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  • 1
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; SURVIVAL ; tumor ; TUMOR-CELLS ; carcinoma ; CELL LUNG-CANCER ; Germany ; VITRO ; DISEASE ; LINES ; PATIENT ; ACTIVATION ; RECEPTOR EXPRESSION ; prognosis ; CELL-LINES ; PROGRESSION ; ASSAY ; DESIGN ; NUMBER ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; LINE ; CANCER-CELLS ; MIGRATION ; RECEPTORS ; BEHAVIOR ; POOR-PROGNOSIS ; cell lines ; CELL-MIGRATION ; chemokine ; LOCATION ; ANTAGONIST ; intensity ; LYMPH-NODE METASTASIS ; CHEMOKINE RECEPTORS ; cell migration ; ASSAYS ; DISSEMINATION ; CELL-DERIVED FACTOR ; DISEASE PROGRESSION ; MATURE DENDRITIC CELLS
    Abstract: Purpose: The expression of chemokine receptors CXCR4 and CCR.7 has been associated with tumor dissemination and poor prognosis in a limited number of tumor entities. However, no data are currently available on the impact of chemokine receptor expression on disease progression and prognosis in human colorectal cancer. Experimental Design: The expression of CXCR4 and CCR7 was evaluated in 96 patients with histologically confirmed colorectal cancers and in four colorectal cancer cell lines by immunohistochemical staining. Furthermore, cell migration assays were done with SW480, SW620, and LS174T cancer cells to confirm the effect of the CXCR4 ligand stromal cell-derived factor 1alpha on migration. Results: Human colorectal cancer specimens and cell lines displayed a CXCR4 and CCR7 expression with variable intensities. Interestingly, strong expression of CXCR4, but not of CCR7, was significantly associated with higher Union International Contre Cancer stages 3/4 (P = 0.0017), lymph node metastasis (P = 0.00375), and distant metastasis (P = 0.00003) and further correlated with a reduced 3-year survival rate (P = 0.1). Strong CXCR4 and CCR7 expression positively correlated with the location of the primary tumor in the rectum (P 〈 0.01). Furthermore, activation of CXCR4-expressing cancer cells by stromal cell-derived factor 1alpha resulted in a significant increase of cell migration (P 〈 0.014). Conclusion: Strong expression of CXCR4 by colorectal cancer cells is significantly associated with lymphatic and distant dissemination in patients with colorectal cancer as well as with cancer cell migration in vitro
    Type of Publication: Journal article published
    PubMed ID: 15755995
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  • 2
    Keywords: CANCER ; EXPRESSION ; Germany ; GENE ; PROTEIN ; PROTEINS ; transcription ; TISSUE ; SURGERY ; LINES ; PATIENT ; COMPLEX ; DOMAIN ; tumour ; CELL-LINES ; SEQUENCE ; PROGRESSION ; ASSAY ; Drosophila ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; LINE ; REGION ; MUTATIONS ; ADHESION ; MIGRATION ; cytoskeleton ; POLYMERASE-CHAIN-REACTION ; cell lines ; CELL-MIGRATION ; BINDS ; CELL POLARITY ; MAPS ; colon cancer ; TUMORIGENESIS ; cell adhesion ; cell migration ; ASSAYS ; SUPPRESSOR ; tumour suppressor ; APC ; 17P11.2 ; Hugl-1 ; II HEAVY-CHAIN ; LETHAL-GIANT-LARVAE ; lgl
    Abstract: The human gene, human giant larvae (Hugl-1/Llg1/Lgl1) has significant homology to the Drosophila tumour suppressor gene lethal( 2) giant larvae (lgl). The lgl gene codes for a cortical cytoskeleton protein, Lgl, that binds Myosin II and is involved in maintaining cell polarity and epithelial integrity. The human protein, Hugl-1 contains several conserved functional domains found in Lgl, suggesting that these proteins may have closely related functions. Whether loss of Hugl expression plays a role in human tumorigenesis has so far not been extensively investigated. Thus, we evaluated tumour tissues from 94 patients undergoing surgery for colorectal cancer (CRC) for loss of Hugl-1 transcription and compared our findings with the clinical data from each of these patients. We found that Hugl-1 was lost in 75% of tumour samples and these losses were associated with advanced stage and particularly with lymph node metastases. Reduced Hugl-1 expression during the adenoma-carcinoma sequence occurring as early as in colorectal adenomas was detected by both immunohistochemical and reverse transcription polymerase chain reaction analysis. Functional assays with ecdysone-inducible cell lines revealed that Hugl-1 expression increased cell adhesion and decreased cell migration. Our studies thus indicate that downregulation of Hugl-1 contributes to CRC progression
    Type of Publication: Journal article published
    PubMed ID: 15735678
