Abstract 2976: Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy

Abstract

Abstract Many reports have shown that hypoxia and gliosis could promote tumor cells by shielding from the immune response and relapsing, but their roles on brain tumor therapies are still unclear. Using an invasive murine astrocytoma tumor model, ALTS1C1, we found that tumor invasion front is associated with a specific hypoxia region, naming tumor peripheral hypoxia, contributes to brain tumor therapy resistant and may be responsible for tumor recurrence after the therapy. Using this tumor model, we found that the overgrowing tumor caused the shortage of vessels and resulted in the hypoxia in the early stage of tumor progression, which is conventionally called chronic hypoxia or avascular hypoxia. When tumor continues to grow, a rim of hypoxia area was formed at tumor edge and subsequently activated nearby astrocytes. At the same time, the outward reactive astrocytes enhanced tumor invasion into normal parenchyma tissues. As a result, a specific hypoxia was produced in tumor peripheral, which has relative high microvascular density (MVD) and is associated with highly reactive astrocytosis. We explored the role of this region on the response to therapies. By quantitative counting the apoptotic tumor cells across the tumor cross-section following radiation- or chemo-therapy, we found that cells at the active astrocytic region (the peripheral region) are more resistant than cells in tumor core. These results indicate that the peripheral hypoxia, not the chronic hypoxia, is the main cause of the failure of brain tumor therapy. Most importantly, we found that the formation of tumor peripheral hypoxia might be associated with the activation of astrocytes. Therefore, tactics that can suppress astrocytosis and prevent the formation of peripheral hypoxia may be alternative approaches for complementing the shortage of traditional brain tumor therapy. Citation Format: Chiu-Min Lin, Chi-Shiun Chiang. Critical role of spatial location of hypoxia and its association with astrocytes in the resistance of brain tumor to therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2976. doi:10.1158/1538-7445.AM2017-2976