Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas
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Lukas Jennewein1, Michael W. Ronellenfitsch2,3, Patrick Antonietti4, Elena I. Ilina1, Jennifer Jung5, Daniela Stadel5, Lisa-Marie Flohr1, Jenny Zinke1, Janusz von Renesse1, Ulrich Drott1, Peter Baumgarten1,6, Anne K. Braczynski1, Cornelia Penski1,3, Michael C. Burger2, Jean-Philippe Theurillat7, Joachim P. Steinbach2,3, Karl-Heinz Plate1,3, Ivan Dikic3,5, Simone Fulda3,8, Christian Brandts3,9, Donat Kögel3,4, Christian Behrends3,5, Patrick N. Harter1,3, Michel Mittelbronn1,3
1Neurological Institute (Edinger Institute), Goethe University, Frankfurt am Main, Germany
2Senckenberg Institute of Neurooncology, Goethe University, Frankfurt am Main, Germany
3German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
4Experimental Neurosurgery, Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany
5Institute of Biochemistry II, Goethe University, Frankfurt am Main, Germany
6Department of Neurosurgery, Goethe University, Frankfurt am Main, Germany
7Institute of Cell Biology, ETH Zürich, Switzerland
8Institute for Experimental Cancer Research in Pediatrics, Goethe University, Frankfurt am Main, Germany
9Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
Michel Mittelbronn, e-mail: [email protected]
Keywords: astrocytoma, glioblastoma, autophagy, apoptosis, LC3B
Received: September 09, 2015 Accepted: February 15, 2016 Published: March 04, 2016
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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