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  • carcinoma  (19)
  • 1
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; tumor ; TUMOR-CELLS ; carcinoma ; Germany ; human ; INHIBITION ; PATHWAY ; PATHWAYS ; DEATH ; HEPATOCELLULAR-CARCINOMA ; PROTEINS ; RNA ; DRUG ; MONOCLONAL-ANTIBODY ; TUMORS ; RELEASE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; MECHANISM ; FAMILY ; DOMAIN ; INDUCTION ; mechanisms ; DOWN-REGULATION ; CYTOCHROME-C ; MITOCHONDRIA ; UNITED-STATES ; RECEPTORS ; OVEREXPRESSION ; TUMOR CELLS ; Bcl-2 ; HUMAN HEPATOCYTES ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; CD95 ; CASPASE ; INHIBITORS ; signaling ; FAMILIES ; SOLID TUMORS ; CYCLOOXYGENASE-2 ; TUMOR-CELL ; death receptor ; downregulation ; function ; caspases ; DRUGS ; cyclooxygenase ; RELEVANCE ; NECROSIS ; MCL-1 ; CELECOXIB-INDUCED APOPTOSIS ; PRIMARY HUMAN HEPATOCYTES
    Abstract: Inhibition of cyclooxygenase (COX)-2 elicits chemopreventive and therapeutic effects in solid tumors that are coupled with the induction of apoptosis in tumor cells. We investigated the mechanisms by which COX-2 inhibition induces apoptosis in hepatocellular carcinoma (HCC) cells. COX-2 inhibition triggered expression of the CD95, tumor necrosis factor (TNIF)-R, and TNF-related apoptosis-inducing ligand (TRAIL)-R1 and TRAIL-R2 death receptors. Addition of the respective specific ligands further increased apoptosis, indicating that COX-2 inhibition induced the expression of functional death receptors. Overexpression of a dominant-negative Fas-associated death domain mutant reduced COX-2 inhibitor-mediated apoptosis. Furthermore, our findings showed a link between COX-2 inhibition and the mitochondrial apoptosis pathway. COX-2 inhibition led to a rapid down-regulation of myeloid cc leukemia-1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, followed by translocation of Bax to mitochondria and cytochrome c release front mitochondria. Consequently, overexpression of Mcl-1 led to inhibition of COX-2 inhibitor-mediated apoptosis. Furthermore, blocking endogenous Mcl-1 function using a small - interfering RNA approach enhanced COX-2 inhibitor-mediated apoptosis. It is of clinical importance that celecoxib acted synergistically with chemotherapeutic drugs in the induction of apoptosis in HCC cells. The clinical relevance of these results is further substantiated by the finding that COX-2 inhibitors did not sensitize primary human hepatocytes toward chemotherapy-induced apoptosis. In conclusion, COX-2 inhibition engages different apoptosis pathways in HCC cells stimulating death receptor signaling, activation of caspases, and apoptosis originating from mitochondria
    Type of Publication: Journal article published
    PubMed ID: 16849551
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  • 2
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; carcinoma ; CELL ; Germany ; INHIBITION ; THERAPY ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; TISSUE ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; CELL-LINES ; treatment ; hepatocellular carcinoma ; resistance ; AGE ; metastases ; NUDE-MICE ; CELL-LINE ; chemotherapy ; leukemia ; LINE ; MODULATION ; p53 ; CANCER-PATIENTS ; CARCINOMAS ; CISPLATIN ; CANCER PATIENTS ; cell lines ; CANCER-THERAPY ; protein expression ; P53 STATUS ; GEMCITABINE ; RE ; cancer therapy ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; corticosteroids ; GLUCOCORTICOIDS ; correlation ; GAMMA-IRRADIATION ; viability ; 5-FU ; xenograft
    Abstract: The glucocorticoid dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. While the potent pro-apoptotic properties and the supportive effects of glucocorticoids to tumour therapy in lymphoid cells are well studied, the impact to cytotoxic treatment of colorectal and hepatocellular carcinoma is unknown. We tested apoptosis-induction, viability, tumour growth and protein expression using 8 established cell lines, 18 surgical specimen and a xenograft on nude mice. In the presence of dexamethasone we found strong inhibition of apoptosis in response to 5-FU, cisplatin, gemcitabine or gamma-irradiation, enhanced viability and tumour growth of colorectal and hepatocellular carcinomas. No correlation with age, gender, histology, TNM, the p53 status and induction of therapy resistance by dexamethasone cotreatment could be detected. These data show that glucocorticoid-induced resistance occurs not occasionally but is common in colorectal and hepatocellular carcinomas implicating that the use of glucocorticoids may be harmful for cancer patients. (c) 2005 Elsevier Ireland Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 16338063
