to liver cancer. Mechanistically, STAT5 deficiency led to the up-regulation of prolipogenic sterol regulatory element binding protein 1 (SREBP-1) and peroxisome proliferator activated receptor gamma (PPAR-gamma) signaling. Combined loss of STAT5/GR resulted in GH resistance and hypercortisolism. The combination of both induced expression of adipose tissue lipases, adipose tissue lipid mobilization, and lipid flux to the liver, thereby aggravating STAT5-dependent steatosis. The metabolic dysfunctions in STAT5/GR compound knockout animals led to the development of hepatic dysplasia at 9 months of age. At 12 months, 35% of STAT5/GR-deficient livers harbored dysplastic nodules and similar to 60% hepatocellular carcinomas (HCCs). HCC development was associated with GH and insulin resistance, enhanced tumor necrosis factor alpha (TNF-alpha) expression, high reactive oxygen species levels, and augmented liver and DNA damage parameters. Moreover, activation of the c-Jun N-terminal kinase 1 (JNK1) and STAT3 was prominent. Conclusion: Hepatic STAT5/GR signaling is crucial for the maintenance of systemic lipid homeostasis. Impairment of both signaling cascades causes severe metabolic liver disease and promotes spontaneous hepatic tumorigenesis.
    Type of Publication: Journal article published
    PubMed ID: 21725989
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  • 6
    Keywords: CANCER ; KINASE ; DISEASE ; MICE ; T-CELLS ; IDENTIFICATION ; FUSION ; TRANSFORMATION ; HEMATOPOIETIC STEM-CELLS ; NPM-ALK
    Abstract: Cancer stem cells or tumour-propagating cells (TPCs) have been identified for a number of cancers, but data pertaining to their existence in lymphoma so far remain elusive. We show for the first time that a small subset of cells purified from human anaplastic lymphoma kinase (ALK)-positive and -negative, anaplastic large cell lymphoma cell lines and primary patient tumours using the side population (SP) technique have serial tumour-propagating capacity both in vitro and in vivo; they give rise to both themselves and the bulk tumour population as well as supporting growth of the latter through the production of soluble factors. In vivo serial dilution assays utilising a variety of model systems inclusive of human cell lines, primary human tumours and nucleophosmin (NPM)-ALK-induced murine tumours demonstrate the TPC frequency to vary from as many as 1/54 to 1/1336 tumour cells. In addition, the SP cells express higher levels of pluripotency-associated transcription factors and are enriched for a gene expression profile consistent with early thymic progenitors. Finally, our data show that the SP cells express higher levels of the NPM-ALK oncogene and are sensitive to an ALK inhibitor.
    Type of Publication: Journal article published
    PubMed ID: 24814516
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  • 7
    Keywords: GENE-EXPRESSION ; INDUCED APOPTOSIS ; STEM-CELLS ; SUPPRESSOR GENE ; ACUTE MYELOID-LEUKEMIA ; WNT pathway ; MESENCHYMAL TRANSITION ; FUNCTIONAL-ROLE ; PROTEIN-COUPLED RECEPTOR ; ONCOGENE AF1Q
    Abstract: AF1q is an MLL fusion partner that was identified from acute myeloid leukemia (AML) patients with t (1; 11) (q21; q23) chromosomal abnormality. The function of AF1q is not yet fully known, however, elevated AF1q expression is associated with poor clinical outcomes in various malignancies. Here, we show that AF1q specifically binds to T-cell-factor-7 (TCF7) in the Wnt signaling pathway and results in transcriptional activation of CD44 as well as multiple downstream targets of the TCF7/LEF1. In addition, enhanced AF1q expression promotes breast cancer cell proliferation, migration, mammosphere formation, and chemo-resistance. In xenograft models, enforced AF1q expression in breast cancer cells also promotes liver metastasis and lung colonization. In a cohort of 63 breast cancer patients, higher percentages of AF1q-positive cancer cells in primary sites were associated with significantly poorer overall survival (OS), disease-free survival (DFS), and brain metastasis-free survival (b-MFS). Using paired primary/metastatic samples from the same patients, we demonstrate that AF1q-positive breast cancer cells become dynamically dominant in the metastatic sites compared to the primary sites. Our findings indicate that breast cancer cells with a hyperactive AF1q/TCF7/CD44 regulatory axis in the primary sites may represent "metastatic founder cells" which have invasive properties.