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  • 3
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; IN-VITRO ; INVASION ; proliferation ; CELL ; Germany ; IN-VIVO ; LUNG ; MODEL ; PATHWAY ; VITRO ; VIVO ; SAMPLE ; SAMPLES ; transcription ; DIFFERENTIATION ; LINES ; MICE ; IMPACT ; prognosis ; CELL-LINES ; PHOSPHORYLATION ; TARGET ; ASSAY ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; metastases ; SIGNALING PATHWAY ; CANCER-CELLS ; MIGRATION ; POLYMERASE-CHAIN-REACTION ; adenocarcinoma ; TARGETS ; cell lines ; AKT ; HOMEOBOX GENE ; signaling ; HUMAN PROSTATE ; development ; ASSAYS ; PROGENITORS ; colorectal ; TAIL ; MicroRNAs ; POLYMERASE ; CANCER-CELL-LINES ; RESTRICTION ; Homeobox ; HOXB8 ; HUMAN LUNG CANCERS ; Micro-RNA ; miR-196a
    Abstract: AIM: To analyze the relevance of the microRNA miR-196a for colorectal oncogenesis. METHODS: The impact of miR-196a on the restriction targets HoxA7, HoxB8, HoxC8 and HoxD8 was analyzed by reverse transcription polymerase chain reaction (RT-PCR) after transient transfection of SW480 cancer cells. The miR-196a transcription profile in colorectal cancer samples, mucosa samples and diverse cancer cell lines was quantified by RT-PCR. Transiently miR-196a-transfected colorectal cancer cells were used for diverse functional assays in vitro and for a xenograft lung metastasis model in vivo. RESULTS: HoxA7, HoxB8, HoxC8 and HoxD8 were restricted by miR-196a in a dose-dependent and gene-specific manner. High levels of miR-196a activated the AKT signaling pathway as indicated by increased phosphorylation of AKT. In addition, high levels of miR-196a promoted cancer cell detachment, migration, invasion and chemosensitivity towards platin derivatives but did not impact on proliferation or apoptosis. Furthermore, miR-196a increased the development of lung metastases in mice after tail vein injection. CONCLUSION: miR-196a exerts a pro-oncogenic influence in colorectal cancer.(C) 2009 The WIG Press and Baishideng. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 19418581
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; tumor ; carcinoma ; CELL ; Germany ; CLASSIFICATION ; SURGERY ; T-CELL ; T-CELLS ; BREAST-CANCER ; PROGRESSION ; immunohistochemistry ; METASTASIS ; colorectal cancer ; COLORECTAL-CANCER ; LYMPHOCYTES ; CANCER-PATIENTS ; IMMUNITY ; GASTRIC-CANCER ; inflammation ; CHEMOKINE RECEPTOR ; CCR5 ; PROGNOSTIC-FACTOR ; IMMUNE ; CCL5/RANTES ; T-cell infiltration
    Abstract: Chemokines and their receptors have been proposed to distinctly contribute to tumor growth, dissemination, and local immune escape. The aim of this study was to evaluate the relevance of the chemokine receptor CCR5 expression for the progression of human colorectal cancer. CCR5 expression was assessed by RT-PCR analysis in 103 colorectal cancer patients. Intensity of CCR5 expression was correlated with both tumor and patient characteristics. Infiltration of tumor margins with CD8(+) T cells in the context of CCR5 expression was analyzed by immunohistochemistry in additional 18 colorectal cancer specimens. Human colorectal cancer revealed variable intensities of CCR5 expression ranging from absent (48/103: 47%), weak (30/103: 29%), intermediate (13/103: 13%), to strong (12/103: 12%). Absent or weak CCR5 expression was significantly associated with advanced UICC stages (P = 0.02) and lymphatic metastasis (P = 0.05). In addition, CCR5 expression positively correlated with CD8(+) T-cell infiltration in tumor margins (P = 0.001). In summary, intermediate and strong CCR5 expression was significantly associated with nonmetastatic colorectal cancer and increased CD8(+) T-cell infiltration
    Type of Publication: Journal article published
    PubMed ID: 20054600
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  • 5
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; SURVIVAL ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; KINASE ; TYROSINE KINASE ; GENES ; SURGERY ; IMPACT ; ALPHA ; TARGET ; PROGRESSION ; PATTERNS ; METASTASIS ; STOMACH ; adenocarcinoma ; RECEPTORS ; CELL CARCINOMA ; PATTERN ; overall survival ; UPDATE ; LYMPH-NODE ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; gastric ; ESOPHAGEAL ; PDGFR ; gastric adenocarcinoma ; RATIONALE ; COEXPRESSION ; MOLECULAR TARGETING STRATEGY ; RECEPTOR-TYROSINE-KINASE