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  • 3
    Keywords: APOPTOSIS ; CELLS ; carcinoma ; Germany ; LUNG ; THERAPY ; TOOL ; TIME ; resistance ; INITIATION ; pancreas ; RE ; pancreatic ; rectum ; viability ; MOLECULAR ANALYSIS ; tumour specimen ; surgical resection ; rectum carcinoma
    Abstract: Surgical resected tumours are often stored for hours in the clinic upon transfer to the bench leading to apoptosis of tumour cells making them no longer suitable for molecular analysis and diagnostic procedures. The way out of this problem may be a new oxygen-enriched solution (OES). We tested this agent using surgical resections of carcinomas of lung, rectum and pancreas. Immediately after resection, one part of each individual tumour was stored in PBS and the other part in OES, and the content of viable or dead cells was determined by trypan blue exclusion and MTT-assay. We found that OES keeps tumour cells up to 3 days and longer more viable than PBS and reduces the percentage of dead cells without inducing therapy resistance and affecting the outcome of experimental procedures. Thus, storing freshly resected tumours in OES may save time for tumour transfer and initiation of experiments
    Type of Publication: Journal article published
    PubMed ID: 16596178
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; carcinoma ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; GENE ; GENES ; LINES ; MICE ; PATIENT ; IMPACT ; INDUCTION ; treatment ; 5-FLUOROURACIL ; prevention ; resistance ; AGE ; NUDE-MICE ; CELL-LINE ; chemotherapy ; LINE ; CARCINOMAS ; specificity ; CISPLATIN ; pancreatic cancer ; CANCER-THERAPY ; CYTOTOXICITY ; signaling ; GEMCITABINE ; RE ; PANCREATIC-CANCER ; cancer therapy ; pancreatic ; GENDER ; dexamethasone ; GLUCOCORTICOID-INDUCED APOPTOSIS ; NAUSEA ; HISTOLOGY ; in vivo ; surgical resection
    Abstract: Background: Chemotherapy for pancreatic carcinoma often has severe side effects that limit its efficacy. The glucocorticoid (GC) dexamethasone (DEX) is frequently used as co-treatment to prevent side effects of chemotherapy such as nausea, for palliative purposes and to treat allergic reactions. While the potent pro-apoptotic properties and the supportive effects of GCs to tumour therapy in lymphoid cells are well studied, the impact of GCs to cytotoxic treatment of pancreatic carcinoma is unknown. Methods: A prospective study of DEX-mediated resistance was performed using a pancreatic carcinoma xenografted to nude mice, 20 surgical resections and 10 established pancreatic carcinoma cell lines. Antiapoptotic signaling in response to DEX was examined by Western blot analysis. Results: In vitro, DEX inhibited drug-induced apoptosis and promoted the growth in all of 10 examined malignant cells. Ex vivo, DEX used in physiological concentrations significantly prevented the cytotoxic effect of gemcitabine and cisplatin in 18 of 20 freshly isolated cell lines from resected pancreatic tumours. No correlation with age, gender, histology, TNM and induction of therapy resistance by DEX co-treatment could be detected. In vivo, DEX totally prevented cytotoxicity of chemotherapy to pancreatic carcinoma cells xenografted to nude mice. Mechanistically, DEX upregulated pro-survival factors and anti-apoptotic genes in established pancreatic carcinoma cells. Conclusion: These data show that DEX induces therapy resistance in pancreatic carcinoma cells and raise the question whether GC-mediated protection of tumour cells from cancer therapy may be dangerous for patients
    Type of Publication: Journal article published
    PubMed ID: 16539710
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  • 5
    Keywords: APOPTOSIS ; CELLS ; SURVIVAL ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; MODEL ; PATHWAY ; TISSUE ; TUMORS ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; INDUCTION ; TISSUES ; treatment ; resistance ; chemotherapy ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; EXTRACELLULAR-MATRIX ; EPITHELIAL-CELLS ; MAMMARY EPITHELIAL-CELLS ; RADIATION-INDUCED APOPTOSIS ; GLYCOGEN-SYNTHASE KINASE-3 ; corticosteroids ; GLUCOCORTICOIDS ; DEXAMETHASONE-INDUCED APOPTOSIS ; OVARIAN FOLLICULAR CELLS ; PACLITAXEL-INDUCED APOPTOSIS ; PHOSPHATIDYLINOSITOL 3-KINASE/AKT PATHWAY
