Tami-67. Investigation of the Complement System in the Irradiated Brain Tumor Microenvironment

Abstract

Glioblastoma is the most common and aggressive primary brain tumor in adults. Despite treatment through surgery, irradiation and chemotherapy all patients suffer recurrence of treatment-resistant tumors and the survival prognosis remains poor. The recurrence of tumors is driven by the invasive nature of the tumor and appears to be related to cells with stem like characteristics that are present in perivascular and hypoxic niches. Previous studies from our lab showed that astrocytes grown in hypoxic or irradiated conditions increase the stemness of glioma cells. The altered behavior of the astrocytes leads to increased cell size and a change in secreted cytokines. Reactive astrocytes are important in other central nervous system (CNS) diseases involved in tissue repair such as traumatic brain injury and Alzheimer’s disease. Interestingly, in several neurological diseases, reactive astrocytes upregulate complement proteins, especially complement component 3 (C3). However, it remains relatively unexplored how these complement proteins in stromal astrocytes are expressed in glioblastoma. Tissue sections from our glioma mouse model shows presence of C3 around hypoxic areas where there is an abundance of astrocytes. We have also shown that astrocytes grown at 21%, 1% and 0.1% oxygen upregulate complement protein C3 as well as other proteins associated with a more extensive infiltrative phenotype of glioblastoma. Datasets with human patients showed that C3 expression was correlated with higher grade tumors and that patients with tumors expressing C3 had more risk to get new tumors after primary treatment (including but not limited to radiotherapy). In this ongoing project, we are investigating whether activation of the complement system in the tumor microenvironment contributes to tumor progression. The upregulation of C3 in astrocytes in hypoxic conditions could therefore through local complement activation possibly led to tumor promoting signaling leading to beneficial survival of therapies of nearby glioma cells.