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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; Germany ; KINASE ; PROTEIN ; TISSUE ; TUMORS ; PATIENT ; ACTIVATION ; COMPLEX ; COMPLEXES ; prognosis ; RAT ; ASSOCIATION ; ALPHA ; DESIGN ; colorectal cancer ; COLORECTAL-CANCER ; COLON-CANCER ; BETA ; ADHESION ; MIGRATION ; INTEGRIN ; adenocarcinoma ; POOR-PROGNOSIS ; HUMAN EPIDERMAL-KERATINOCYTES ; HEALTHY ; CELL-MIGRATION ; ALPHA-6-BETA-4 INTEGRIN ; RE ; TUMOR INVASION ; cell migration ; INTERNALIZATION ; ALPHA-3-BETA-1 INTEGRIN ; BETA(1) INTEGRINS ; EXTRACELLULAR-MATRIX PROTEINS ; laminin ; METASTASIS SUPPRESSOR ; TRANSMEMBRANE 4 SUPERFAMILY
    Abstract: Purpose: Patients with pancreatic adenocarcinoma have a poor prognosis due to the extraordinary high invasive capacity of this tumor. Altered integrin and tetraspanin expression is suggested to be an important factor. We recently reported that after protein kinase C activation, colocalization of alpha 6 beta 4 with the tetraspanin CO-029 strongly supports migration of a rat pancreatic adenocarcinoma. The finding led us to explore whether and which integrin-tetraspanin complexes influence the motility of human pancreatic tumors. Experimental Design: Integrin and tetraspanin expression of pancreatic and colorectal adenocarcinoma was evaluated with emphasis on colocalization and the impact of integrin-tetraspanin associations on tumor cell motility. Results: The majority of pancreatic and colorectal tumors expressed the alpha 2, alpha 3, alpha 6, beta 1, and beta 4 integrins and the tetraspanins CD9, CD63, CD81, CD151, and CO-029. Expression of alpha 6 beta 4 and CO-029 was restricted to tumor cells, whereas alpha 1, alpha 2, a3, a6, 1, and CD9, CD81, CD151 were also expressed by the surrounding stroma. CD63, CD81, and beta 1 expression was observed at comparably high levels in healthy pancreatic tissue. alpha 3 beta 1 frequently colocalized and coimmunoprecipitated with CD9, CD81, and CD151, whereas alpha 6 beta 4 colocalized and coimmunoprecipitated mostly with CD151 and CO-029. Notably, protein kinase C activation strengthened only the colocalization of CD151 and CO-029 with beta 4 and was accompanied by internalization of the integrin-tetraspanin complex, decreased laminin 5 adhesion, and increased cell migration. Conclusion: alpha 6 beta 4 is selectively up-regulated in pancreatic and colorectal cancer. The association of alpha 6 beta 4 with CD151 and CO-029 correlates with increased tumor cell motility
    Type of Publication: Journal article published
    PubMed ID: 15837731
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  • 2
    Keywords: ANGIOGENESIS ; endothelial cells ; HISTONE DEACETYLASES ; DEACETYLATION ; cortactin
    Abstract: Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of alpha-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting.
    Type of Publication: Journal article published
    PubMed ID: 21847094
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  • 3
    Keywords: RECEPTOR ; ANGIOGENESIS ; GROWTH-FACTOR ; proliferation ; SYSTEM ; DIFFERENTIATION ; INDUCTION ; HOMEOBOX GENES ; VASCULAR MORPHOGENESIS ; NOTCH
    Abstract: The HLX gene encoding a diverged homeobox transcription factor has been found to be up-regulated by vascular endothelial growth factor-A (VEGF-A) in endothelial cells. We have now investigated the gene repertoire induced by HLX and its potential biologic function. HLX strongly increased the transcripts for several repulsive cell-guidance proteins including UNC5B, plexin-A1, and semaphorin-3G. In addition, genes for transcriptional repressors such as HES-1 were up-regulated. In line with these findings, adenoviral overexpression of HLX inhibited endothelial cell migration, sprouting, and vessel formation in vitro and in vivo, whereas proliferation was unaffected. This inhibition of sprouting was caused to a significant part by HLX-mediated up-regulation of UNC5B as shown by short hairpin RNA (shRNA)-mediated down-modulation of the respective mRNA. VEGF-A stimulation of endothelial cells induced elevated levels of HLX over longer time periods resulting in especially high up-regulation of UNC5B mRNA as well as an increase in cells displaying UNC5B at their surface. However, induction of HLX was strongly reduced and UNC5B up-regulation completely abrogated when cells were exposed to hypoxic conditions. These data suggest that HLX may function to balance attractive with repulsive vessel guidance by up-regulating UNC5B and to down-modulate sprouting under normoxic conditions.