    Abstract: More than a quarter of a century ago, the phenomenon of glucocorticoid-induced apoptosis in the majority of hematological cells was first recognized. More recently, glucocorticoid-induced antiapoptotic signaling associated with apoptosis resistance has been identified in cells of epithelial origin, most of malignant solid tumors and some other tissues. Despite these huge amount of data demonstrating differential pro- and anti-apoptotic effects of glucocortioids, the underlying mechanisms of cell type specific glucocorticoid signaling are just beginning to be described. This review summarizes our present understanding of cell type-specific pro- and anti-apoptotic signaling induced by glucocorticoids. In the first section we give a summary and update of known glucocorticoid-induced pathways mediating apoptosis in hematological cells. We shortly introduce mechanisms of glucocorticoid resistance of hematological cells. We highlight and discuss the emerging molecular evidence of a general induction of survival signaling in epithelial cells and carcinoma cells by glucocorticoids. We provide a model for glucocorticoid-induced resistance in cells growing in a tissue formation. Thus, attachment to the extracellular matrix and cell-cell contacts typical for e.g. epithelial and tumor cells may be crucially involved in switching the balance of several interacting pathways to survival upon treatment with glucocorticoids
    Type of Publication: Journal article published
    PubMed ID: 17191112
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  • 6
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; neoplasms ; DIAGNOSIS ; NEW-YORK ; microarray ; transcription ; TISSUE ; DNA ; MICROARRAY DATA ; MUTATIONS ; Jun ; PHENOTYPE ; vimentin ; HEAD ; adenocarcinoma ; pathology ; BEHAVIOR ; MICROARRAY ANALYSIS ; expression profiling ; TUMOR CELLS ; DIFFERENTIAL-DIAGNOSIS ; CELL CARCINOMA ; OF-THE-LITERATURE ; pancreas ; review ; DUCTAL ADENOCARCINOMA ; AUTOPSY ; analysis ; pancreatic ; TUMOR-CELL ; GENOTYPE ; DNA-MICROARRAY ; USA ; pancreatic ductal adenocarcinoma ; MYOEPITHELIAL CARCINOMA ; pancreatic neoplasm ; PSEUDOPAPILLARY TUMORS
    Abstract: Pancreatic neoplasms have been reliably classified on the basis of their histopathology and immunophenotype. In this study, we report on a pancreatic tumor whose phenotype and genotype could not be assigned to any known tumor entity. The tumor was observed in the pancreatic head of a 54-year-old woman. It was found to be a solid infiltrating carcinoma with abundant clear cells. Apart from cytokeratin, the tumor cells expressed vimentin, S100, and MUC-1. DNA microarray analysis revealed a transcription profile clearly differing from that of normal pancreatic tissue and pancreatic ductal adenocarcinoma. Despite metastatic behavior, the tumor displayed a more favorable course than conventional pancreatic ductal adenocarcinoma. We suggest that this tumor be called solid type clear cell carcinoma of the pancreas
    Type of Publication: Journal article published
    PubMed ID: 17453235
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  • 7
    Keywords: EXPRESSION ; carcinoma ; Germany ; human ; KINASE ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; liver ; NEW-YORK ; PROTEIN ; PROTEINS ; SAMPLE ; SAMPLES ; transcription ; TISSUE ; TRANSDUCTION ; PATIENT ; ACTIVATION ; TRANSCRIPTION FACTOR ; CONTRAST ; PHOSPHORYLATION ; protein kinase ; PROTEIN-KINASE ; signal transduction ; SIGNAL ; antibodies ; antibody ; FORM ; TRANSCRIPTION FACTORS ; DECREASE ; genetics ; SIGNAL-TRANSDUCTION ; MUSCLE ; Jun ; DEGRADATION ; SKELETAL-MUSCLE ; ATROPHY ; pancreatic cancer ; heredity ; REGULATOR ; REGULATORS ; BIOPSY ; ANIMAL-MODELS ; CHAIN ; pancreas ; RE ; PANCREATIC-CANCER ; INCREASE ; TUMORIGENESIS ; HEAVY ; PROTEIN-SYNTHESIS ; WEIGHT ; LEVEL ; PHOSPHATIDYLINOSITOL 3-KINASE ; ANIMAL-MODEL ; USA ; LOSSES ; cachexia ; animal ; ACTIN ; animal model ; BIOPSIES ; comparison ; HYPERTROPHY ; FOXO TRANSCRIPTION FACTORS ; Skeletal muscle ; UBIQUITIN LIGASES
