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  • DKFZ Publication Database  (1,658)
  • tumor  (1,658)
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  • Articles  (111)
  • DKFZ Publication Database  (1,658)
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  • 1
    Keywords: tumor ; HEPATOCELLULAR-CARCINOMA ; RADIOFREQUENCY ABLATION ; embolization ; HEPATIC BLOOD-FLOW ; PIG-LIVER ; COAGULATION DIAMETER ; TRANSCATHETER ARTERIAL CHEMOEMBOLIZATION ; RF-ABLATION ; LIPIODOL
    Abstract: PURPOSE: To evaluate the effect of previous transarterial iodized oil tissue marking (ITM) on technical parameters, three-dimensional (3D) computed tomographic (CT) rendering of the electroporation zone, and histopathology after CT-guided irreversible electroporation (IRE) in an acute porcine liver model as a potential strategy to improve IRE performance. METHODS: After Ethics Committee approval was obtained, in five landrace pigs, two IREs of the right and left liver (RL and LL) were performed under CT guidance with identical electroporation parameters. Before IRE, transarterial marking of the LL was performed with iodized oil. Nonenhanced and contrast-enhanced CT examinations followed. One hour after IRE, animals were killed and livers collected. Mean resulting voltage and amperage during IRE were assessed. For 3D CT rendering of the electroporation zone, parameters for size and shape were analyzed. Quantitative data were compared by the Mann-Whitney test. Histopathological differences were assessed. RESULTS: Mean resulting voltage and amperage were 2,545.3 +/- 66.0 V and 26.1 +/- 1.8 A for RL, and 2,537.3 +/- 69.0 V and 27.7 +/- 1.8 A for LL without significant differences. Short axis, volume, and sphericity index were 16.5 +/- 4.4 mm, 8.6 +/- 3.2 cm(3), and 1.7 +/- 0.3 for RL, and 18.2 +/- 3.4 mm, 9.8 +/- 3.8 cm(3), and 1.7 +/- 0.3 for LL without significant differences. For RL and LL, the electroporation zone consisted of severely widened hepatic sinusoids containing erythrocytes and showed homogeneous apoptosis. For LL, iodized oil could be detected in the center and at the rim of the electroporation zone. CONCLUSION: There is no adverse effect of previous ITM on technical parameters, 3D CT rendering of the electroporation zone, and histopathology after CT-guided IRE of the liver.
    Type of Publication: Journal article published
    PubMed ID: 24870700
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  • 2
    Keywords: tumor ; MONOCLONAL-ANTIBODY ; MICE ; RECOGNITION ; BETA-CELLS ; MELLITUS ; NK-CELLS ; VIRUS-INFECTED CELLS ; CYTOTOXICITY RECEPTOR NKP44 ; STREPTOZOTOCIN
    Abstract: Natural killer (NK) cells belong to the innate lymphoid cells. Their cytotoxic activity is regulated by the delicate balance between activating and inhibitory signals. NKp46 is a member of the primary activating receptors of NK cells. We previously reported that the NKp46 receptor is involved in the development of type 1 diabetes (T1D). Subsequently, we hypothesized that blocking this receptor could prevent or hinder disease development. To address this goal, we developed monoclonal antibodies for murine NKp46. One mAb, named NCR1.15, recognizes the mouse homologue protein of NKp46, named Ncr1, and was able to down-regulate the surface expression of NKp46 on primary murine NK cells following antibody injection in vivo. Additionally, NCR1.15 treatments were able to down-regulate cytotoxic activity mediated by NKp46, but not by other NK receptors. To test our primary assumption, we examined T1D development in two models, non-obese diabetic mice and low-dose streptozotocin. Our results show a significantly lower incidence of diabetic mice in the NCR1.15-treated group compared to control groups. This study directly demonstrates the involvement of NKp46 in T1D development and suggests a novel treatment strategy for early insulitis.
    Type of Publication: Journal article published
    PubMed ID: 25719382
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  • 3
    Keywords: ANGIOGENESIS ; GROWTH ; tumor ; CELL LUNG-CANCER ; mechanisms ; chemotherapy ; MURINE MODEL ; NERVE ; BEVACIZUMAB ; HYPERALGESIA
    Abstract: Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life. Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain. Tumor-derived VEGF-A, PLGF-2, and VEGF-B augment pain sensitivity through selective activation of VEGF receptor 1 (VEGFR1) expressed in sensory neurons in human cancer and mouse models. Sensory-neuron-specific genetic deletion/silencing or local or systemic blockade of VEGFR1 prevented tumor-induced nerve remodeling and attenuated cancer pain in diverse mouse models in vivo. These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies.
    Type of Publication: Journal article published
    PubMed ID: 26058077
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  • 4
    Keywords: EXPRESSION ; IN-VITRO ; tumor ; GENE ; DOWN-REGULATION ; STEM-CELLS ; NATURAL-KILLER-CELLS ; GLIOMA-CELLS ; MALIGNANT GLIOMA ; IFN-BETA
    Abstract: Immunotherapy targeting glioblastoma initiating cells (GIC) is considered a promising strategy. However, GIC are prone to evade immune response and there is a need for potent adjuvants. IFN-beta might enhance the immune response and here we define its net effect on the innate immunogenicity of GIC. The transcriptomes of GIC treated with IFN-beta and controls were assessed by microarray-based expression profiling for altered expression of immune regulatory genes. Several genes involved in adaptive and innate immune responses were regulated by IFN-beta. We validated these results using reverse transcription (RT)-PCR and flow cytometry for corresponding protein levels. The up-regulation of the NK cell inhibitory molecules HLA-E and MHC class I was balanced by immune stimulating effects including the up-regulation of nectin-2. In 3 out of 5 GIC lines tested we found a net immune stimulating effect of IFN-beta in cytotoxicity assays using NKL cells as effectors. IFN-beta therefore warrants further investigation as an adjuvant for immunotherapy targeting GIC.
    Type of Publication: Journal article published
    PubMed ID: 26441059
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  • 5
    Keywords: tumor ; PATIENT ; ANTIGENS ; MEMORY ; VACCINES ; vaccination ; CANCER-IMMUNOTHERAPY ; CD4(+) T-CELLS ; ADVANCED MELANOMA ; IPILIMUMAB
    Abstract: The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
    Type of Publication: Journal article published
    PubMed ID: 25548167
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  • 6
    Keywords: ANGIOGENESIS ; tumor ; IN-VIVO ; MODEL ; CHORIOALLANTOIC MEMBRANE ASSAY
    Abstract: Fertilized chicken eggs are suggested as an alternative to mammalian models. The chorioallantoic membrane (CAM) of the chick embryo is widely used for examination of angiogenesis, xenotransplants and for virus production. Unfortunately, it is mostly not taken into account, that the chick embryo's ability to experience pain starts to develop at day 7 of breeding. In our view, this model is only in accordance with the 3 R principles, if an appropriate anesthesia of the chick embryo in potentially painful procedures is provided. Although many experimental approaches are performed on the none-innervated CAM, the euthanasia of the embryo strongly requires a more human technique than the usually used freezing at -20 degrees C, decapitation or in ovo fixation with paraformaldehyde without prior anesthesia. However, protocols regarding feasible and ethical methods for anesthesia and euthanasia of avian embryos are currently not available. Therefore, we established an easy and reliable method for the euthanasia and short-term anesthesia of the chick embryo.
    Type of Publication: Journal article published
    PubMed ID: 25592390
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  • 7
    Keywords: tumor ; GENE-EXPRESSION ; skin carcinogenesis ; COLORECTAL-CANCER ; STEM-CELLS ; SQUAMOUS-CELL CARCINOMA ; beta-catenin ; COLON-CANCER CELLS ; E-cadherin ; WNT ACTIVITY
    Abstract: Aberrant Wnt regulation, detectable by nuclear translocation of beta-catenin, is a hallmark of many cancers including skin squamous cell carcinomas (SCCs). By analyzing primary human skin SCCs, we demonstrate that nuclear beta-catenin is not restricted to SCC cells but also detected in stromal fibroblasts, suggesting an important role for aberrant Wnt regulation also in the tumor microenvironment. When human keratinocytes and fibroblasts were treated with Wnt-3a, fibroblasts proved to be more responsive. Accordingly, Wnt-3a did not alter HaCaT cell functions in a cell-autonomous manner. However, when organotypic cultures (OTCs) were treated with Wnt-3a, HaCaT keratinocytes responded with increased proliferation. As nuclear beta-catenin was induced only in the fibroblasts, this argued for a Wnt-dependent, paracrine keratinocyte stimulation. Global gene expression analysis of Wnt-3a-stimulated fibroblasts identified genes encoding interleukin-8 (IL-8) and C-C motif chemokine 2 (CCL-2) as well as matrix metalloproteinase-1 (MMP-1) as Wnt-3a targets. In agreement, we show that IL-8 and CCL-2 were secreted in high amounts by Wnt-3a-stimulated fibroblasts also in OTCs. The functional role of IL-8 and CCL-2 as keratinocyte growth regulators was confirmed by directly stimulating HaCaT cell proliferation in conventional cultures. Most important, neutralizing antibodies against IL-8 and CCL-2 abolished the Wnt-dependent HaCaT cell hyperproliferation in OTCs. Additionally, MMP-1 was expressed in high amounts in Wnt-3a-stimulated OTCs and degraded the stromal matrix. Thus, our data show that Wnt-3a stimulates fibroblasts to secrete both keratinocyte proliferation-inducing cytokines and stroma-degrading metalloproteinases, thereby providing evidence for a novel Wnt deregulation in the tumor-stroma directly contributing to skin cancer progression. What's new? The Wnt signaling pathway plays a role in many cancers. The central player in this pathway is beta-catenin; when this protein is knocked out, tumors wither and cancer stem cells disappear. In this study, the authors found beta-catenin hanging out in the stromal fibroblasts of a quarter of skin carcinomas. The authors further showed that an active Wnt pathway in the fibroblasts would turn on various growth-promoting elements, including chemokines IL-8 and CCL-2, and matrix-degrading metalloproteinases. These results suggest that activation of the Wnt pathway in the tumor microenvironment helps spur the growth and spread of skin cancer.
