Abstract
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.
Highlights
Glioblastomas are the most common malignant primary brain tumors
Glioblastoma in the elderly has been 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
Tumor-infiltrating leukocyte subpopulations were analyzed in more detail by flow cytometry in syngeneic mouse glioma models of young and old mice with (SMA540) and without (SMA-497) a survival difference by host age (Figure 1B, 1C, Supplementary Figure 1F-1K)
Summary
More than 40% of glioblastoma patients are older than 65 years of age [1]. It has remained unclear why elderly people develop such tumors more frequently, and more importantly, it remains incompletely understood why elderly glioma patients benefit less from the current www.impactjournals.com/oncotarget treatment options of radiotherapy and concomitant and maintenance temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ) [2, 3]. Isocitrate dehydrogenase (IDH) mutations, which confer a better prognosis, are virtually absent in glioblastomas of the elderly. While this may contribute to differential outcome between younger and older glioblastoma patients, age remains a negative prognostic factor even if an analysis of outcome by age is restricted to patients with IDH wildtype glioblastoma [4]. Age-specific hypermethylation in polycomb group protein target genes and the upregulation of angiogenesis-related genes have been identified, but no fundamental differences compared with tumors from younger patients [5]
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