    Abstract: In animal models of cachexia, alterations in the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway have been demonstrated in atrophying skeletal muscles. Therefore, we assessed the activity of proteins in this pathway in muscle and liver biopsies from 16 patients undergoing pancreatectomy for suspect of carcinoma. Patients were divided in a non-cachectic or cachectic group according to their weight loss before operation. Extracts of skeletal muscle and liver tissue from eight cachectic patients with pancreas carcinoma and eight non-cachectic patients were analysed by Western blotting using pan- and phospho-specific antibodies directed against eight important signal transduction proteins of the PI3-K/Akt pathway. Muscle samples from cachectic patients revealed significantly decreased levels of myosin heavy chain (-45%) and actin (-18%) in comparison to non-cachectic samples. Akt protein level was decreased by -55%. The abundance and/or phosphorylation of the transcription factors Foxo1 and Foxo3a were reduced by up to fourfold in muscle biopsies from cachectic patients. Various decreases of the phosphorylated forms of the protein kinases mTOR (-82%) and p70S6K (-39%) were found. In contrast to skeletal muscle, cachexia is associated with a significant increase in phosphorylated Akt level in the liver samples with a general activation of the PI3-K/Akt cascade. Our study demonstrates a cachexia-associated loss of Akt-dependent signalling in human skeletal muscle with decreased activity of regulators of protein synthesis and a disinhibition of protein degradation
    Type of Publication: Journal article published
    PubMed ID: 17333095
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; tumor ; AGENTS ; carcinoma ; CELL ; Germany ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; SAMPLES ; TUMORS ; TIME ; PATIENT ; INDUCTION ; cell cycle ; CELL-CYCLE ; CYCLE ; treatment ; PROGRESSION ; resistance ; INDUCED APOPTOSIS ; PLASMA ; prostate cancer ; PROSTATE-CANCER ; chemotherapy ; ACUTE LYMPHOBLASTIC-LEUKEMIA ; DERIVATIVES ; HEPATOMA-CELLS ; EPITHELIAL-CELLS ; CARCINOMAS ; PHARMACOKINETICS ; AGENT ; SINGLE ; ONCOLOGY ; RE ; EX-VIVO ; SOLID TUMORS ; MEDIATED APOPTOSIS ; MOLECULAR-MECHANISMS ; LEVEL ; analysis ; methods ; PLASMA-LEVELS ; dexamethasone ; PROMOTION ; USA ; GLUCOCORTICOIDS ; prospective ; in vivo ; clinical study
    Abstract: Background: Glucocorticoids have been used widely in conjunction with cancer therapy due to their ability to induce apoptosis in hematological cells and to prevent nausea and emesis. However, recent data including ours, suggest induction of therapy resistance by glucocorticoids in solid tumors, although it is unclear whether this happens only in few carcinomas or is a more common cell type specific phenomenon. Material and Methods: We performed an overall statistical analysis of our new and recent data obtained with 157 tumor probes evaluated in vitro, ex vivo and in vivo. The effect of glucocorticoids on apoptosis, viability and cell cycle progression under diverse clinically important questions was examined. Results: New in vivo results demonstrate glucocorticoid - induced chemotherapy resistance in xenografted prostate cancer. In an overall statistical analysis we found glucocorticoid - induced resistance in 89% of 157 analysed tumor samples. Resistance is common for several cytotoxic treatments and for several glucocorticoid - derivatives and due to an inhibition of apoptosis, promotion of viability and cell cycle progression. Resistance occurred at clinically achievable peak plasma levels of patients under anti - emetic glucocorticoid therapy and below, lasted for a long time, after one single dose, but was reversible upon removal of glucocorticoids. Two nonsteroidal alternative anti - emetic agents did not counteract anticancer treatment and may be sufficient to replace gluco corticoids in cotreatment of carcinoma patients. Conclusion: These data demonstrate the need for prospective clinical studies as well as for detailed mechanistic studies of GC - induced cell - type specific pro - and anti - apoptotic signalling
    Type of Publication: Journal article published
    PubMed ID: 17224649
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  • 9
    Keywords: CANCER ; INVASION ; tumor ; carcinoma ; evaluation ; Germany ; CT ; DIAGNOSIS ; FOLLOW-UP ; SPIRAL CT ; TOOL ; DISEASE ; TUMORS ; computed tomography ; RESOLUTION ; PATIENT ; primary ; NO ; METASTASIS ; adenocarcinoma ; COMPUTED-TOMOGRAPHY ; sensitivity ; specificity ; VESSELS ; QUESTIONNAIRE ; pancreatic carcinoma ; HELICAL CT ; HYDRO-CT ; methods ; ROW CT ; CURVED PLANAR REFORMATIONS ; invasion score ; MULTISLICE SPIRAL CT ; resectability ; VASCULAR INVASION