    Type of Publication: Journal article published
    PubMed ID: 25403422
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  • 8
    Keywords: tumor ; SYSTEM ; FUSION ; FEASIBILITY ; BIOPSY ; aggressiveness ; 3 T ; GLEASON SCORE ; WEIGHTED MRI ; COEFFICIENT VALUES
    Abstract: OBJECTIVES: The purpose of the study was to evaluate and validate diffusion kurtosis imaging (DKI) for detection grading of peripheral zone prostate cancer (PCa) compared with standard diffusion-weighted imaging (DWI) in a cohort of patients with biopsy-proven PCa. MATERIALS AND METHODS: In this retrospective, single-institutional study, 55 patients (age, 67.5 +/- 6.9 years; range, 52-84 years) who underwent multiparametric magnetic resonance imaging (MRI) before transperineal magnetic resonance/transrectal ultrasound-guided fusion biopsy were included. Suspicious lesions identified in multiparametric MRI underwent image-guided targeted biopsy procedure using a hybrid magnetic resonance/transrectal ultrasound-guided fusion biopsy system. Multiparametric MRI examinations were performed at 3.0 T using a 16-channel phased array coil. Diffusion kurtosis imaging has been acquired with 9 b values (0, 50, 250, 500, 750, 1000, 1250, 1500, and 2000 s/mm). In patients with histologically proven PCa, a representative tumor region was determined as region of interest (ROI) on axial T2-weighted images in consensus by 2 board-certified radiologists. For quantitative evaluation, ROIs located in malignant and contralateral tumor-free regions were transferred to diffusion-weighted images. Diffusion kurtosis imaging parameters (Dapp and Kapp) and apparent diffusion coefficient (ADC) values of the ROIs in tumor and contralateral remote areas were calculated. Estimation of the kurtosis-derived parameters was performed using a voxel-by-voxel fit followed by an ROI-based averaging and a second fit to ROI-averaged signal values. A subgroup analysis was performed to determine the influence of aggressiveness of PCa using ADC, Dapp, and Kapp. The receiver operating characteristic (ROC) curves were calculated for DKI parameters and ADC values. RESULTS: In the 55 patients, the average prostate-specific antigen level was 12.4 +/- 12.6 ng/mL (range, 2.7-75.0 ng/mL), and the median Gleason score was 7 (range, 6-10). Dapp (units, 10 mm/s) was significantly lower in tumor compared with control regions (1.48 +/- 0.35 vs 2.00 +/- 0.32, P 〈 0.05), and Kapp was significantly higher (1.01 +/- 0.21 vs 0.76 +/- 0.14, P 〈 0.05). Dapp was significantly higher than standard ADC (units, 10 mm/s) both in tumor regions and in controls (1.48 +/- 0.35 vs 1.10 +/- 0.25 and 2.00 +/- 0.32 vs 1.43 +/- 0.25, P 〈 0.05). Neither the ROI-based calculation of the kurtosis parameters nor the application of the noise correction significantly changed the DKI parameter estimation. There was no significant difference for the applied fitting method for DKI-derived parameters considering the differentiation between tumor and control tissue. Subsequent ROC analyses did not reveal a significant difference between DKI and ADC for detection of PCa. Sensitivities derived by Youden J statistics cutoff values ranged from 69% to 91% for DKI parameters; specificities ranged from 71% to 89%. Subgroup analysis for DKI (Dapp, Kapp) and ADC for assessing aggressiveness of PCa found significant difference (P 〈 0.05) for discrimination between high- and low-grade findings. However, no significant difference could be obtained between standard DWI- and DKI-derived parameters. CONCLUSIONS: The results of this study demonstrated no significant benefit of DKI for detection and grading of PCa as compared with standard ADC in the peripheral zone determined from b values of 0 and 800 s/mm. For clinical routine application, ADC derived from monoexponential fitting of DWI data remains the standard for characterizing peripheral zone cancer of the prostate.
    Type of Publication: Journal article published
    PubMed ID: 25867657
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  • 9
    Keywords: INVASION ; SURVIVAL ; tumor ; THERAPY ; CLASSIFICATION ; MANAGEMENT ; SOCIETY ; LUNG-CANCER PATIENTS ; CHEMORADIOTHERAPY ; SECTION CT FINDINGS
    Abstract: OBJECTIVE: To characterize the morphological computed tomography (CT) features of pulmonary squamous cell carcinomas (SQCC) submitted to therapeutic resection; to correlate these features with patients' outcomes; and to compare with pulmonary adenocarcinomas (ADC). MATERIALS AND METHODS: Two chest radiologists retrospectively evaluated CT exams of 123 patients with SQCC resected between 2002 and 2008. Tumors' size, location (central vs. peripheral), shape, margins, attenuation, enhancement, presence of calcification, cavitation, internal air bronchograms and pleural tags were assigned by consensus. Prevalence of features was compared with patients' survival data and a previously studied population of ADC surgically resected at the same time period. RESULTS: Cavitation correlated negatively with overall (hazard ratio=3.04), disease-specific (HR=3.67) and disease-free survival (HR=2.69), independent from age, gender, tumor pathological stage, size, and location. In relation to ADC, SQCC presented different shape, margins, attenuation, enhancement, with more cavitation, rare internal air bronchograms, and less pleural tags. Differences were also significant when comparing only the peripheral type of tumors. CONCLUSIONS: Cavitation at CT was an independent and negative predictive factor for SQCC. Different CT morphological features were described for SQCC and ADC. Image evaluation of lung lesions should go beyond measuring and addressing adjacent structures invasion. Adequate imaging characterization not only helps to differentiate benign versus malignant disease and to determine malignancy staging, it may also imply the histologic subtype and improve the prognostic assessment of lung cancer patients.
    Type of Publication: Journal article published
    PubMed ID: 24840477
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  • 10
    Keywords: CELLS ; tumor ; PROTEIN ; immunohistochemistry ; MUTATION ; MELANOMA ; OF-THE-LITERATURE ; LOW-GRADE GLIOMAS ; VEMURAFENIB ; INFANCY
    Abstract: AimsDesmoplastic infantile astrocytoma/ganglioglioma (DIA/DIG) is a rare primary neuroepithelial brain tumour typically affecting paediatric patients younger than 24 months. Knowledge about genetic alterations in DIA/DIG is limited. However, a previous study on BRAF V600E mutation in paediatric glioma revealed a BRAF mutation in one of two tested DIAs/DIGs. The limited number of cases in that study did not allow any conclusion about mutation frequency of BRAF in this tumour entity. MethodsWe collected a series of 18 DIAs/DIGs for testing BRAF V600E mutational status by BRAF V600E immunohistochemistry (clone VE1). Cases with sufficient DNA were tested for BRAF V600E mutation by pyrosequencing. ResultsThree out of 18 DIAs/DIGs presented with VE1 binding. A considerable proportion of BRAF V600E mutated tumour cells was detected in the cortical tumour component, whereas the pronounced leptomeningeal tumoural stroma was predominantly negative for VE1 binding. Pyrosequencing confirmed BRAF V600E mutation in two of three VE1-positive cases. ConclusionBRAF V600E mutation affects a subset of DIAs/DIGs and offers new therapeutic opportunities.
    Type of Publication: Journal article published
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  • 11
    Keywords: tumor ; INHIBITION ; GENE ; METASTATIC MELANOMA ; CUTANEOUS MELANOMA ; IMPROVED SURVIVAL ; BRAF V600E MUTATION ; NRAS MUTATIONS
    Abstract: BACKGROUND: The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial. PATIENTS AND METHODS: We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options. RESULTS: No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p〈0.001). The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p〈0.001) and an elevated serum LDH (hazard ratio 2.5; p〈0.001) were the only factors, which independently predicted survival. CONCLUSIONS: No differences in prognosis were observed according to the BRAF mutational status in patients with distant metastasis treated with monochemotherapy.
