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The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy
The Journal of pathology, 2019-11, Vol.249 (3), p.332-342
Reader, Claire S
Vallath, Sabari
Steele, Colin W
Haider, Syed
Brentnall, Adam
Desai, Ami
Moore, Kate M
Jamieson, Nigel B
Chang, David
Bailey, Peter
Scarpa, Aldo
Lawlor, Rita
Chelala, Claude
Keyse, Stephen M
Biankin, Andrew
Morton, Jennifer P
Evans, TR Jeffry
Barry, Simon T
Sansom, Owen J
Kocher, Hemant M
Marshall, John F
2019
Volltextzugriff (PDF)
Details
Autor(en) / Beteiligte
Reader, Claire S
Vallath, Sabari
Steele, Colin W
Haider, Syed
Brentnall, Adam
Desai, Ami
Moore, Kate M
Jamieson, Nigel B
Chang, David
Bailey, Peter
Scarpa, Aldo
Lawlor, Rita
Chelala, Claude
Keyse, Stephen M
Biankin, Andrew
Morton, Jennifer P
Evans, TR Jeffry
Barry, Simon T
Sansom, Owen J
Kocher, Hemant M
Marshall, John F
Titel
The integrin αvβ6 drives pancreatic cancer through diverse mechanisms and represents an effective target for therapy
Ist Teil von
The Journal of pathology, 2019-11, Vol.249 (3), p.332-342
Ort / Verlag
Chichester, UK: John Wiley & Sons, Ltd
Erscheinungsjahr
2019
Quelle
Wiley Blackwell Single Titles
Beschreibungen/Notizen
Pancreatic ductal adenocarcinoma (PDAC) has a 5‐year survival rate of less than 4% and desperately needs novel effective therapeutics. Integrin αvβ6 has been linked with poor prognosis in cancer but its potential as a target in PDAC remains unclear. We report that transcriptional expression analysis revealed that high levels of β6 mRNA correlated strongly with significantly poorer survival (n = 491 cases, p = 3.17 × 10−8). In two separate cohorts, we showed that over 80% of PDACs expressed αvβ6 protein and that paired metastases retained αvβ6 expression. In vitro, integrin αvβ6 promoted PDAC cell growth, survival, migration, and invasion. Treatment of both αvβ6‐positive human PDAC xenografts and transgenic mice bearing αvβ6‐positive PDAC with the αvβ6 blocking antibody 264RAD, combined with gemcitabine, significantly reduced tumour growth (p < 0.0001) and increased survival (log‐rank test, p < 0.05). Antibody therapy was associated with suppression of tumour cell activity (suppression of pErk growth signals, increased apoptosis seen as activated caspase‐3) and suppression of the pro‐tumourigenic microenvironment (suppression of TGFβ signalling, fewer αSMA‐positive myofibroblasts, decreased blood vessel density). These data show that αvβ6 promotes PDAC growth through both tumour cell and tumour microenvironment mechanisms and represents a valuable target for PDAC therapy. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Sprache
Englisch
Identifikatoren
ISSN: 0022-3417
eISSN: 1096-9896
DOI: 10.1002/path.5320
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6852434
Format
–
Schlagworte
264RAD
,
Adenocarcinoma
,
Animals
,
Antigens, Neoplasm - genetics
,
Antigens, Neoplasm - metabolism
,
Antineoplastic Agents, Immunological - pharmacology
,
Apoptosis
,
Blocking antibodies
,
cancer
,
Carcinoma, Pancreatic Ductal - drug therapy
,
Carcinoma, Pancreatic Ductal - metabolism
,
Carcinoma, Pancreatic Ductal - mortality
,
Carcinoma, Pancreatic Ductal - secondary
,
Caspase
,
Cell Line, Tumor
,
Cell migration
,
Cell Movement
,
Cell Proliferation
,
Cell survival
,
Dual Specificity Phosphatase 6 - genetics
,
Female
,
Gemcitabine
,
Gene Expression Regulation, Neoplastic
,
Genes, ras
,
Humans
,
Immunotherapy
,
Integrases - genetics
,
integrin
,
Integrins - antagonists & inhibitors
,
Integrins - genetics
,
Integrins - metabolism
,
Italy
,
Medical prognosis
,
Metastases
,
Mice, Nude
,
Mice, Transgenic
,
mouse model
,
Neoplasm Invasiveness
,
Original Paper
,
Original Papers
,
pancreas
,
Pancreatic cancer
,
Pancreatic Neoplasms - drug therapy
,
Pancreatic Neoplasms - metabolism
,
Pancreatic Neoplasms - mortality
,
Pancreatic Neoplasms - pathology
,
PDAC
,
Rank tests
,
Signal Transduction
,
Survival
,
Transcription
,
transgenic
,
Transgenic mice
,
Tumor Burden
,
Tumor Microenvironment
,
Tumors
,
United Kingdom
,
Xenograft Model Antitumor Assays
,
Xenografts
,
αvβ6
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