    Abstract: Objective: It was the aim of this study to evaluate a new infiltration score to determine the resectability of pancreatic carcinomas in preoperative planning. Materials and Methods: Eighty patients with suspected pancreatic tumor were examined prospectively using 16-row spiral CT. The scans were evaluated for the presence of pancreatic carcinoma, peripancreatic tumor extension and vascular invasion using a standardized questionnaire. Invasion of the surgically relevant vessels was evaluated using a new invasion score. The operative and histological findings and the clinical follow-up served as the gold standard. Results: Forty patients had a pancreatic carcinoma, 5 had metastasis of a different primary tumor, and in 35 patients, there was no malignant pancreatic disease. The sensitivity for tumor detection was 100%, with a specificity of 88% for differentiating between malignant and benign pancreatic tumors. Invasion of the surrounding vessels was evaluated correctly using the invasion score, with a sensitivity of 89% and a specificity of 99%. In evaluation of resectability, a sensitivity of 94% and a specificity of 89% were achieved. Conclusion: Using 16-row spiral CT, the invasion score is a valid tool for correctly assessing invasion in relevant vessels in cases of pancreatic carcinoma and for determining resectability. Copyright (C) 2008 S. Karger AG, Basel and IAP
    Type of Publication: Journal article published
    PubMed ID: 18434758
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  • 10
    Keywords: APOPTOSIS ; CANCER ; CANCER CELLS ; CELLS ; EXPRESSION ; GROWTH ; INVASION ; proliferation ; SURVIVAL ; tumor ; carcinoma ; CELL-PROLIFERATION ; Germany ; human ; FOLLOW-UP ; DISEASE ; liver ; PROTEIN ; MOLECULES ; TISSUE ; TUMORS ; TIME ; PATIENT ; MARKER ; DONOR ; prognosis ; TISSUES ; MOLECULE ; BREAST-CANCER ; GLYCOPROTEIN ; IDENTIFICATION ; MALIGNANCIES ; METASTASIS ; metastases ; PCR ; CANCER-CELLS ; ADHESION ; MIGRATION ; CANCER-PATIENTS ; adenocarcinoma ; LIVER METASTASES ; CANCER PATIENTS ; HEALTHY ; pancreatic cancer ; chronic pancreatitis ; SERUM ; ELISA ; MALIGNANCY ; RECOMBINANT ; PANCREATIC-CANCER ; TUMOR-GROWTH ; DUCTAL ADENOCARCINOMA ; INCREASE ; extracellular matrix ; REAL-TIME ; cell adhesion ; cell proliferation ; LEVEL ; OSTEOPONTIN ; SERUM-LEVELS ; downregulation ; function ; BLOCKADE ; IMMUNOHISTOCHEMICAL ANALYSIS ; INVASIVENESS ; lymph node ; LYMPH-NODE ; PLASMA OSTEOPONTIN ; restricting ; serum marker
    Abstract: Pancreatic ductal adenocarcinoma ( PDAC) is one of the most aggressive malignancies, with an overall 5-year survival rate of less than 5%. Invasive tumor growth and early metastasis are two important reasons for this dismal prognosis. Osteopontin ( OPN) is a secretory protein with a variety of functions, for example in cell adhesion and migration, inflammatory reaction and apoptosis. In this study the functional role of OPN in human pancreatic cancer and its potential use as a disease marker were analyzed. By real time quantitative PCR, there was a 2.2- fold and 1.6- fold increase of OPN mRNA in pancreatic cancers (n = 23) and chronic pancreatitis samples (n = 22), respectively, compared to normal pancreatic tissues (n = 20). Immunohistochemical analysis demonstrated OPN staining in 60% of the primary pancreatic tumors and in 72% of the lymph node and liver metastases. ELISA analysis of serum samples obtained from pancreatic cancer patients (n = 70), chronic pancreatitis patients (n = 12), and healthy donors (n = 20) showed a 1.6-fold increase in OPN serum levels in patients with tumors and a 1.9-fold increase in patients with chronic pancreatitis. Recombinant human OPN significantly increased the invasiveness of pancreatic cancer cells, without having any impact on cell proliferation. In addition, downregulation of OPN by specific siRNA molecules decreased pancreatic cancer cell invasion. In conclusion, OPN serum levels in pancreatic cancer and chronic pancreatitis patients are not significantly different, thereby restricting its role as a prognostic or follow-up marker. Our results do suggest, however, that blockade of OPN might be useful as a therapeutic approach to inhibit invasion and metastasis of pancreatic cancer cells
    Type of Publication: Journal article published
    PubMed ID: 15970685
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