Angiotensin signalling in GBM: AT2R as a novel therapeutic target

Authors

  1. Mr. Alexander Renziehausen (Imperial College London)
  2. Dr. Jennifer Eschbacher (Barrow Neurological Institute)
  3. Dr. Andreas Tzakos (University of Ioannina)
  4. Dr. Kevin O’Neill (Imperial College London)
  5. Dr. Tim Crook (Southend University Hospital)
  6. Dr. Nelofer Syed (Imperial College London)

Abstract

INTRODUCTION: Locally expressed components (angiotensin II type 1 and type 2 receptors, AT1R and AT2R respectively) of the renin-angiotensin system have been implicated in non-cardiovascular functions including cancer progression. Drugs targeting angiotensin signalling to manage blood pressure therefore have the potential to be repurposed to treat cancer. Moreover, a recent retrospective study highlighted improvements in clinical outcomes of GBM patients treated with Ang-II inhibitors in combination with RT and TMZ. While the involvement of AT1R in cancer has been well studied, the role of AT2R is largely unknown. The aim of this study is to investigate the influence of angiotensin signalling on the growth, migration and induction of angiogenesis in GBM and determine its therapeutic potential.

METHODS: GBM cell lines, both primary and established were profiled for expression of AT1R and AT2R by qPCR and pyrosequencing. The antihypertensive drug Losartan and the AT2R antagonist PD123319 were used alone or in combination with the ligand angiotensin II in various assays. Colorimetric proliferation assays were used to assess the impact on growth and wound healing assays to assess migration, a determinant of GBM invasiveness. In addition, the induction of angiogenesis was also examined using conditioned media from GBM cells and analysing the effect on proliferation, migration and tube formation of the brain microvascular endothelial cell line hCMEC/D3.
RESULTS: Inhibition of AT1R signalling via Losartan had no effect on the growth of GBM whereas inhibition of AT2R with PD123319 significantly reduces GBM cell proliferation, migration and the induction of angiogenesis.
CONCLUSION: Our data suggest that AT2R rather than AT1R is the main receptor promoting GBM cell growth, migration and the induction of angiogenesis. Therefore, inhibition of AT2R signalling could have potential in the treatment of GBM.