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

Lukas Jennewein, Michael W. Ronellenfitsch, Patrick Antonietti, Elena I. Ilina, Jennifer Jung, Daniela Stadel, Lisa Marie Flohr, Jenny Zinke, Janusz von Renesse, Ulrich Drott, Peter Baumgarten, Anne K. Braczynski, Cornelia Penski, Michael C. Burger, Jean Philippe Theurillat, Joachim P. Steinbach, Karl Heinz Plate, Ivan Dikic, Simone Fulda, Christian BrandtsDonat Kögel, Christian Behrends, Patrick N. Harter, Michel Mittelbronn*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)20016-20032
Number of pages17
JournalOncotarget
Volume7
Issue number15
DOIs
Publication statusPublished - 12 Apr 2016
Externally publishedYes

Keywords

  • Apoptosis
  • Astrocytoma
  • Autophagy
  • Glioblastoma
  • LC3B

Fingerprint

Dive into the research topics of 'Diagnostic and clinical relevance of the autophago-lysosomal network in human gliomas'. Together they form a unique fingerprint.

Cite this