Tumor hypoxic microenvironment causes
hypoxia inducible factor 1 alpha (HIF-1α) activation and
necrosis with
alarmins release. Importantly, HIF-1α also controls the expression of
alarmin receptors in
tumor cells that can bind to and be activated by
alarmins. Human
tumor tissues possess 1-2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of
tumors. Our hypothesis is that hypoxic CSCs express
alarmin receptors that can bind
alarmins released during
necrosis, an event favoring CSCs migration. To investigate this aspect,
glioblastoma stem-like cell (GSC) lines were kept under
hypoxia to determine the expression of hypoxic markers as well as
receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1α inhibition by
digoxin or
acriflavine prevented the response of GSCs to
hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that
hypoxia is important not only for GSCs maintenance but also for guiding their response to external
necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by
glioblastoma stem cells (GSCs).