    Type of Publication: Journal article published
    PubMed ID: 24586605
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  • 12
    Keywords: CANCER ; tumor ; carcinoma ; COMBINATION ; PERFUSION ; MRI ; prostate carcinoma ; BIOPSY ; aggressiveness ; IVIM ; diffusion imaging
    Abstract: Objective: To compare 2 previously presented algorithms for extracting parameters from intravoxel incoherent motion (IVIM) studies and investigate them in the context of tissue differentiation. Methods: Magnetic resonance imaging (MRI) was performed in 23 patients without histologically proven prostate carcinoma (PCa) and 27 patients with histologically proven PCa. Two methods were used to determine IVIM parameters (f, D, D*). Receiver operating characteristic analysis was performed for IVIM parameters and apparent diffusion coefficient for discrimination of prostate tissue. Results: The IVIM parameters showed no significant difference between patients without PCa and normal areas in patients with PCa (r = 0.46-0.99). Results for D were not significantly different for both methods (P = 0.22), whereas f from method 1 was significantly higher than the f from method 2 (P 〈 0.05). The diffusion parameters D (both methods) and apparent diffusion coefficient could discriminate between tumor and normal areas (receiver operating characteristic analysis, area under the curve, 〉= 0.90). Additionally, in subgroup analysis, only D was able to discriminate between low-and high-grade PCa. Conclusions: For tumor detection, IVIM diffusion does not yield a clear added value, but the perfusion-free diffusion constant D may hold potential for improved image-based tumor grading
    Type of Publication: Journal article published
    PubMed ID: 24733005
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  • 13
    Keywords: EXPRESSION ; tumor ; POPULATION ; chromosome ; LYMPHOCYTES ; OUTCOMES ; LOCUS ; GENOME-WIDE ASSOCIATION ; CONFER SUSCEPTIBILITY ; COMMON VARIANTS
    Abstract: Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2p36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 x 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.
    Type of Publication: Journal article published
    PubMed ID: 24937182
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  • 14
    Keywords: ANGIOGENESIS ; GROWTH-FACTOR ; tumor ; MICE ; BREAST-CANCER ; PROGRESSION ; POOR-PROGNOSIS ; MATRIX METALLOPROTEINASES ; COLLAGENASE-3 EXPRESSION ; SKIN CARCINOMA
    Abstract: Matrix metalloproteinases like MMP-13 cleave and remodel the extracellular matrix and thereby play a crucial role in tumor progression in vivo. Using a highly selective inhibitor to block MMP-13 protein activity, we demonstrate a striking inhibitory effect on invasive tumor growth and vascularization in murine skin squamous cell carcinoma (SCC). Therapy outcome critically depends on animal age in C57Bl/6 mice and was successful in old female but not in young female mice. Treatment success was recovered by ovariectomy in young and abolished by 17ss-estradiol supplementation in old mice, suggesting a hormone dependent inhibitor effect. Responsiveness of the tumorigenic keratinocytes BDVII and fibroblasts to 17ss-estradiol was confirmed in vitro, where MMP-13 inhibitor treatment led to a reduction of cell invasion and vascular endothelial growth factor (VEGF) release. This correlated well with a less invasive and vascularized tumor in treated mice in vivo. 17ss-estradiol supplementation also reduced invasion and VEGF release in vitro with no additional reduction on MMP-13 inhibitor treatment. This suggests that low 17ss-estradiol levels in old mice in vivo lead to enhanced MMP-13 levels and VEGF release, allowing a more effective inhibitor treatment compared to young mice. In our study, we present a strong link between lower estrogen levels in old female mice, an elevated MMP-13 level, which results in a more effective MMP-13 inhibitor treatment in fibroblasts and SCC cells in vitro and in vivo.
    Type of Publication: Journal article published
    PubMed ID: 24676718
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  • 15
    Keywords: CANCER ; tumor ; RADIATION-THERAPY ; VARIABILITY ; HEAD ; FRAMEWORK ; adaptive radiotherapy
    Abstract: The purpose of this study was to test the accuracy of a commercially available deformable image registration tool in a clinical situation. In addition, to demonstrate a method to evaluate the resulting transformation of such a tool to a reference defined by multiple experts. For 16 patients (seven head and neck, four thoracic, five abdominal), 30-50 anatomical landmarks were defined on recognizable spots of a planning CT and a corresponding fraction CT. A commercially available deformable image registration tool, Velocity AI, was used to align all fraction CTs with the respective planning CTs. The registration accuracy was quantified by means of the target registration error in respect to expert-defined landmarks, considering the interobserver variation of five observers. The interobserver uncertainty of the landmark definition in our data sets is found to be 1.2 +/- 1.1 mm. In general the deformable image registration tool decreases the extent of observable misalignments from 4-8 mm to 1-4 mm for nearly 50% of the landmarks (to 77% in sum). Only small differences are observed in the alignment quality of scans with different tumor location. Smallest residual deviations were achieved in scans of the head and neck region (79%, 〈= 4 mm) and the thoracic cases (79%, 〈= 4 mm), followed by the abdominal cases (59%, 〈= 4 mm). No difference is observed in the alignment quality of different tissue types (bony vs. soft tissue). The investigated commercially available deformable image registration tool is capable of reducing a mean target registration error to a level that is clinically acceptable for the evaluation of retreatment plans and replanning in case of gross tumor change during treatment. Yet, since the alignment quality needs to be improved further, the individual result of the deformable image registration tool has still to be judged by the physician prior to application.
    Type of Publication: Journal article published
    PubMed ID: 24423856
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  • 16
    Keywords: SURVIVAL ; tumor ; MUTATIONS ; REVEALS ; BRAF ; ACQUIRED-RESISTANCE ; CANCER GENOME ; VEMURAFENIB ; SEQUENCING DATA ; MEK
    Abstract: Most patients with BRAF(V600)-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAF(V600)-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a "long tail" of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAF(V600)-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.
    Type of Publication: Journal article published
    PubMed ID: 24265153
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  • 17
    Keywords: EXPRESSION ; tumor ; IDENTIFICATION ; HEAD ; NECK-CANCER ; CPG ISLAND SHORES ; GENE PROMOTER HYPERMETHYLATION ; SALIVARY RINSES ; BODY-FLUIDS ; OPCML
    Abstract: OBJECTIVES: The objective of this study was to identify novel survival-associated biomarkers in oral rinse samples collected from patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: We screened for putative survival-associated markers using publicly available methylation array data from 88 OSCC tumors. Cox models were then fit to methylation array data restricted to these putative loci in oral rinse samples of 82 OSCC patients from greater Boston. Pyrosequencing assays were designed for each locus that replicated in the oral rinse samples and applied to a validation set of oral rinse samples from another 61 OSCC patients. RESULTS: We identified 7 survival-associated methylation markers in oral rinse samples from OSCC patients, and have validated one, located in the body of GABBR1, by pyrosequencing. CONCLUSION: The 7 CpG loci identified through this study represent novel prognostic biomarkers for patients with OSCC that can be detected using a non-invasive oral rinse collection technique.
    Type of Publication: Journal article published
    PubMed ID: 25242135
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  • 18
    Keywords: tumor ; THERAPY ; chemotherapy ; METASTATIC MELANOMA ; IMMUNOTHERAPY ; INTERLEUKIN-2 ; CARCINOMA PATIENTS ; INCREASED INTENSITY LYMPHODEPLETION ; MEDIATE REGRESSION ; LYSATE
    Abstract: Adoptive transfer of in vitro-expanded tumor-infiltrating lymphocytes (TIL) has shown great clinical benefit in patients with malignant melanoma. TIL therapy itself has little side effects, but conditioning chemo- or radiotherapy and postinfusion interleukin 2 (IL-2) injections are associated with severe adverse advents. We reasoned that combining TIL infusion with dendritic cell (DC) vaccination could circumvent the need for conditioning and IL-2 support and thus represent a milder treatment approach. Eight patients with stage IV melanoma were enrolled in the MAT01 study, consisting of vaccination with autologous tumor-lysate-loaded DC, followed by TIL infusion. Six of eight patients were treated according to protocol, while one patient received only TIL and one only DC. Treatments were well tolerated with a single grade 3 adverse event. The small study size precludes analysis of clinical responses, though interestingly one patient showed a complete remission and two had stable disease. Analysis of the infusion products revealed that mature DC were generated in all cases. TIL after expansion were CD3+ T cells, dominated by effector memory CD8+ cytotoxic T cells. Analysis of the T cell receptor repertoire revealed presence of highly dominant clones in most infusion products, and many of these could be detected in the circulation for weeks after T cell transfer. Here, we report the first combination of DC vaccination and TIL infusion in malignant melanoma. This combined treatment was safe and feasible, though after evaluating both clinical and immunological parameters, we expect that administration of lymphodepleting chemotherapy and IL-2 will likely increase treatment efficacy.
