Role of endolysosomes and pH in the pathogenesis and treatment of glioblastoma

Peter Halcrow, Gaurav Datta, Joyce E. Ohm, Mahmoud L. Soliman, Xuesong Chen, Jonathan D. Geiger

Research output: Contribution to journalReview articlepeer-review

3 Scopus citations

Abstract

Background: Glioblastoma multiforme (GBM) is a Grade IV astrocytoma with an aggressive disease course and a uniformly poor prognosis. Pathologically, GBM is characterized by rapid development of primary tumors, diffuse infiltration into the brain parenchyma, and robust angiogenesis. The treatment options that are limited and largely ineffective include a combination of surgical resection, radiotherapy, and chemotherapy with the alkylating agent temozolomide. Recent findings: Similar to many other forms of cancer, the extracellular environment near GBM tumors is acidified. Extracellular acidosis is particularly relevant to tumorgenesis, and the concept of tumor cell dormancy because of findings that decreased pH reduces proliferation, increases resistance to apoptosis and autophagy, promotes tumor cell invasion, increases angiogenesis, obscures immune surveillance, and promotes resistance to drug and radio-treatment. Factors known to participate in the acidification process are nutrient starvation, oxidative stress, hypoxia, and high levels of anaerobic glycolysis that lead to increases in lactate. Also involved are endosomes and lysosomes (hereafter termed endolysosomes), acidic organelles with highly regulated stores of hydrogen (H+) ions. Endolysosomes contain more than 60 hydrolases as well as about 50 proteins that are known to affect the number, sizes, and distribution patterns of these organelles within cells. Recently, vacuolar ATPase (v-ATPase), the main proton pump that is responsible for maintaining the acidic environment in endolysosomes, was identified as a novel therapeutic target for glioblastoma. Conclusions: Thus, a greater understanding of the role of endolysosomes in regulating cellular and extracellular acidity could result in a better elucidation of GBM pathogenesis and new therapeutic strategies.

Original languageEnglish (US)
Article numbere1177
JournalCancer Reports
Volume2
Issue number6
DOIs
StatePublished - Dec 1 2019
Externally publishedYes

Keywords

  • endolysosomes
  • glioblastoma multiforme (GBM)
  • lysosome destabilizing drugs
  • pH
  • vacuolar ATPase

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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