Investigação do impacto da comunicação entre glioma e macrófagos na progressão e quimioresistência tumoral

Abstract

Gliomas are tumors that affect the central nervous system and share morphological similarities and gene expression in glial cells. Glioblastoma multiforme is the most common and devastating form of brain tumor, they are unstable with extensive infiltration capacity, angiogenesis and chemotherapy resistance. Alterations in the immune system and the purinergic system have been described as pathways involved in the progression of these tumors where an inflammatory infiltrate is positively correlated with malignancy and poor prognosis for patients with glioma. In this context, the relationship between inflammation, innate immunity and cancer is accepted; however, many of the molecular and cellular mechanisms that mediate this relationship remain unclear, The objective of this study was evaluate the macrophage polarization, oxidative stress parameters, activity of ectonucleotidases and ATP cytotoxicity in macrophages exposed to glioma-conditioned medium (CM) or co-culture direct (CC) with glioma temozolomide sensitive or resistant cells. The treatment of macrophages with glioma CM and CC induced M2-like macrophage polarization and GL261 TMZ-resistant cells seems to be more effective in induce an immunosuppressive environment when compared to GL261 TMZ-sensitive cells. Macrophage exposition to CM or co-cultured with GL261TMZ cells promoted a significant increase of antioxidant activity of SOD, catalase and GPx. Finally, macrophage glioma crosstalk promoted a decrease of ATPase, ADPase and AMPase hydrolysis which was followed by increased sensibility to ATP induced death. The results suggest a differential modulation of macrophage by glioma sensitive or TMZresistant cells, which may be important to develop new strategies to overcome chemoresistance.