Age-associated and therapy-induced alterations in the cellular microenvironment of experimental gliomas
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Hannah Schneider1, Birthe Lohmann1, Hans-Georg Wirsching1, Kathy Hasenbach1, Elisabeth J. Rushing3, Karl Frei2,4, Martin Pruschy5, Ghazaleh Tabatabai1,* and Michael Weller1,2
1Laboratory of Molecular Neuro-Oncology, Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland
2Center of Neuroscience, University of Zurich, Zurich, Switzerland
3Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland
4Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
5Laboratory for Molecular Radiobiology, Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland
*Current/Present address: Interdisciplinary Division of Neuro-Oncology, Laboratory of Clinical and Experimental Neuro-Oncology, Hertie Institute for Clinical Brain Research, Eberhard Karls University, Tubingen, Germany
Hannah Schneider, email: [email protected]
Keywords: age, glioblastoma, VEGF, radiotherapy, microenvironment
Received: December 02, 2016 Accepted: July 16, 2017 Published: August 03, 2017
The poor prognosis associated with advanced age in patients with glioblastoma remains poorly understood. Glioblastoma in the elderly has been particularly associated with vascular endothelial growth factor (VEGF)-dependent angiogenesis, and early uncontrolled studies suggested that the anti-angiogenic agent bevacizumab (BEV), an antibody to VEGF, might be preferentially active in this patient population.
Accordingly, we explored host age-dependent differences in survival and benefit from radiotherapy (RT) or BEV in syngeneic mouse glioma models. Survival was inferior in older mice in the SMA-540 and and less so in SMA-560, but not in the SMA-497 or GL-261 models. Detailed flow cytometric studies revealed increased myeloid and decreased effector T cell population frequencies in SMA-540 tumors of old compared to young mice, but no such difference in the SMA-497 model. Bone marrow transplantation (BMT) from young to old mice had no effect, whereas survival was reduced with BMT from old to young mice. BEV significantly decreased vessel densities in gliomas of old, but not young mice. Accordingly, old, but not young SMA-540 tumor-bearing mice benefited from BEV alone or in combination with RT. End-stage tumors of old BEV- and BEV/RT-treated mice exhibited increased infiltration of T helper and cytotoxic T cells compared to tumors of young mice.
The SMA-540 model may provide a valuable tool to evaluate the influence of host age on glioblastoma progression and treatment response. The biological host factors that modulate glioma growth in old as opposed to young mice remain to be identified.
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