    Abstract: Background/Aims: This study was initiated in order to define the (co-)expression patterns of target receptor tyrosine kinases (RTKs) in human gastric adenocarcinoma and to correlate them with clinicopathological parameters. Methodology: The (co-)expression pattern of VEGFR1, VEGFR2,VEGFR3, PDGFR alpha, PDGFR beta and EGFR1 was analyzed in 56 samples of human gastric adenocarcinoma and correlated with staging and survival. Results: VEGFR1,VEGFR2, VEGFR3, PDGFRa, PDGFR beta and EGFR1 were expressed at relevant levels in 79%, 50%, 50%, 63%, 55% and 30%, respectively. VEGFR2,VEGFR3, and PDGFR beta were significantly co-expressed. Thirty-four percent of gastric adenocarcinoma samples revealed a co-expression of 6 receptors, 27% expressed 5 receptors and only 23% showed expression of 3 receptors or less. Expression of VEGFR1, VEGFR2, VEGFR3, PDGFR alpha, PDGFR beta and EGFR1 in gastric adenocarcinoma did not significantly correlate with a higher pT-category, the presence of lymph node metastasis (pN+) or overall survival. However, a trend towards a higher pT-category was seen for expression of VEGFR1 without reaching statistical significance. Conclusions: The data obtained reveal that specific RTKs are significantly co-expressed. However, co-expression of RTKs did not impact on staging or survival. It has to be further analyzed, if the expression of the respective ligands is of higher relevance than the expression of the receptor itself
    Type of Publication: Journal article published
    PubMed ID: 20583450
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; EXPRESSION ; GROWTH-FACTOR ; IN-VITRO ; HEPATOCELLULAR-CARCINOMA ; GASTRIC-CANCER ; Gadd45 ; MULTIKINASE INHIBITOR SORAFENIB ; INFUSIONAL FLUOROURACIL
    Abstract: We initiated this preclinical study in order to analyze the impact of sorafenib single treatment versus combination treatment in human colorectal cancer. The effect of increasing sorafenib doses on proliferation, apoptosis, migration, and activation of signal cascades was analyzed in vitro. The effect of sorafenib single treatment versus 5-fluorouracil (5-FU) single treatment and combination therapy on in vivo proliferation and target cytokine receptor/ligand expression was analyzed in a human colon cancer xenograft mouse model using HT29 tumor cells. In vitro, SW480 and HT29 cell lines were sensitive to sorafenib, as compared to Caco2 and SW620 cell lines, independent of the mutation status of K-ras, Raf, PTEN, or PI3K. The effect on migration was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib + 5-FU; irinotecan) and disadvantageous in others (sorafenib + oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. Sensitive cell lines revealed a downregulation of AKT and had a weak expression level of GADD45 beta. In resistant cell lines, pp53 and GADD45 beta levels decreased upon sorafenib exposure. In vivo, the combination treatment of sorafenib and 5-FU was equally effective as the respective monotherapy concerning tumor proliferation. Interestingly, treatment with either sorafenib or 5-FU resulted in a significant decrease of VEGFR1 and PDGFR beta expression intensity. In colorectal cancer, a sensitivity towards sorafenib exists, which seems similarly effective as a 5-FU monotherapy. A combination therapy, in contrast, does not show any additional effect.
    Type of Publication: Journal article published
    PubMed ID: 22983756
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; COMBINATION ; ENDOTHELIAL GROWTH-FACTOR ; Germany ; human ; THERAPY ; GENES ; SAMPLE ; SAMPLES ; TUMORS ; ALPHA ; TARGET ; NO ; PROGRESSION ; MEMBRANE ; METASTASIS ; BETA ; CARCINOMAS ; RT-PCR ; STRATEGIES ; STOMACH ; adenocarcinoma ; ADENOCARCINOMAS ; TUMOR CELLS ; VEGF ; targeting ; molecular ; PATTERN ; THERAPIES ; EGFR ; analysis ; methods ; TUMOR-CELL ; NUCLEAR ; CANCERS ; receptor tyrosine kinase ; RECEPTOR TYROSINE KINASES ; gastric ; PDGFR ; SUNITINIB ; VEGFR
    Abstract: AIM: To define the (co-)expression pattern of target receptor-tyrosine-kinases (RTK) in human gastric adenocarcinoma. METHODS: The (co-)expression pattern of VEGFRI-3, PDGFR alpha/beta and EGFR1 was analyzed by RT-PCR in 51 human gastric adenocarcinomas. In addition, IHC staining was applied for confirmation of expression and analysis of RTK localisation. RESULTS: The majority of samples revealed a VEGFR1 (98%), VEGFR2 (80%), VEGFR3 (67%), PDGFR alpha (82%) and PDGFR beta (82%) expression, whereas only 62% exhibited an EGFR1 expression. 78% of cancers expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRa revealed a predominantly cytoplasmatic staining in tumor cells, accompanied by an additional nuclear staining for VEGFR3, EGFR1 was almost exclusively detected on the membrane of tumor cells. PDGFR,8 was restricted to stromal pericytes, which also depicted a PDGFRa expression. CONCLUSION: Our results reveal a high rate ofreceptor-tyrosine-kinases coexpression in gastric adenocarcinoma and might therefore encourage an application of multiple-target RTK-inhibitors within a combination therapy. (c) 2007 WJG. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17659711