    Type of Publication: Journal article published
    PubMed ID: 26079538
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  • 8
    Abstract: BACKGROUND & AIMS: Inhibitors of the epidermal growth factor receptor (EGFR) are the first-line therapy for patients with metastatic colorectal tumors without RAS mutations. However, EGFR inhibitors are ineffective in these patients, and tumor level of EGFR does not associate with response to therapy. We screened human colorectal tumors for EGFR-positive myeloid cells and investigated their association with patient outcome. We also performed studies in mice to evaluate how EGFR expression in tumor cells and myeloid cells contributes to development of colitis-associated cancer and ApcMin-dependent intestinal tumorigenesis. METHODS: We performed immunohistochemical and immunofluorescent analyses of 116 colorectal tumor biopsies to determine levels of EGFR in tumor and stroma; we also collected information on tumor stage and patient features and outcomes. We used the Mann-Whitney U and Kruskal-Wallis tests to correlate tumor levels of EGFR with tumor stage, and the Kaplan-Meier method to estimate patients' median survival time. We performed experiments in mice lacking EGFR in intestinal epithelial cells (Villin-Cre; Egfrf/f and Villin-CreERT2; Egfrf/f mice) or myeloid cells (LysM-Cre; Egfrf/f mice) on a mixed background. These mice were bred with ApcMin/+ mice; colitis-associated cancer and colitis were induced by administration of dextran sodium sulfate (DSS), with or without azoxymethane (AOM), respectively. Villin-CreERT2 was activated in developed tumors by administration of tamoxifen to mice. Littermates that expressed full-length EGFR were used as controls. Intestinal tissues were collected; severity of colitis, numbers and size of tumors, and intestinal barrier integrity were assessed by histologic, immunohistochemical, quantitative reverse transcription polymerase chain reaction, and flow cytometry analyses. RESULTS: We detected EGFR in myeloid cells in the stroma of human colorectal tumors; myeloid cell expression of EGFR associated with tumor metastasis and shorter patient survival time. Mice with deletion of EGFR from myeloid cells formed significantly fewer and smaller tumors than the respective EGFR-expressing controls in an ApcMin/+ background as well as after administration of AOM and DSS. Deletion of EGFR from intestinal epithelial cells did not affect tumor growth. Furthermore, tamoxifen-induced deletion of EGFR from epithelial cells of established intestinal tumors in mice given AOM and DSS did not reduce tumor size. EGFR signaling in myeloid cells promoted activation of STAT3 and expression of survivin in intestinal tumor cells. Mice with deletion of EGFR from myeloid cells developed more severe colitis after DSS administration, characterized by increased intestinal inflammation and intestinal barrier disruption, than control mice or mice with deletion of EGFR from intestinal epithelial cells. EGFR-deficient myeloid cells in the colon of DSS-treated LysM-Cre; Egfrf/f mice had reduced expression of interleukin 6 (IL6), and epithelial STAT3 activation was reduced compared with controls. Administration of recombinant IL6 to LysM-Cre; Egfrf/f mice given DSS protected them from weight loss and restored epithelial proliferation and STAT3 activation, compared with administration of DSS alone to these mice. CONCLUSIONS: Increased expression of EGFR in myeloid cells from the colorectal tumor stroma associates with tumor progression and reduced survival time of patients with metastatic colorectal cancer. Deletion of EGFR from myeloid cells, but not intestinal epithelial cells, protects mice from colitis-induced intestinal cancer and ApcMin-dependent intestinal tumorigenesis. Myeloid cell expression of EGFR increases activation of STAT3 and expression of survivin in intestinal epithelial cells and expression of IL6 in colon tissues. These findings indicate that expression of EGFR by myeloid cells of the colorectal tumor stroma, rather than the cancer cells themselves, contributes to tumor development.
