Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas

Recently, the conserved intracellular digestion mechanism ‘autophagy’ has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing
Recently, the conserved intracellular digestion mechanism ‘autophagy’ has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing debate about whether blocking autophagy has positive or negative effects in tumor cells. Since there is only poor data about the clinico-pathological relevance of autophagy in gliomas in vivo, we first established a cell culture based platform for the in vivo detection of the autophago-lysosomal components. We then investigated key autophagosomal (LC3B, p62, BAG3, Beclin1) and lysosomal (CTSB, LAMP2) molecules in 350 gliomas using immunohistochemistry, immunofluorescence, immunoblotting and qPCR. Autophagy was induced pharmacologically or by altering oxygen and nutrient levels. Our results show that autophagy is enhanced in astrocytomas as compared to normal CNS tissue, but largely independent from the WHO grade and patient survival. A strong upregulation of LC3B, p62, LAMP2 and CTSB was detected in perinecrotic areas in glioblastomas suggesting micro-environmental changes as a driver of autophagy induction in gliomas. Furthermore, glucose restriction induced autophagy in a concentration-dependent manner while hypoxia or amino acid starvation had considerably lesser effects. Apoptosis and autophagy were separately induced in glioma cells both in vitro and in vivo. In conclusion, our findings indicate that autophagy in gliomas is rather driven by micro-environmental changes than by primary glioma-intrinsic features thus challenging the concept of exploitation of the autophago-lysosomal network (ALN) as a treatment approach in gliomas.
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Metadaten
Author:Lukas Jennewein, Michael Wilfried Ronellenfitsch, Patrick Antonietti, Elena Ilina, Jennifer Jung, Daniela Stadel, Lisa-Marie Flohr, Jenny Zinke, Janusz von Renesse, Ulrich Drott, Peter Baumgarten, Anne Kristin Braczynski, Cornelia Penski, Michael Christian Burger, Jean-Philippe Theurillat, Joachim Peter Steinbach, Karl H. Plate, Ivan Dikic, Simone Fulda, Christian Hubertus Brandts, Donat Kögel, Christian Behrends, Patrick Nikolaus Harter, Michel Guy André Mittelbronn
URN:urn:nbn:de:hebis:30:3-403254
URL:http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=7910
URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991435
DOI:http://dx.doi.org/10.18632/oncotarget.7910
ISSN:1949-2553
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=26956048
Parent Title (English):OncoTarget
Publisher:Impact Journals LLC
Place of publication:[s. l.]
Document Type:Article
Language:English
Date of Publication (online):2016/12/12
Date of first Publication:2016/03/04
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2016/12/12
Tag:LC3B; apoptosis; astrocytoma; autophagy; glioblastoma
Volume:7
Issue:15
Pagenumber:17
First Page:20016
Last Page:20032
Note:
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
HeBIS PPN:421384409
Institutes:Medizin
Exzellenzcluster Makromolekulare Komplexe
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0

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