Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression.

Marco Papale,Lucia Ricci-Vitiani,Cristiana Mollinari,Matteo A Russo,Mariachiara Buccarelli,Roberto Pallini,Marco Tafani

doi:10.3390/ijms21082660

Abstract

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).

Highlights

Cancer onset and progression cannot be considered a simple accumulation of mutations but a more complex process involving a wide number of molecules regulating metabolism, survival and cell proliferation [1]
In the case of glioblastoma stem-like cell (GSC) #1, an increase in HIF-1α mRNA was observed after 48 h of hypoxia whereas VEGF and Hexokinase 2 (HK2) increased at 24 h and 48 h (Figure 1A)
No mRNA increase for HIF-1α was observed after hypoxia for GSC #61 whereas, VEGF and HK2 mRNA increased after 4 and 24 and 4, 24 and 48 h, respectively. (Figure 1B)

Summary

Introduction

Cancer onset and progression cannot be considered a simple accumulation of mutations but a more complex process involving a wide number of molecules regulating metabolism, survival and cell proliferation [1]. The binding of alarmins to plasma membrane receptors activates a signaling cascade that ends with the activation of the transcription factor NF-kB At this point, cancer cells, through HIF-1 and NF-kB activation, reprogram molecular pathways of metabolism, ROS production/scavenging, autophagy, apoptosis, etc., increasing survival and resistance to stress and acquiring a more aggressive phenotype promoting tumor progression [21]. Cancer cells, through HIF-1 and NF-kB activation, reprogram molecular pathways of metabolism, ROS production/scavenging, autophagy, apoptosis, etc., increasing survival and resistance to stress and acquiring a more aggressive phenotype promoting tumor progression [21] Another important and recently discovered aspect of tumors is the presence of cancer stem cells (CSCs) [22]. Since the CSC paradigm has been developed, a number of data supporting their ability to promote tumor growth have been collected concerning different kinds of tumors such as cerebral [25], pulmonary [26], colon [27], ovary [28], pancreas [29], prostate [30] and thyroid [31], in addition to many other neoplasms, both

Objectives

Methods

Results

Discussion

Conclusion