Cell quiescence correlates with enhanced glioblastoma cell invasion and cytotoxic resistance

Exp Cell Res. 2019 Jan 15;374(2):353-364. doi: 10.1016/j.yexcr.2018.12.010. Epub 2018 Dec 15.


Glioblastoma (GBM) tumor cells exhibit drug resistance and are highly infiltrative. GBM stem cells (GSCs), which have low proliferative capacity are thought to be one of the sources of resistant cells which result in relapse/recurrence. However, the molecular mechanisms regulating quiescent-specific tumor cell biology are not well understood. Using human GBM cell lines and patient-derived GBM cells, Oregon Green dye retention was used to identify and isolate the slow-cycling, quiescent-like cell subpopulation from the more proliferative cells in culture. Sensitivity of cell subpopulations to temozolomide and radiation, as well as the migration and invasive potential were measured. Differential expression analysis following RNAseq identified genes enriched in the quiescent cell subpopulation. Orthotopic transplantation of cells into mice was used to compare the in vivo malignancy and invasive capacity of the cells. Proliferative quiescence correlated with better TMZ resistance and enhanced cell invasion, in vitro and in vivo. RNAseq expression analysis identified genes involved in the regulation cell invasion/migration and a three-gene signature, TGFBI, IGFBP3, CHI3L1, overexpressed in quiescent cells which correlates with poor GBM patient survival.

Keywords: Cancer stem cells; GBM; Gene expression; Glioblastoma; Invasion; Migration; Oregon green; Proliferation; Quiescence; Resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Brain Neoplasms / drug therapy
  • Brain Neoplasms / pathology*
  • Cell Division / drug effects
  • Cell Division / physiology*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / physiology
  • Cell Proliferation / drug effects
  • Cell Proliferation / physiology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / physiology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / drug therapy
  • Glioblastoma / pathology*
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / pathology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Temozolomide / pharmacology
  • Xenograft Model Antitumor Assays / methods


  • Antineoplastic Agents
  • Temozolomide