    Type of Publication: Journal article published
    PubMed ID: 24993563
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  • 19
    Keywords: tumor ; INHIBITION ; RESPONSES ; DENDRITIC CELLS ; REGULATORY T-CELLS ; CATABOLISM ; IDO ; INDOLEAMINE 2,3-DIOXYGENASE ACTIVITY ; ARYL-HYDROCARBON RECEPTOR ; L-TRYPTOPHAN TRANSPORT
    Abstract: The tryptophan (TRP) to kynurenine (KYN) metabolic pathway is now firmly established as a key regulator of innate and adaptive immunity. A plethora of preclinical models suggests that this immune tolerance pathway - driven by the key and rate-limiting enzymes indoleamine-2,3-dioxygenase and TRP-2,3-dioxygenase - is active in cancer immunity, autoimmunity, infection, transplant rejection, and allergy. Drugs targeting this pathway, specifically indoleamine-2,3-dioxygenase, are already in clinical trials with the aim at reverting cancer-induced immunosuppression. In the past years, there has been an increase in our understanding of the regulation and downstream mediators of TRP metabolism, such as the aryl hydrocarbon receptor as a receptor for KYN and kynurenic acid. This more detailed understanding will expand our opportunities to interfere with the pathway therapeutically on multiple levels. Here, we discuss the perspective of targeting TRP metabolism at these different levels based on reviewing recent insight into the regulation of TRP metabolism and its downstream effectors.
    Type of Publication: Journal article published
    PubMed ID: 25628622
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  • 20
    Keywords: CELLS ; GROWTH ; tumor ; PATHWAYS ; PANCREATIC-CANCER ; EGFR ; antiangiogenic therapy ; MYCOPHENOLIC-ACID ; MAMMALIAN PROTEIN ; AKT/PKB
    Abstract: The mTOR signaling plays an integral role in cellular homeostasis controlling the transition between the catabolic and anabolic states. Originally approved as immunosuppressive agents preventing allograft rejection, inhibitors of mTOR signaling have recently entered the arena of cancer therapy. Using rapamycin derivative (RAD001) as a prototype inhibitor, we aimed to systematically analyze the molecular mechanisms underlying the pleiotropic effects of mTOR signaling. Using proliferation- and clonogenic survival assays, a preferential sensitivity of microvascular endothelial cells (HDMVEC) followed by fibroblasts and U87 gliblastoma to RAD001 treatment was found. In contrast, lung- and prostate tumor cells demonstrated relative resistance against RAD001 treatment. In co-culture with fibroblasts, RAD001 exerted potent antiangiogenic effects by inhibiting endothelial cell tube formation. Further, RAD001 treatment efficiently prevented tumor growth in U87 tumor xenografts. Integrative transcriptome analysis was performed to decipher the molecular mechanism underlying RAD001 -induced anti-tumor and antiangiogenic effects. The predominant expression pattern was downregulation of genes after RAD001 treatment in all three sensitive cell types. Among the RAD001 downregulated genes, a transcriptional network was discovered enriched for genes related to angiogenesis processes and extracellular matrix remodeling, e. g., VEGF, HIF1A, CXCLs, IL6, FN, PAI-1 or NRP1. Of note, key components of PI3K upstream (PDK1) as well as mTORC2 downstream signaling (SGK1, NDRG) were downregulated by RAD001. Decreased expression of IMPDH and 139 common gene targets between mycophenolic acid and RAD001 suggested in part shared mechanisms underlying their antiangiogenic and immunosuppressive effects. In summary, key genetic participants governing anti-tumor and anti-angiogenic effects of mTOR inhibition were identified.
    Type of Publication: Journal article published
    PubMed ID: 23530502
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  • 21
    Keywords: SURVIVAL ; tumor ; carcinoma ; SURGERY ; ASSOCIATION ; PROGNOSTIC-SIGNIFICANCE ; STAGE-I ; PREOPERATIVE CHEMOTHERAPY ; EXTENT ; RETRIEVAL
    Abstract: BACKGROUND: Neoadjuvant chemotherapy (NC) is an established therapy in breast cancer, able to downstage positive axillary lymph nodes, but might hamper their detectibility. Even if clinical observations suggest lower lymph node yield (LNY) after NC, data are inconclusive and it is unclear whether NC dependent parameters influence detection rates by axillary lymph node dissection (ALND). METHODS: We analyzed retrospectively the LNY in 182 patients with ALND after NC and 351 patients with primary ALND. Impact of surgery or pathological examination and specific histomorphological alterations were evaluated. Outcome analyses regarding recurrence rates, disease free (DFS) and overall survival (OS) were performed. RESULTS: Axillary LNY was significantly lower in the NC in comparison to the primary surgery group (median 13 vs. 16; p 〈 0.0001). The likelihood of incomplete axillary staging was four times higher in the NC group (14.8% vs. 3.4%, p 〈 0.0001). Multivariate analyses excluded any influence by surgeon or pathologist. However, the chemotherapy dependent histological feature lymphoid depletion was an independent predictive factor for a lower LNY. Outcome analyses revealed no significant impact of the LNY on local and regional recurrence rates as well as DFS and OS, respectively. CONCLUSION: NC significantly reduces the LNY by ALND and has profound effects on the histomorphological appearance of lymph nodes. The current recommendations for a minimum removal of 10 lymph nodes by ALND are clearly compromised by the clinically already established concept of NC. The LNY of less than 10 by ALND after NC might not be indicative for an insufficient axillary staging.
    Type of Publication: Journal article published
    PubMed ID: 24386929
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  • 22
    Keywords: tumor ; SYSTEM ; ANTIGEN ; METASTATIC MELANOMA ; VACCINE ; PERIPHERAL-BLOOD ; CARCINOMA PATIENTS ; DOSE INTERLEUKIN-2 ; CLINICAL CANCER STAGE ; IV-MELANOMA
    Abstract: PURPOSE: To analyze the prognostic relevance and relative impact of circulating myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) compared with functional tumor antigen-specific T cells in patients with melanoma with distant metastasis. EXPERIMENTAL DESIGN: The percentage of CD14(+)CD11b(+)HLA-DR(-/low) MDSCs, CD4(+)CD25(+)FoxP3(+) Tregs, and the presence of NY-ESO-1- or Melan-A-specific T cells was analyzed in 94 patients and validated in an additional cohort of 39 patients by flow cytometry. Univariate survival differences were calculated according to Kaplan-Meier and log-rank tests. Multivariate analyses were performed using Cox regression models. RESULTS: NY-ESO-1-specific T cells, the M-category, and the frequency of MDSCs were associated with survival. The absence of NY-ESO-1-specific T cells and the M-category M1c independently increased the risk of death. In a second Cox model not considering results on antigen-specific T cells, a frequency of 〉11% MDSCs showed independent impact. Its association with survival was confirmed in the additional patient cohort. Median survival of patients with a lower frequency of MDSCs was 13 months versus 8 months for others (P 〈 0.001, combined cohorts). We observed a strong correlation between high levels of MDSCs and the absence of melanoma antigen-specific T cells implying a causal and clinically relevant interaction. No prognostic impact was observed for Tregs. CONCLUSIONS: Circulating CD14(+)CD11b(+)HLA-DR(-/low) MDSCs have a negative impact on survival and inversely correlate with the presence of functional antigen-specific T cells in patients with advanced melanoma. Our findings provide a rationale to investigate MDSC-depleting strategies in the therapeutic setting especially in combination with vaccination or T-cell transfer approaches. Clin Cancer Res; 20(6); 1601-9. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 24323899
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  • 23
    Keywords: tumor ; carcinoma ; MIGRATION ; IMMUNE-RESPONSE ; DUCTAL ADENOCARCINOMA ; collagen ; CCR5 ; Nab-paclitaxel ; CHEMOKINE RECEPTORS CXCR3 ; MATRIX ARCHITECTURE
    Abstract: PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC. EXPERIMENTAL DESIGN: T-cell distribution and ECM structure within tumors were analyzed. Chemokine concentrations in human PDAC were compared with the levels of immune cell infiltration. We assessed the influences of selected chemokines and collagen on directed and random T-cell movement using in vitro migration systems. RESULTS: PDAC overproduced several T-cell-active chemokines, but their levels were not correlated with intratumoral T-cell infiltration. In the absence of collagen, directed migration of activated T cells was induced by chemokines. Interestingly, collagen itself promoted high migratory activity of T cells, but completely abolished chemokine-guided movement. This effect was not altered by a beta1-integrin blocking antibody. Activated T cells actively migrated in low-density collagen matrices, but migration was inhibited in dense collagen. Accordingly, T cells were heterogeneously distributed in the pancreatic cancer stroma, with the majority residing in areas of low-density collagen far from tumor clusters. CONCLUSION: The excessive desmoplasia in PDAC promotes T-cell migration by contact guidance, which abrogates tumor cell-directed movement. Furthermore, dense collagen networks represent a physical barrier, additionally rearranging T-cell distribution to favor tumor stroma. These mechanisms are mainly responsible for intrastromal T-cell trapping in pancreatic cancer and may hinder the development of T-cell-based immunotherapies.
