Abstract
Hypoxic tumor region is deemed as a critical source for therapy resistant in clinic. Previous studies indicate that tumor hypoxia frequently results in immunosuppression, radio- and chemo-resistance. In addition, tumor hypoxia can also enhance tumor invasion and tumor mobility. Astrocytes are the prime glial cells in brain tissue. They play important roles in angiogenesis and immune-regulation during the process of brain restoration. In this research, we found the appearance of a non-homogeneous peripheral hypoxia in brain tumor and studied their consequent effects on the response of brain tumor to therapies. Using GL261 glioma and ALTS1C1 astrocytoma tumor models, two frequently used brain tumor research models, we found that tumor cells could adjust themselves to adapt the constant change of brain microenvironments during tumor progression. Meanwhile astrocytes detect the tumor-induced microenvironmental changes and are subsequently activated. Activated astrocytes start to adhere to tumor edge and further invade into tumor core to become vascular template that consequently induces endothelial cell adhesion for angiogenesis to re-oxygenate tumors. On the other hand, normal brain tissue is continuously oppressed and become hemorrhage during brain tumor progression. When tumors grow to detectable size, tumor hypoxia could be separated into two parts, peripheral hypoxia and inner hypoxia. Their vasculatures are different, and so do the vessel function. It is therefore concluded that they are different types of hypoxia and formed by different mechanism. By quantifying therapy-induced apoptotic cells at tumor edge versus tumor core, this study also shows that hypoxia indeed reduces cytotoxic effect of irradiation or chemotherapy. In summary, the study found that two types of tumor hypoxia could be generated in brain tumor. The formation of peripheral hypoxic tumor region is a unique phenomenon during brain tumor progression and it is indeed a barrier for brain tumor therapy.