    Type of Publication: Journal article published
    PubMed ID: 28400195
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  • 9
    Abstract: The insulin-like growth factor (IGF)2/IGF1 receptor (IGF1R) signaling axis has an important role in intestinal carcinogenesis and overexpression of IGF2 is an accepted risk factor for colorectal cancer (CRC) development. Genetic amplifications and loss of imprinting contribute to the upregulation of IGF2, but insufficiently explain the extent of IGF2 expression in a subset of patients. Here, we show that IGF2 was specifically induced in the tumor stroma of CRC and identified cancer-associated fibroblasts (CAFs) as the major source. Further, we provide functional evidence that stromal IGF2, via the paracrine IGF1R/insulin receptor axis, activated pro-survival AKT signaling in CRC cell lines. In addition to its effects on malignant cells, autocrine IGF2/IGF1R signaling in CAFs induced myofibroblast differentiation in terms of alpha-smooth muscle actin expression and contractility in floating collagen gels. This was further augmented in concert with transforming growth factor-beta (TGFbeta) signaling suggesting a cooperative mechanism. However, we demonstrated that IGF2 neither induced TGFbeta/smooth muscle actin/mothers against decapentaplegic (SMAD) signaling nor synergized with TGFbeta to hyperactivate this pathway in two dimensional and three dimensional cultures. IGF2-mediated physical matrix remodeling by CAFs, but not changes in extracellular matrix-modifying proteases or other secreted factors acting in a paracrine manner on/in cancer cells, facilitated subsequent tumor cell invasion in organotypic co-cultures. Consistently, colon cancer cells co-inoculated with CAFs expressing endogenous IGF2 in mouse xenograft models exhibited elevated invasiveness and dissemination capacity, as well as increased local tumor regrowth after primary tumor resection compared with conditions with IGF2-deficient CAFs. In line, expression of IGF2 correlated with elevated relapse rates and poor survival in CRC patients. In agreement with our results, high-level coexpression of IGF2 and TGFbeta was predicting adverse outcome with higher accuracy than increased expression of the individual genes alone. Taken together, we demonstrate that stroma-induced IGF2 promotes colon cancer progression in a paracrine and autocrine manner and propose IGF2 as potential target for tumor stroma cotargeting strategies.
    Type of Publication: Journal article published
    PubMed ID: 28534511
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  • 10
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; GROWTH-FACTOR ; IN-VITRO ; FACTOR RECEPTOR ; IN-VIVO ; VITRO ; DISEASE ; GENE ; PROTEIN ; PROTEINS ; MICE ; ARTHRITIS ; AP-1 ; tumour ; CONTRAST ; KERATINOCYTES ; SKIN ; T-CELLS ; C-JUN ; DOWN-REGULATION ; SUSCEPTIBILITY ; DELETION ; TRANSGENIC MICE ; LESIONS ; REGION ; B-CELLS ; STEM-CELLS ; Jun ; PHENOTYPE ; MOUSE MODEL ; epidermis ; NEUTROPHILS ; PSORIASIS ; molecular ; ADULT ; RE ; keratinocyte ; development ; RECRUITS ; NECROSIS-FACTOR ; signalling ; ACTIVATED KERATINOCYTES ; MICE LACKING JUNB
    Abstract: Psoriasis is a frequent, inflammatory disease of skin and joints with considerable morbidity. Here we report that in psoriatic lesions, epidermal keratinocytes have decreased expression of JunB, a gene localized in the psoriasis susceptibility region PSORS6. Likewise, inducible epidermal deletion of JunB and its functional companion c-Jun in adult mice leads ( within two weeks) to a phenotype resembling the histological and molecular hallmarks of psoriasis, including arthritic lesions. In contrast to the skin phenotype, the development of arthritic lesions requires T and B cells and signalling through tumour necrosis factor receptor 1 ( TNFR1). Prior to the disease onset, two chemotactic proteins (S100A8 and S100A9) previously mapped to the psoriasis susceptibility region PSORS4, are strongly induced in mutant keratinocytes in vivo and in vitro. We propose that the abrogation of JunB/activator protein 1 (AP-1) in keratinocytes triggers chemokine/cytokine expression, which recruits neutrophils and macrophages to the epidermis thereby contributing to the phenotypic changes observed in psoriasis. Thus, these data support the hypothesis that epidermal alterations are sufficient to initiate both skin lesions and arthritis in psoriasis
    Type of Publication: Journal article published
    PubMed ID: 16163348
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