Figure 1.

Effects of RT on the glioblastoma (GBM) tumor microenvironment (TME). ECM and its interaction with cellular components such as Glia (microglia and astrocytes), glioma cells, endothelia, pericytes and peripherally derived tumor infiltrating leukocytes (TILs), play a central role in the GBM TME, which contributes to tumor cell survival, proliferation, migration, and invasion. The illustration represents the key pathophysiological processes and their interactions within the radiated TME. Outer blue circle represents biological phenomenon (1–8) that are directly impacted by RT. The inner green circle represents the reactive GBM TME, with its various processes, alterations or adaptive mechanisms that are upregulated in effect of RT, described from (a–i). Blue arrows indicate the “cause and effect” interactions between these processes facilitating GBM pathology and, dark blue arrows signify the primary role of the respective alterations in facilitating cell motility and invasiveness and thus aggressive tumor recurrence. Radiation injury leads to neuronal damage, overactivation of M1 microglia, and elicits acute inflammatory response, with high ROS production in neurons and glia cells. There is alteration in ECM composition, and ECM-cell interactions. MMP/TIMP disbalance degrades Col-IV in basement membranes, which leads to blood brain barrier leakage. Pronounced inflammation causes infiltration of leukocytes (monocyte derived cell populations, macrophages), which along with activated microglia form the TAMs. TME of progressive tumors favor M2 phenotype and establishment of chronic inflammation. Redox dysregulation in effect of RT causes exacerbation of SASP phenotype and tumor cell adaptive processes, like Hypoxia, metabolic shifts, and redox regulation (ROS/NO production), leading to neo-angiogenesis and ECM remodeling. These alterations collectively make the TME permissive to glioma cell migration and invasion, thereby contributing to resistance and an aggressive tumor recurrence. All these biological processes in the reactive TME are potential therapeutic targets for improved glioblastoma care, with having ECM-cell interactions central to the manifestation of each of these phenomenon. RT, Radiation therapy; ECM, extracellular matrix; TAM, Tumor associated macrophages; TILs, Tumor infiltrating leukocytes; MMP, matrix metalloproteases; TIMP, Tissue inhibitor of metalloproteases; Col-IV, collagen-type IV; BBB, blood brain barrier; ROS, reactive oxygen species; NO, Nitric oxide; SASP, Senescence associated secretory phenotype; M1/M2, proinflammatory or immune suppressive phenotypes of TAMs, respectively.