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  • 8
    Keywords: RECEPTOR ; EXPRESSION ; carcinoma ; CELL ; VOLUME ; DISEASE ; chemokine ; CELL CARCINOMA ; renal cell carcinoma ; ONCOLOGY ; correlates ; CORRELATE ; RENAL-CELL
    Type of Publication: Journal article published
    PubMed ID: 19266088
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  • 9
    Keywords: BLOOD ; carcinoma ; liver ; MESSENGER-RNA ; colorectal cancer ; DISSEMINATED TUMOR-CELLS ; MICROMETASTASES ; IMMUNITY ; T-LYMPHOCYTES ; LIVER METASTASES ; TUMOR CELLS ; RECTAL-CANCER ; CHEMOKINE RECEPTOR ; CCR5 ; PROGNOSTIC-FACTOR ; LYMPH-NODE ; Molecular metastases
    Abstract: Molecular metastases are precursors of postoperative recurrence, detected by molecular-biological tools. Chemokines and their receptors contribute to dissemination and local immune recognition. A strong expression of the chemokine receptor CCR5 is associated with non-metastatic colorectal cancer and increased CD8+ T-cell infiltration. The aim of this study was to analyze whether CCR5 expression correlates with the presence of hepatic molecular metastases (MM). Ninety-three patients undergoing elective surgery for colorectal cancer were assessed. The K-ras mutation status was defined by PCR-RFLP, and the CCR5 expression status was analyzed by CCR5-specific reverse transcription (RT-PCR) analysis. Liver biopsy samples had been intra-operatively taken to screen for MM. MM were detected by K-ras-specific PCR-RFLP and nested CK20/GCC RT-PCR. Prevalence of MM was correlated with CCR5 expression status. Human colorectal cancer harboured K-ras mutations in 53% (codon 12: 47%; codon 13: 6%) of cases. Among K-ras mutants, MM were detected in 27-53% of patients, dependent on the technique applied (K-ras-specific PCR-RFLP assay vs. nested CK20/GCC RT-PCR approach (P = 0.004)). CCR5 expression of K-ras mutants ranged from absent (23/49: 47%), weak (17/49: 35%), intermediate (4/49: 8%) to strong (5/49: 10%). MM were found in 30% of CCR5 negative and in 23% of CCR5 positive cancer patients by the K-ras-specific PCR-RFLP assay. The nested CK20/GCC RT-PCR assay detected MM in 87% of CCR5 negative and in 27% of CCR5 positive colorectal cancer patients (P = 0.00002). Thus, CCR5 expression of the primary cancer might be a valuable biomarker indicating the absence of hepatic molecular metastases
    Type of Publication: Journal article published
    PubMed ID: 21468700
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  • 10
    Keywords: RECEPTOR ; CANCER ; EXPRESSION ; GROWTH ; IN-VITRO ; INVASION ; SURVIVAL ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; DISEASE ; PATIENT ; STAGE ; PROGRESSION ; immunohistochemistry ; TUMOR PROGRESSION ; METASTASIS ; metastases ; ADHESION ; MIGRATION ; INTEGRIN ; pancreatic cancer ; ANTAGONIST ; IMMUNE ESCAPE ; CHEMOKINE RECEPTOR ; pancreas ; PANCREATIC-CANCER ; TUMOR-GROWTH ; chemokines ; ESCAPE ; pancreatic ; CXCR4 ; METASTATIC BEHAVIOR
    Abstract: Certain chemokines have been proposed to distinctly contribute to tumor growth, dissemination and local immune escape. Expression of the chemokine receptor CXCR4 has been linked to tumor progression in diverse tumor entities. The aim of this study was to evaluate if the expression of CXCR4 influences progression of human pancreatic cancer. CXCR4 expression of pancreatic cancer was retrospectively assessed by immunohistochemistry in 103 patients with pancreatic cancer. Intensity of CXCR4 expression was correlated with both tumor and patient characteristics. Human pancreatic cancer revealed variable intensities of CXCR4 expression. Strong CXCR4 expression was significantly associated with advanced UICC stages (P = 0.03) and revealed a trend for hematogenous metastasis (P = 0.09) and progressed local tumor stages (P = 0.15). In summary, strong expression of CXCR4 was significantly associated with advanced pancreatic cancer
    Type of Publication: Journal article published
    PubMed ID: 17089032
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