Abstract
Tumor vasculatures and hypoxia are critical tumor micro-environmental factors associated with tumor response to the therapy and heterogeneous in both time- and location-dependent manner. Using a murine orthotopic anaplastic astrocytoma model, ALTS1C1, this study showed that brain tumor edge had a very unique microenvironment, having higher microvascular density (MVD) and better vessel function than the tumor core, but on the other hand was also positive for hypoxia markers, such as pimonidazole (PIMO), hypoxia inducible factor-1α (HIF-1α), and carbonic anhydrase IV (CAIX). The hypoxia at tumor edge was transient, named as peripheral hypoxia, and caused by different mechanisms from the chronic hypoxia in tumor core. The correlation of CAIX staining with astrocyte activation marker, glial fibrillary acid protein (GFAP), at the tumor edge indicated the involvement of astrocyte activation on the development of peripheral hypoxia. Peripheral hypoxia was a specific trait of orthotopic brain tumors at tumor edge, regardless of tumor origin. The hypoxic cells were resistant to the therapy, regardless of their location. Surviving cells, particularly those at the hypoxic region of tumor edge, are likely the cause of tumor recurrence after the therapy. New therapeutic platform that targets cells in tumor edge is likely to achieve better treatment outcomes.
Highlights
High-grade gliomas such as anaplastic astrocytoma and grade IV glioblastomas remain as lethal cancers even after aggressive treatment
We found the tumor microenvironment, in terms of the number of tumor-associated macrophages, microvascular density, and expression of matrix metalloproteinase-2 (MMP-2), in the recurrent tumor after radiotherapy is different between primary tumor core and tumor edge [14, 17]
The results revealed that tumor hypoxia developed in ALTS1C1 tumors derived from these three models, but peripheral hypoxia was only observed in tumors from I.C. model (Figure 5A), suggesting that peripheral tumor hypoxia is a unique feature of high-grade glioma in brain
Summary
High-grade gliomas such as anaplastic astrocytoma and grade IV glioblastomas remain as lethal cancers even after aggressive treatment. The median survival rate for gliomas is
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