Document Detail


Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment.
MedLine Citation:
PMID:  22262369     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy resistant cancer stem cells (CSC) capable of self-renewal and migration. We examined whether autophagy might be involved in survival of CSC despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSC and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia-starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC(high) ), while pancreatic tumour cells with less stem cell markers (CSC(low) ) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC(high) cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC(low) cells as found by RT-PCR and Western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines as evaluated by Western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes to a higher extend in CSC(high) cells. Modulation of autophagy by inhibitors and activators re-sensitized CSC(high) to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest enhanced autophagy levels may enable survival of CSC(high) cells under H/S. Interference with autophagy activating or inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Authors:
Vanessa Rausch; Li Liu; Anja Apel; Theresa Rettig; Jury Gladkich; Sabrina Labsch; Georgios Kallifatidis; Adam Kaczorowski; Ariane Groth; Wolfgang Gross; Martha M Gebhard; Peter Schemmer; Jens Werner; Alexei V Salnikov; Hanswalter Zentgraf; Markus W Büchler; Ingrid Herr
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-19
Journal Detail:
Title:  The Journal of pathology     Volume:  -     ISSN:  1096-9896     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-1-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0204634     Medline TA:  J Pathol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Affiliation:
Molecular OncoSurgery, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany; Department of General Surgery, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany.
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