    Type of Publication: Journal article published
    PubMed ID: 24763614
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  • 24
    Keywords: RECEPTOR ; EXPRESSION ; tumor ; THERAPY ; RISK ; BREAST ; OVARIAN-CANCER ; FACTOR-I ; BINDING PROTEIN-3 ; GENOME-WIDE ASSOCIATION
    Abstract: Background The insulin-like growth factor (IGF) signaling pathway has been implicated in prostate cancer (PCa) initiation, but its role in progression remains unknown. Methods Among 5887 PCa patients (704 PCa deaths) of European ancestry from seven cohorts in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium, we conducted Cox kernel machine pathway analysis to evaluate whether 530 tagging single nucleotide polymorphisms (SNPs) in 26 IGF pathway-related genes were collectively associated with PCa mortality. We also conducted SNP-specific analysis using stratified Cox models adjusting for multiple testing. In 2424 patients (313 PCa deaths), we evaluated the association of prediagnostic circulating IGF1 and IGFBP3 levels and PCa mortality. All statistical tests were two-sided. Results The IGF signaling pathway was associated with PCa mortality (P = .03), and IGF2-AS and SSTR2 were the main contributors (both P = .04). In SNP-specific analysis, 36 SNPs were associated with PCa mortality with P-trend less than .05, but only three SNPs in the IGF2-AS remained statistically significant after gene-based corrections. Two were in linkage disequilibrium (r(2) = 1 for rs1004446 and rs3741211), whereas the third, rs4366464, was independent (r(2) = 0.03). The hazard ratios (HRs) per each additional risk allele were 1.19 (95% confidence interval [CI] = 1.06 to 1.34; P-trend = .003) for rs3741211 and 1.44 (95% CI = 1.20 to 1.73; P-trend 〈 .001) for rs4366464. rs4366464 remained statistically significant after correction for all SNPs (P-trend.corr =.04). Prediagnostic IGF1 (HRhighest vs lowest quartile = 0.71; 95% CI = 0.48 to 1.04) and IGFBP3 (HR = 0.93; 95% CI = 0.65 to 1.34) levels were not associated with PCa mortality. Conclusions The IGF signaling pathway, primarily IGF2-AS and SSTR2 genes, may be important in PCa survival.
    Type of Publication: Journal article published
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  • 25
    Keywords: PEPTIDE ; EXPRESSION ; tumor ; DENDRITIC CELLS ; TOLERANCE ; MELANOMA-CELLS ; thymic epithelium ; ALPHA-CHAIN ; PERIPHERAL-TISSUE ANTIGENS ; MEDULLARY EPITHELIAL-CELLS
    Abstract: Immunity to tumor differentiation antigens, such as melanoma antigen recognized by T cells 1 (MART-1), has been comprehensively studied. Intriguingly, CD8(+) T cells specific for the MART-1(26(27)-35) epitope in the context of HLA-A0201 are about 100 times more abundant compared with T cells specific for other tumor-associated antigens. Moreover, MART-1-specific CD8(+) T cells show a highly biased usage of the Valpha-region gene TRAV12-2. Here, we provide independent support for this notion, by showing that the combinatorial pairing of different TCRalpha- and TCRbeta- chains derived from HLA-A2-MART-1(26-35) -specific CD8(+) T-cell clones is unusually permissive in conferring MART-1 specificity, provided the CDR1alpha TRAV12-2 region is used. Whether TCR bias alone accounts for the unusual abundance of HLA-A2-MART-1(26-35) -specific CD8(+) T cells has remained conjectural. Here, we provide an alternative explanation: misinitiated transcription of the MART-1 gene resulting in truncated mRNA isoforms leads to lack of promiscuous transcription of the MART-1(26-35) epitope in human medullary thymic epithelial cells and, consequently, evasion of central self-tolerance toward this epitope. Thus, biased TCR usage and leaky central tolerance might act in an independent and additive manner to confer high frequency of MART-1(26-35) -specific CD8(+) T cells.
    Type of Publication: Journal article published
    PubMed ID: 24846220
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  • 26
    Keywords: GROWTH-FACTOR ; tumor ; FACTOR RECEPTOR ; NECROSIS-FACTOR-ALPHA ; DNA-DAMAGE ; HUMAN FIBROBLASTS ; PROSTATE-CANCER CELLS ; CELLULAR SENESCENCE ; SECRETORY PHENOTYPE ; CONVERTING ENZYME
    Abstract: Cellular senescence, a state of persistent cell cycle arrest, has emerged as a potent tumor suppressor mechanism by restricting proliferation of cells at risk for neoplastic transformation. Senescent cells secrete various growth factors, cytokines, and other proteins that can either elicit the clearance of tumor cells or potentially promote tumor progression. In addition, this senescence-associated secretory phenotype (SASP) includes various factors that are synthesized as transmembrane precursors and subsequently converted into their soluble counterparts. Despite the importance of the SASP to tumor biology, it is virtually unknown how transmembrane proteins are released from senescent cancer cells. Here we show in different models of senescence that the metalloprotease A disintegrin and metalloproteinase 17 (ADAM17) is activated and releases the epidermal growth factor receptor ligand amphiregulin and tumor necrosis factor receptor I (TNFRI) from the surface of senescent cells by ectodomain shedding. ADAM17 activation involves phosphorylation of its cytoplasmic tail by mitogen-activated protein kinase (MAPK) p38. Interestingly, unlike amphiregulin and TNFRI, full-length intercellular adhesion molecule 1 (ICAM1) is released from senescent cells by microvesicles independently of ADAM17. Thus, our results suggest that transmembrane proteins can be released by two distinct mechanisms and point to a crucial role for ADAM17 in shaping the secretory profile of senescent cells.-Effenberger, T., von der Heyde, J., Bartsch, K., Garbers, C., Schulze-Osthoff, K., Chalaris, A., Murphy, G., Rose-John, S., Rabe, B. Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding.
    Type of Publication: Journal article published
    PubMed ID: 25077560
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  • 27
    Keywords: tumor ; CELL-PROLIFERATION ; GENE-EXPRESSION ; SUBCELLULAR-LOCALIZATION ; JUNCTION PROTEIN CLAUDIN-7 ; membrane microdomains ; TIGHT JUNCTION ; CD44 VARIANT ISOFORMS ; metastasis formation ; ANTIGEN EPCAM
    Abstract: Pancreatic cancer has a dismal prognosis because of early metastatic spread, a suggested feature of cancer-initiating cells (CIC). To control for a functional contribution of the pancreatic CIC-marker EpCAM, we explored metastasis formation by a stable EpCAM-knockdown (ASML-EpC(kd) ) of the rat pancreatic adenocarcinoma line BSp73ASML (ASML(wt) ). As EpCAM associates with claudin-7, an ASML-claudin-7-knockdown (ASML-cld7(kd) ) was included to differentiate between EpC- and EpC-cld7-mediated effects. The metastatic capacity of ASML-EpC(kd) and more pronounced ASML-cld7(kd) cells is strikingly reduced. EpC-associated cld7 interferes with EpC-mediated cell-cell adhesion and supports migration. This requires cld7 phosphorylation and formation of an EpC-cld7-tetraspanin-alpha6beta4 complex in glycolipid-enriched membrane domains (GEM), where cld7 associates via the tetraspanin-alpha6beta4 complex with phosphorylated ezrin. The association of cld7 with alpha6beta4 and cytoskeleton strongly stimulates tumor cell migration. However, EpC does not actively contribute. Instead, GEM-located cld7 associates with presenilin-2, which facilitates EpC cleavage and thereby tumor cell proliferation. Finally, the EpC-cld7 complex promotes drug resistance. Both EpC and cld7 support MAPK and JNK activation, such that in ASML-EpC(kd) and ASML-cld7(kd) cells an undue expansion of proapoptotic molecules is observed. Only cld7 promotes activation of the PI3K/Akt pathway by a strong downregulation of Pten. Accordingly, cisplatin treatment prolongs the survival time of ASML-cld7(kd) -bearing rats. Taken together, cld7 supports tumorigenic features of EpC by provoking EpC cleavage and thereby its cotranscription factor activity. On the other hand, only cld7 is directly engaged in motility and apoptosis resistance. Thus, at least in concern of migrating CIC, it is cld7 that acts as a CIC biomarker.