    Type of Publication: Journal article published
    PubMed ID: 21224470
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  • 4
    Keywords: GROWTH ; GENE-EXPRESSION ; DIFFERENTIATION ; mechanisms ; MIGRATION ; TUMOR ANGIOGENESIS ; CANCER-THERAPY ; REGULATOR ; INHIBITORS ; ZEBRAFISH
    Abstract: OBJECTIVE: Histone deacetylases (HDACs) modulate gene expression by deacetylation of histone and nonhistone proteins. Several HDACs control angiogenesis, but the role of HDAC9 is unclear. METHODS AND RESULTS: Here, we analyzed the function of HDAC9 in angiogenesis and its involvement in regulating microRNAs. In vitro, silencing of HDAC9 reduces endothelial cell tube formation and sprouting. Furthermore, HDAC9 silencing decreases vessel formation in a spheroid-based Matrigel plug assay in mice and disturbs vascular patterning in zebrafish embryos. Genetic deletion of HDAC9 reduces retinal vessel outgrowth and impairs blood flow recovery after hindlimb ischemia. Consistently, overexpression of HDAC9 increases endothelial cell sprouting, whereas mutant constructs lacking the catalytic domain, the nuclear localization sequence, or sumoylation site show no effect. To determine the mechanism underlying the proangiogenic effect of HDAC9, we measured the expression of the microRNA (miR)-17-92 cluster, which is known for its antiangiogenic activity. We demonstrate that silencing of HDAC9 in endothelial cells increases the expression of miR-17-92. Inhibition of miR-17-20a rescues the sprouting defects induced by HDAC9 silencing in vitro and blocking miR-17 expression partially reverses the disturbed vascular patterning of HDAC9 knockdown in zebrafish embryos. CONCLUSIONS: We found that HDAC9 promotes angiogenesis and transcriptionally represses the miR-17-92 cluster.
    Type of Publication: Journal article published
    PubMed ID: 23288173
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  • 5
    Keywords: ENDOTHELIAL-CELLS ; NF-KAPPA-B ; MESSENGER-RNA ; CANCER-PATIENTS ; MALIGNANT-MELANOMA ; TNF-ALPHA ; SERUM ; MACROPHAGE INFILTRATION ; PANCREATIC RIBONUCLEASE ; ICAM-1 EXPRESSION
    Abstract: Extracellular RNA (eRNA) released from injured cells promotes tissue permeability, thrombosis, and inflammation in vitro and in vivo, and RNase1 pretreatment can reduce all these effects. In this study, we investigated the role of the eRNA/RNase1 system in tumor progression and metastasis. Under quiescent and stimulatory conditions, tumor cells released much higher levels of endogenous extracellular RNA (eRNA) than nontumor cells. In glioblastomas, eRNA was detected at higher levels in tumors than nontumor tissue. eRNA induced tumor cells to adhere to and migrate through human cerebral microvascular endothelial cells (HCMEC/D3), in a manner requiring activation of VEGF signaling. In addition, eRNA liberated TNF-alpha from macrophages in a manner requiring activation of the TNF-alpha-converting enzyme TACE. Accordingly, supernatants derived from eRNA-treated macrophages enhanced tumor cell adhesion to HCMEC/D3. TNF-alpha release evoked by eRNA relied upon signaling activation of mitogen-activated protein kinases and the NF-kappaB pathway. In subcutaneous xenograft models of human cancer, administration of RNase1 but not DNase decreased tumor volume and weight. Taken together, these results suggest that eRNA released from tumor cells has the capacity to promote tumor cell invasion through endothelial barriers by both direct and indirect mechanisms, including through a mechanism involving TNF-alpha release from tumor-infiltrating monocytes/macrophages. Our findings establish a crucial role for eRNA in driving tumor progression, and they suggest applications for extracellular RNase1 as an antiinvasive regimen for cancer treatment. Cancer Res; 73(16); 5080-9. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23774209
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  • 6
    Abstract: BACKGROUND: Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS: In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. CONCLUSION: Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
    Type of Publication: Journal article published
    PubMed ID: 27084345
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  • 7
    Abstract: BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS: In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. CONCLUSION: Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.
