Abstract A18: Changes in cholesterol metabolism support high-density cell growth and therapeutic resistance in glioblastoma multiforme

Glioblastoma Multiforme (GBM) is a highly aggressive, therapeutically resistant brain tumor that arises from cells of astrocytic lineage. The five year survival rate is just below 10% and this statistic has changed very little in the past decade. Amplification and activating mutations of receptor tyrosine kinases (RTKs) are common in GBM; however despite their oncogenic importance, RTK inhibition with tyrosine kinase inhibitors (TKIs) has been clinically ineffective for GBM. The gap between promising laboratory results and clinical success is a common obstacle in cancer research in part because cell culture models do not accurately mimic complex in vivo conditions and cell behavior, such as therapeutic resistance. Many cell culture studies and high throughput screens of pharmacological agents are performed in cells plated at sub-confluence, or low density. We have found that GBM tumor initiating cells (GBM-TICs) are sensitive to TKIs at low density; however as culture density increases they become resistant, despite equal inhibition of the target RTK and downstream signals. Thus, culturing cells at low and high density provides a novel, isogenic system for studying the cellular mechanisms of therapeutic response. While density does not affect the cell cycle profile of GBM-TICs, we have found that high density cells have lower levels of reactive oxygen species and ATP than low density cells and reduced mitochondrial membrane potential. This suggests a switch to aerobic glycoly...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Cancer Metabolic Pathways: Poster Presentations - Proffered Abstracts Source Type: research