    Type of Publication: Journal article published
    PubMed ID: 23390083
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  • 28
    Keywords: EXPRESSION ; tumor ; BREAST-CANCER ; COLORECTAL-CANCER ; SQUAMOUS-CELL CARCINOMA ; UROKINASE RECEPTOR ; ALPHA(6)BETA(4) INTEGRIN ; ALPHA-6-BETA-4 INTEGRIN ; STRUCTURAL HOMOLOG ; LAMININ-5 GAMMA-2 CHAIN
    Abstract: C4.4A is a metastasis-associated molecule that functions appear to rely on associated alph6beta4 integrin. To corroborate the impact of the C4.4A-alpha6beta4 integrin association on metastasis formation, C4.4A was knocked-down in a highly metastatic rat pancreatic adenocarcinoma (ASML, ASML-C4.4Akd). Metastasis formation by ASML-C4.4Akd cells after intrafootpad application was strongly retarded in draining nodes and lung colonization was rare. Furthermore, cisplatin treatment significantly prolonged the survival time only of ASML-C4.4Akd-bearing rats. ASML-C4.4Akd cells display reduced migratory activity and impaired matrix protein degradation due to inefficient MMP14 activation; loss of drug-resistance is due to mitigated PI3K/Akt pathway activation. These losses of function rely on the laminin receptor C4.4A recruiting activated alpha6beta4 integrin into rafts, where C4.4A cooperates with alpha6beta4 and via alpha6beta4 with MMP14. Within this raft-located complex, MMP14 provokes focalized matrix degradation and mostly alpha6beta4 integrin promotes BAD phosphorylation and upregulated Bcl2 and BclXl expression. Thus, metastasis-promoting activities of C4.4A are not genuine characteristics of C4.4A. Instead, the raft-located laminin receptor C4.4A recruits alpha6beta4 integrin and supports via the alpha6beta4 integrin MMP14 activation. Thereby C4.4A acts as a linker to facilitate several steps in the metastatic cascade. Taking the restricted C4.4A expression in non-transformed tissue, this knowledge should pave the way toward the use of C4.4A as a therapeutic target.
    Type of Publication: Journal article published
    PubMed ID: 23727360
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  • 29
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; CLASSIFICATION ; ASSOCIATION ; chemotherapy ; GLIOMAS ; EUROPEAN ORGANIZATION ; temozolomide ; GLIOBLASTOMA ; IDH1 ; ADJUVANT PROCARBAZINE ; PHASE-3 TRIAL ; 1p/19q ; BRAIN-TUMOR GROUP
    Abstract: OBJECTIVE: To explore whether the isocitrate dehydrogenase 1 (IDH1) or 1p/19q status determines the prognostic vs predictive role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial anaplastic glioma biomarker cohort. METHODS: Patients (n = 183) of the NOA-04 trial with known MGMT and IDH1 status were analyzed for interdependency of the prognostic vs predictive role of MGMT promoter methylation from IDH1 or 1p/19q status and treatment, using progression-free survival (PFS) as an endpoint. An independent validation cohort of the German Glioma Network (n = 75) and the NOA-08 trial (n = 34) served as a confirmation cohort. RESULTS: In tumors with IDH1 mutation, MGMT promoter methylation was associated with prolonged PFS with chemotherapy +/- radiotherapy (RT) or RT-only groups, and is thus prognostic. In tumors without IDH1 mutation, MGMT promoter methylation was associated with increased PFS in patients treated with chemotherapy, but not in those who received RT alone as the first-line treatment, and is thus chemotherapy-predictive. In contrast, 1p/19q codeletions showed no such association with the prognostic vs predictive value of MGMT. CONCLUSIONS: MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1-wild-type, but not IDH1-mutant, malignant gliomas of World Health Organization grades III/IV. Combined IDH1/MGMT assessment may help to individualize clinical decision-making in neuro-oncology.
    Type of Publication: Journal article published
    PubMed ID: 24068788
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  • 30
    Keywords: EXPRESSION ; IONIZING-RADIATION ; SURVIVAL ; tumor ; DIAGNOSIS ; FOLLOW-UP ; COHORT ; GLUTATHIONE ; METALLOTHIONEIN ; GENOME-WIDE ASSOCIATION
    Abstract: We assessed whether variants in 22 oxidative stress-related genes are associated with mortality of breast cancer patients and whether the associations differ according to radiotherapy. Using a prospective cohort of 1348 postmenopausal breast cancer patients, we estimated hazard ratios (HR) and 95% confidence intervals (CI) for 109 single nucleotide polymorphisms (SNPs) using Cox proportional hazards regression. Validation of results was attempted using two Scandinavian studies. Eleven SNPs in MT2A, NFE2L2, NQO1, PRDX1, and PRDX6 were significantly associated with overall mortality after a median follow-up of 5.7 years. Three SNPs in NQO1 (rs2917667) and in PRDX6 (rs7314, rs4916362) were consistently associated with increased risk of dying across all three study populations (pooled: HRNQO1_rs2917667 1.20, 95% CI 1.00-1.44, p = 0.051; HRPRDX6_rs7314 1.16, 95% CI 1.00-1.35, p = 0.056, HRPRDX6_rs4916362 1.14 95% CI 1.00-1.32, p = 0.062). Potential effect modification by radiotherapy was found for CAT_rs769218. In conclusion, genetic variants in NQO1 and PRDX6 may modify breast cancer prognosis.
    Type of Publication: Journal article published
    PubMed ID: 23489758
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  • 31
    Keywords: tumor ; COMBINATION ; QUANTIFICATION ; GENE ; CARCINOEMBRYONIC ANTIGEN ; IMMUNOTHERAPY ; ANTITUMOR IMMUNITY ; GM-CSF ; PANCREATIC-CANCER ; IMMUNOCOMPETENT MURINE MODEL
    Abstract: Abstract Oncolytic measles viruses (MV) derived from the live attenuated vaccine strain have been engineered for increased antitumor activity, and are currently under investigation in clinical phase 1 trials. Approaches with other viral vectors have shown that insertion of immunomodulatory transgenes enhances the therapeutic potency. In this study, we engineered MV for expression of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). For the first time, therapeutic efficacy and adaptive immune response in the context of MV oncolysis could be evaluated in the previously established immunocompetent murine colon adenocarcinoma model MC38cea. MC38cea cells express the human carcinoembryonic antigen (CEA), allowing for infection with retargeted MV. Intratumoral application of MV-GMCSF significantly delayed tumor progression and prolonged median overall survival compared with control virus-treated mice. Importantly, more than one-third of mice treated with MV-GMCSF showed complete tumor remission and rejected successive tumor reengraftment, demonstrating robust long-term protection. An enhanced cell-mediated tumor-specific immune response could be detected by lactate dehydrogenase assay and interferon-gamma enzyme-linked immunospot assay. Furthermore, MV-GMCSF treatment correlated with increased abundance of tumor-infiltrating CD3(+) lymphocytes analyzed by quantitative microscopy of tumor sections. These findings underline the potential of oncolytic, GM-CSF-expressing MV as an effective therapeutic cancer vaccine actively recruiting adaptive immune responses for enhanced therapeutic impact and tumor elimination. Thus, the treatment benefit of this combined immunovirotherapy approach has direct implications for future clinical trials.
    Type of Publication: Journal article published
    PubMed ID: 23642239
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  • 32
    Keywords: EXPRESSION ; tumor ; CELL-LINES ; p53 ; acetylation ; DNA-DAMAGE ; HDAC inhibitors ; CANCER-THERAPY ; valproic acid ; RECEPTOR-MEDIATED APOPTOSIS
    Abstract: BACKGROUND: Osteosarcomas (OS) are highly malignant and radioresistant tumors. Histone deacetylase inhibitors (HDACi) constitute a novel class of anticancer agents. We sought to investigate the effect of combined treatment with suberoylanilide hydroxamic acid (SAHA) and radiotherapy in OS in vivo. METHODS: Clonogenic survival of human OS cell lines as well as tumor growth delay of OS xenografts were tested after treatment with either vehicle, radiotherapy (XRT), SAHA, or XRT and SAHA. Tumor proliferation, necrosis, microvascular density, apoptosis, and p53/p21 were monitored by immunohistochemistry. The CD95 pathway was performed by flow cytometry, caspase (3/7/8) activity measurements, and functional inhibition of CD95 death signaling. RESULTS: Combined treatment with SAHA and XRT markedly reduced the surviving fraction of OS cells as compared to XRT alone. Likewise, dual therapy significantly inhibited OS tumor growth in vivo as compared to XRT alone, reflected by reduced tumor proliferation, impaired angiogenesis, and increased apoptosis. Addition of HDACi to XRT led to elevated p53, p21, CD95, and CD95L expression. Inhibition of CD95 signaling reduced HDACi- and XRT-induced apoptosis. CONCLUSION: Our data show that HDACi increases the radiosensitivity of osteosarcoma cells at least in part via ligand-induced apoptosis. HDACi thus emerge as potentially useful treatment components of OS.