    Type of Publication: Journal article published
    PubMed ID: 27085692
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  • 8
    Keywords: ANGIOGENESIS ; CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; proliferation ; PATHWAY ; segmentation ; GENE ; PROTEIN ; DIFFERENTIATION ; MICE ; PHOSPHORYLATION ; IDENTIFICATION ; MORPHOGENESIS ; TUMOR-GROWTH ; CYTOPLASMIC DOMAIN ; NOTCH ; blood vessels ; DLL4 ; endothelial cell differentiation ; SYNJ2BP ; PDZ DOMAIN
    Abstract: Rationale: The formation of novel blood vessels is initiated by vascular endothelial growth factor. Subsequently, DLL4-Notch signaling controls the selection of tip cells, which guide new sprouts, and trailing stalk cells. Notch signaling in stalk cells is induced by DLL4 on the tip cells. Moreover, DLL4 and DLL1 are expressed in the stalk cell plexus to maintain Notch signaling. Notch loss-of-function causes formation of a hyperdense vascular network with disturbed blood flow. Objective: This study was aimed at identifying novel modifiers of Notch signaling which interact with the intracellular domains of DLL1 and DLL4. Methods and Results: Synaptojanin-2 binding protein (SYNJ2BP; ARIP2) interacted with the PDZ binding motif of DLL1 and DLL4, but not to the Notch ligand JAG1. SYNJ2BP was preferentially expressed in stalk cells, enhanced DLL1 and DLL4 protein stability, and promoted Notch signaling in endothelial cells. SYNJ2BP induced expression of the Notch target genes HEY1, LNFG, and ephrin-B2, reduced phosphorylation of ERK1/2 and decreased expression of the angiogenic factor VEGF-C. It inhibited the expression of genes enriched in tip cells, such as Angiopoietin-2 (ANGPT2), ESM1, and Apelin and impaired tip cell formation. SYNJ2BP inhibited endothelial cell migration, proliferation, and VEGF-induced angiogenesis. This could be rescued by blockade of Notch signaling or application of ANGPT2. SYNJ2BP-silenced human endothelial cells formed a functional vascular network in immunocompromised mice with significantly increased vascular density. Conclusion: These data identify SYNJ2BP as a novel inhibitor of tip cell formation executing its functions predominately by promoting Delta-Notch signaling.
    Type of Publication: Journal article published
    PubMed ID: 24025447
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  • 9
    Abstract: BACKGROUND: Mucosal melanoma (MM) is a rare but diverse cancer entity. Prognostic factors are not well established for Caucasians with MM. PATIENTS AND METHODS: We analysed the disease course of 444 patients from 15 German skin cancer centres. Disease progression was determined with the cumulative incidence function. Survival times were estimated with the Kaplan-Meier method. Prognostic parameters were identified with multivariate Cox regression analysis. RESULTS: Common anatomic sites of primary tumours were head and neck (MMHN, 37.2%), female genital tract (MMFG, 30.4%) and anorectal region (MMAN, 21.8%). MMAN patients showed the highest vertical tumour thickness (p = 0.001), had a more advanced nodal status (p = 0.014) and a higher percentage of metastatic disease (p = 0.001) at diagnosis. Mutations of NRAS (13.8%), KIT (8.6%) and BRAF (6.4%) were evenly distributed across all tumour site groups. Local relapses were observed in 32.4% and most commonly occurred in the MMHN group (p = 0.016). Male gender (p = 0.047), advanced tumour stage (p = 0.001), nodal disease (p = 0.001) and incomplete resection status (p = 0.001) were independent risk factors for disease progression. Overall survival (OS) was highest in the MMFG group (p = 0.030) and in patients without ulceration (p = 0.004). Multivariate risk factors for OS were M stage at diagnosis (p = 0.002) and incomplete resection of the primary tumour (p = 0.001). CONCLUSION: In this large series of MM patients in a European population, anorectal MM was associated with the poorest prognosis.
    Type of Publication: Journal article published
    PubMed ID: 28600969
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  • 10
    Abstract: BACKGROUND: Hotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear. METHODS: The mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed. RESULTS: Mutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p 〈 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 - 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 - 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06-0.48) were significant multivariate risk factors. CONCLUSIONS: NRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.
    Type of Publication: Journal article published
    PubMed ID: 28797232
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