Distinct Tumor Microenvironment at Tumor Edge as a Result of Astrocyte Activation Is Associated With Therapeutic Resistance for Brain Tumor

This study demonstrated that the vessels at the tumor edge are heterogeneous. The transient hypoxia at the tumor edge as the result of the appearance of immature NG2-CD31+ vessels is likely one reason for the radiochemoresistance of brain tumor. Although the heterogeneity of tumor oxygenation in space and time is well-recognized, this study is the first to report two spatially and functionally distinct types of tumor hypoxia in brain tumors, namely peripheral and central hypoxia. As cancer cells frequently proliferate faster than parenchyma, such as endothelia, tumor progression is frequently accompanied with the development of diffusion-limited hypoxia (vessel insufficiency), which leads to chronic hypoxia, or perfusion-limited hypoxia (vessel malfunction), which causes transient hypoxia. We studied the progression of hypoxia in an orthotopic brain tumor model and were surprised to find that hypoxia could be detected in the tumor as early as 3 days after tumor inoculation and throughout the period of examination (up to 21 days), despite the presence of intact, functional vessels in the brain tumors. Most of the hypoxia observed in the tumor core was caused by vascular insufficiency, but some PIMO-positive hypoxic areas began to appear at the tumor periphery in day 10 samples. Peripheral and central hypoxia could be clearly distinguished at days 14 or 21; this was further confirmed by the expression of HIF-1α and CAIX, which are several frequently-used hypoxia-as...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research