    Type of Publication: Journal article published
    PubMed ID: 23801068
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  • 33
    Keywords: tumor ; THERAPY ; RISK ; mechanisms ; LIGHT ; SUBTYPES ; NURSES HEALTH ; CIRCADIAN DISRUPTION ; MELATONIN ; SHIFT-WORK
    Abstract: Objectives The potential mechanisms that link night-shift work with breast cancer have been extensively discussed. Exposure to light at night (LAN) depletes melatonin that has oncostatic and anti-estrogenic properties and may lead to a modified expression of estrogen receptor (ER) alpha. Here, we explored the association between shift work and breast cancer in subgroups of patients with ER-positive and -negative tumors. Methods GENICA (Gene-ENvironment Interaction and breast CAncer) is a population-based case control study on breast cancer with detailed information on shift work from 857 breast cancer cases and 892 controls. ER status was assessed by immunohistochemical staining. Associations between night-shift work and ER-positive and -negative breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders. Results ER status was assessed for 827 cases and was positive in 653 and negative in 174 breast tumors. Overall, 49 cases and 54 controls were "ever employed" in shift work including night shifts for year. In total, "ever shift work" and "ever night work" were not associated with an elevated risk of ER-positive or -negative breast tumors. Night work for 〉= 20 years was associated with a significantly elevated risk of ER-negative breast cancer [odds ratio (OR) 4.73, 95% confidence interval (95% CI) 1.22-18.36]. Conclusions Our case-control study suggests that long-term night-shift work is associated with an increased risk of ER-negative breast cancers. Further studies on histological subtypes and the analysis of other potentially relevant factors are crucial for discovering putative mechanisms.
    Type of Publication: Journal article published
    PubMed ID: 23543199
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  • 34
    Keywords: CANCER ; EXPRESSION ; tumor ; ACTIVATION ; RESPONSES ; C-MYC ; neuroblastoma ; CHROMOSOMES ; SUBGROUPS ; BRD4
    Abstract: Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications.
    Type of Publication: Journal article published
    PubMed ID: 24231268
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  • 35
    Keywords: CANCER ; tumor ; BIOPSY ; RETROPUBIC PROSTATECTOMY ; DECISION ; PRESERVE ; WHETHER ; RESECT
    Abstract: To evaluate the accuracy of presurgical endorectal MRI (eMRI) for local staging before radical prostatectomy (RP) and its influence on neurovascular bundle (NVB) resection during radical prostatectomy. A total of 385 patients with histologically proven prostate cancer (PCa) have been included in this retrospective study between 2004 and 2008. All patients underwent preoperative eMRI at 1.5 T before open RP. Staging results by eMRI were compared with the histopathological findings. The presence of positive surgical margins and extent of nerve-sparing procedure were evaluated. Subgroup analysis of low-risk group and intermediate to high-risk group based on D'Amico criteria was conducted. In 294 (76.4%) patients, pathological stage was correctly predicted, 69 patients (17.9%) were understaged and 22 (5.7%) overstaged. Overall sensitivity, specificity, negative and positive predictive value for predicting extracapsular extension (ECE) were 41.5, 91.8, 78.0 and 69.0%, respectively. One hundred and fifty-two (48.4%) of the patients classified as stage cT2 by eMRI underwent bilateral NVB sparing, whereas 14 (19.7%) patients with reported ECE underwent bilateral NVB sparing (P 〈 0.01). Overall positive surgical margin rate was 14.8%. Sensitivity of predicting ECE and positive predictive value were lower in the low-risk group than in the intermediate and high-risk group. eMRI is effective in predicting extracapsular extension in an intermediate to high-risk group. Preoperative eMRI in patients with low-risk criteria is not recommended as a routine assessment modality. eMRI findings did appear to influence surgical strategy as patients with imaging findings suggesting 〉 cT2 disease were less likely to undergo NVB sparing.
    Type of Publication: Journal article published
    PubMed ID: 22249342
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  • 36
    Keywords: CANCER ; EXPRESSION ; tumor ; ACTIVATION ; DENDRITIC CELLS ; PERIPHERAL-BLOOD ; inflammation ; BLOOD MONONUCLEAR-CELLS ; IMMUNE SUPPRESSION ; B7 FAMILY
    Abstract: Tumors can suppress the host immune system by employing a variety of cellular immune modulators, such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells (MDSC). In the peripheral blood of patients with advanced stage melanoma, there is an accumulation of CD14(+)HLA-DR(lo/-) MDSC that suppress autologous T cells ex vivo in a STAT-3-dependent manner. However, a precise mechanistic basis underlying this effect is unclear, particularly with regard to whether the MDSC induction mechanism relies on cell-cell contact of melanoma cells with CD14(+) cells. Here, we show that early-passage human melanoma cells induce phenotypic changes in CD14(+) monocytes, leading them to resemble MDSCs characterized in patients with advanced stage melanoma. These MDSC-like cells potently suppress autologous T-cell proliferation and IFN-gamma production. Notably, induction of myeloid-suppressive functions requires contact or close proximity between monocytes and tumor cells. Further, this induction is largely dependent on production of cyclooxygenase-2 (COX-2) because its inhibition in these MDSC-like cells limits their ability to suppress T-cell function. We confirmed our findings with CD14(+) cells isolated from patients with advanced stage melanoma, which inhibited autologous T cells in a manner relying up prostaglandin E2 (PGE2), STAT-3, and superoxide. Indeed, PGE2 was sufficient to confer to monocytes the ability to suppress proliferation and IFN-gamma production by autologous T cells ex vivo. In summary, our results reveal how immune suppression by MDSC can be initiated in the tumor microenvironment of human melanoma. Cancer Res; 73(13); 3877-87. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23633486
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  • 37
    Keywords: CANCER ; EXPRESSION ; SURVIVAL ; tumor ; FACTOR RECEPTOR ; GENES ; PROGRESSION ; AMPLIFICATION ; MULTIFORME ; GLIOMA
    Abstract: Background. Patient-derived glioblastoma (GBM) stem-like cells (GSCs) represent a valuable model for basic and therapeutic research. GSCs are usually propagated in serum-free Neural Basal medium supplemented with bFGF and EGF. Yet, the exact influence of these growth factors on GSCs is still unclear. Recently it was suggested that GBM stemlike cells with amplified EGFR should be cultured in stem cell medium without EGF, as the presence of EGF induced rapid loss of EGFR amplification. However, patient biopsies are usually taken into culture before their genomic profiles are defined. Thus, an important question remains whether GBM cells without EGFR amplification also can be cultured in stem cell medium without EGF. Meterials and methods. To address this question, we used two heterogeneous glioblastoma GSC lines (NCH421k and NCH644) that lack EGFR amplification. Results. Although both cell lines showed very low EGFR expression under standard growth conditions, bFGF stimulation induced higher expression of EGFR in NCH644. In both cell lines, expression of the stem cell markers nestin and CD133 was higher upon stimulation with bFGF compared to EGF. Importantly, bFGF stimulated the growth of both cell lines, whereas EGF had no effect. We verified that the growth stimulation by bFGF was either mediated by proliferation (NCH421k) or resistance to apoptosis (NCH644). Conclusions. We demonstrate that GSC cultures without EGFR amplification can be maintained and expanded with bFGF, while the addition of EGF has no significant effect and therefore can be omitted.
    Type of Publication: Journal article published
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    Keywords: tumor ; LESIONS ; GLIOMA ; NERVOUS-SYSTEM LYMPHOMAS ; MRI FEATURES
    Abstract: Introduction: Reliable differentiation between glioblastoma and primary CNS lymphoma (PCNSL) using conventional MR imaging is challenging, since both entities may show similar appearance on structural MR imaging. Here we analyzed if the appearance of intratumoural susceptibility signals (ITSS) on susceptibility weighted imaging (SWI) may differentiate between both entities. Methods and materials: SWI and contrast enhanced T1-weighted images were acquired from 15 patients with newly diagnosed PCNSL (14 B-cell PCNSL, 1 T-cell PCNSL) and 117 patients with newly diagnosed glioblastoma with a 3 Tesla MR. Additional phase images were available in 8 patients with PCNSL and 88 patients with glioblastoma. Appearance of ITSS was assessed by two readers on SWI and the size of the enhancing lesions on contrast enhanced T1-weighted images were measured. Furthermore it was assessed if ITSS displayed more clearly on SWI or on phase images. Results: ITSS were detected in 106 (reader 1) and 109 (reader 2) glioblastoma, respectively. Both readers identified ITSS within the T-cell PCNSL while both readers did not identify any ITSS within the 14 Bcell PCNSL. Interrarter variability as determined by Cohen kappa was excellent for glioblastoma (kappa = 0.938) and for PCNSL (kappa = 1). The medium size of the enhancing lesion of the glioblastoma that did not harbour ITSS was significantly smaller than the size of the glioblastoma exhibiting ITSS (p 〈 0.008). All identified ITSS displayed more clearly on SWI than on phase images. Conclusion: Presence of ITSS differentiates reliably between glioblastoma and B-cell PCNSL and provides a fast bases for the clinical decision without causing any postprocessing work.
    Type of Publication: Journal article published
    PubMed ID: 23238364
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    Keywords: CELLS ; EXPRESSION ; tumor ; GENE ; DELETION ; immunohistochemistry ; MUTATION ; colorectal cancer ; inactivation ; COLON-CANCER ; HOMOLOG ; ADHESION ; NONPOLYPOSIS COLORECTAL-CANCER ; HNPCC ; MLH1 ; MSH2 ; Lynch syndrome ; EPCAM/TACSTD1 ; multiplex ligation-dependent probe amplification (MLPA)
    Abstract: Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage.Modern Pathology advance online publication, 2 March 2012; doi:10.1038/modpathol.2012.30.
