title: Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas.
abstract: 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.
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Jennewein
authors.affiliation: Senckenberg Institute of Neurooncology, Goethe University, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Ronellenfitsch
authors.affiliation: Experimental Neurosurgery, Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Antonietti
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Elena I
authors.initials: EI
authors.lastname: Ilina
authors.affiliation: Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jung
authors.affiliation: Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stadel
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Lisa-Marie
authors.initials: LM
authors.lastname: Flohr
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Zinke
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Janusz
authors.initials: J
authors.lastname: von Renesse
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Drott
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.|Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Baumgarten
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Braczynski
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Penski
authors.affiliation: Senckenberg Institute of Neurooncology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Burger
authors.affiliation: Institute of Cell Biology, ETH Zürich, Switzerland.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Theurillat
authors.affiliation: Senckenberg Institute of Neurooncology, Goethe University, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Plate
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany.
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt am Main, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Brandts
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Experimental Neurosurgery, Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany.
authors.forename: Donat
authors.initials: D
authors.lastname: Kögel
authors.affiliation: German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Behrends
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000378:metabolism; D002401:Cathepsin B / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D005910:Glioma / Q000175:diagnosis* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000378:metabolism; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C414431:BAG3 protein, human; D000071186:Beclin-1; D014408:Biomarkers, Tumor; C497811:LAMP2 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; C502070:MAP1LC3B protein, human; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D016601:RNA-Binding Proteins; C533912:CTSB protein, human; D002401:Cathepsin B
keywords: LC3B; apoptosis; astrocytoma; autophagy; glioblastoma