    Type of Publication: Journal article published
    PubMed ID: 22388758
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  • 40
    Keywords: EXPRESSION ; tumor ; INHIBITION ; PATHWAY ; TUMORS ; prognosis ; CLUSTER ; medulloblastoma ; SUBTYPES ; PROFILES ; hsa-miR-182 ; Metastatic dissemination ; POLYCISTRON ; SHH pathway
    Abstract: The contribution of microRNAs to the initiation, progression, and metastasis of medulloblastoma (MB) remains poorly understood. Metastatic dissemination at diagnosis is present in about 30% of MB patients, and is associated with a dismal prognosis. Using microRNA expression profiling, we demonstrate that the retinal miR-183-96-182 cluster on chromosome 7q32 is highly overexpressed in non-sonic hedgehog MBs (non-SHH-MBs). Expression of miR-182 and miR-183 is associated with cerebellar midline localization, and miR-182 is significantly overexpressed in metastatic MB as compared to non-metastatic tumors. Overexpression of miR-182 in non-SHH-MB increases and knockdown of miR-182 decreases cell migration in vitro. Xenografts overexpressing miR-182 invaded adjacent normal tissue and spread to the leptomeninges, phenotypically reminiscent of clinically highly aggressive large cell anaplastic MB. Hence, our study provides strong in vitro and in vivo evidence that miR-182 contributes to leptomeningeal metastatic dissemination in non-SHH-MB. We therefore reason that targeted inhibition of miR-182 may prevent leptomeningeal spread in patients with non-SHH-MB.
    Type of Publication: Journal article published
    PubMed ID: 22134538
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  • 41
    Keywords: tumor ; PHASE-I ; ANTIGEN ; OVARIAN-CANCER ; PROSTATE-CANCER ; FUSION ; GENE-THERAPY ; ADENOVIRUS ; COLONY-STIMULATING FACTOR ; CYTOSINE DEAMINASE ; SODIUM-IODIDE SYMPORTER ; CELL CARCINOMA ; HNSCC ; EGFR ; VIROTHERAPY ; cetuximab ; oncolytic measles virus ; prodrug converting enzyme
    Abstract: First-line treatment of recurrent and/or refractory head and neck squamous cell carcinoma (HNSCC) is based on platinum, 5-fluorouracil (5-FU) and the monoclonal anti EGFR antibody cetuximab. However, in most cases this chemoimmunotherapy does not cure the disease, and more than 50% of HNSCC patients are dying because of local recurrence of the tumors. In the majority of cases, HNSCC overexpress the epidermal growth factor receptor (EGFR), and its presence is associated with a poor outcome. In this study, we engineered an EGFR-targeted oncolytic measles virus (MV), armed with the bifunctional enzyme cytosine deaminase/uracil phosphoribosyltransferase (CD/UPRT). CD/UPRT converts 5-fluorocytosine (5-FC) into the chemotherapeutic 5-FU, a mainstay of HNSCC chemotherapy. This virus efficiently replicates in and lyses primary HNSCC cells in vitro. Arming with CD/UPRT mediates efficient prodrug activation with high bystander killing of non-infected tumor cells. In mice bearing primary HNSCC xenografts, intratumoral administration of MV-antiEGFR resulted in statistically significant tumor growth delay and prolongation of survival. Importantly, combination with 5-FC is superior to virus-only treatment leading to significant tumor growth inhibition. Thus, chemovirotherapy with EGFR-targeted and CD/UPRT-armed MV is highly efficacious in preclinical settings with direct translational implications for a planned Phase I clinical trial of MV for locoregional treatment of HNSCC.
    Type of Publication: Journal article published
    PubMed ID: 22076043
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  • 42
    Keywords: CANCER ; GROWTH ; INHIBITOR ; SURVIVAL ; tumor ; PATHWAYS ; THERAPY ; TYROSINE KINASE ; DISEASE ; IDENTIFICATION ; LESIONS ; leukemia ; ONCOLOGY ; STI571 ; MOLECULAR ANALYSIS ; Molecular targeted therapy ; Individualized therapy ; Molecular carcinogenesis
    Abstract: Increasing understanding of molecular carcinogenesis has begun to change paradigms in oncology. On the diagnostic side, the characterization of key mutations and molecular pathways responsible for tumor development and progression has led to the identification of a large number of potential targets for diagnostic and therapeutic intervention. On the treatment and prevention side, molecular analysis will be of even greater importance for guiding individualized therapy. Diagnostics of molecular lesions present in each tumor will become a key feature of future clinical care. This will allow prediction of response with substantially increased accuracy, stratification of particular patient groups, and eventually personalization of therapy. Striking examples of molecular targeted therapies that have already been established in clinical practice include tyrosine kinase inhibitors in chronic myelogenous leukemia and gastrointestinal stromal tumors, epidermal growth factor receptor (EGFR) inhibition in EGFR-mutated lung cancer, HER2/neu blockade in HER2/neu-positive breast cancer, and anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALK fusion. The scientific development along this line will change the approach to tumor diseases in the future. Patients will be treated according to the specific molecular profiles found in the individual tumor tissue and preferentially with targeted substances, if available.
    Type of Publication: Journal article published
    PubMed ID: 22286581
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  • 43
    Keywords: CELLS ; EXPRESSION ; tumor ; molecular imaging ; BREAST-CANCER ; IDENTIFICATION ; METASTASIS ; PET ; ANTAGONIST ; TUMOR-GROWTH ; gallium-68 ; CXCR4 ; CHEMOKINE RECEPTOR CXCR4 ; HUMAN CANCER XENOGRAFTS ; N-SUCCINIMIDYL ; T140
    Abstract: The expression of the chemokine receptor CXCR4 in tumors is associated with tumor aggressiveness and poor prognosis for the patient and contributes to metastatic seeding. Therefore it is of high interest to find a specific PET tracer for the imaging of CXCR4 expression in tumors. The aim of this study was the synthesis, Ga-68 labeling and first evaluation of DOTA-4-FBn-TN14003 as a potential PET tracer for this purpose. DOTA-4-FBn-TN14003 was synthesized using solid phase peptide synthesis and radiolabeling of this versatile precursor was performed with (6)8(G)a, which was obtained from a Ge-68/Ga-68 generator. Ga-68-DOTA-4-FBn-TN14003 was reproducibly obtained in isolated radiochemical yields of 72.5 +/- 4.9% with an excellent radiochemical purity of 〉99.5%. Specific activities of up to 29.8 +/- 3.1 GBq/mu mol were achieved. In competition binding assays with SDF-1 alpha, human T cell lymphoma Jurkat cells expressed high levels of CXCR4 whereas human breast cancer MDA-MB-231 cells expressed significantly lower levels of this chemokine receptor. The inhibition constants (IC50) of Ga-DOTA-4-FBn-TN14003 and 4-FBn-TN14003 to CXCR4 were determined in a competition assay against I-125-SDF-1 alpha using Jurkat as well as MDA-MB-231 cells. The IC50 values of Ga-DOTA-4-FBn-TN14003 (1.99 +/- 0.31 nM) and 4-FBn-TN14003 (4.07 +/- 1.00 nM) proved to be comparable, indicating negligible influence of the metal complex. These results suggest Ga-68-DOTA-4-FBn-TN14003 as a promising agent for the imaging of CXCR4 expression in tumors and metastases.
    Type of Publication: Journal article published
    PubMed ID: 22264762
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  • 44
    Keywords: CANCER ; EXPRESSION ; GROWTH ; SURVIVAL ; tumor ; IN-VIVO ; PATHWAY ; METABOLISM ; TUMORS ; MARKERS ; CEREBELLUM ; MUTATIONS ; SONIC HEDGEHOG ; CENTRAL-NERVOUS-SYSTEM ; PRECURSORS ; CELL-CYCLE PROGRESSION ; medulloblastoma ; GLYCOLYSIS ; MYC ; GLUTAMINE-METABOLISM ; SHH ; Pediatric brain tumor ; PPAR gamma ; Tumor metabolism
    Abstract: Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis. Indeed, such Shh-mediated metabolic reprogramming fuels tumor progression, in an E2F1- and FASN-dependent manner. Here, we show that the nutrient sensor PPARgamma is a key component of the Shh metabolic network, particularly its regulation of glycolysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposed medulloblastoma cells-of-origin, Shh stimulation elicits a marked induction of PPARgamma alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPARgamma expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPARgamma and/or Rb inactivation inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcriptional regulator define a novel mechanism through which Shh signaling engages the nutrient sensing machinery in brain cancer, controls the cell cycle, and regulates the glycolytic index. This also reveals a dominant role of Shh in the etiology of glucose metabolism in medulloblastoma and underscores the function of the Shh --〉 E2F1 --〉 PPARgamma axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These findings emphasize the value of PPARgamma downstream of Shh as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors.
    Type of Publication: Journal article published
    PubMed ID: 22407012
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