Abstract
Most glioblastomas frequently recur at sites of radiotherapy, but it is unclear if changes in the tumor microenvironment due to radiotherapy influence glioblastoma recurrence. Here, we demonstrate that radiation-induced senescent glioblastoma cells exhibit a senescence-associated secretory phenotype that functions through NFκB signaling to influence changes in the tumor microenvironment, such as recruitment of Ly6G+ inflammatory cells and vessel formation. In particular, Ly6G+ cells promote conversion of glioblastoma cells to glioblastoma stem cells (GSCs) through the NOS2-NO-ID4 regulatory axis. Specific inhibition of NFκB signaling in irradiated glioma cells using the IκBα super repressor prevents changes in the tumor microenvironment and dedifferentiation of glioblastoma cells. Treatment with Ly6G-neutralizing antibodies also reduces the number of GSCs and prolongs survival in tumor-bearing mice after radiotherapy. Clinically, a positive correlation exists between Ly6G+ cells and the NOS2-NO-ID4 regulatory axis in patients diagnosed with recurrent glioblastoma. Together, our results illustrate important roles for Ly6G+ inflammatory cells recruited by radiation-induced SASP in cancer cell dedifferentiation and tumor recurrence.
Highlights
It has been reported that glioblastoma (GBM) inevitably recurs at the initial tumor site where surgery and radiotherapyEdited by R
We demonstrated that ionizing radiation induces glioblastoma cell senescence and the senescence-associated secretory phenotype (SASP), which in turn promotes Ly6G+ inflammatory cell recruitment with tumor-associated neutrophils (TANs) phenotype into tumor tissues and changes to the tumor microenvironment
Despite the fact that GMDSCs can differentiate into TANs [43], our results suggest that infiltrated Ly6G+ cells in recurrent tumors are similar to neutrophils acting as protumorigenic TANs expressing CCL2, CCL3, and CXCL1 [42]
Summary
It has been reported that glioblastoma (GBM) inevitably recurs at the initial tumor site where surgery and radiotherapy. Our recent study demonstrated that irradiation-induced senescence in glioblastoma cells increased the expression of SASP and promoted tumor progression in vivo [18]. There is, little evidence of a molecular mechanism linking irradiation-induced SASP with tumor recurrence, in the context of SASP and GSCs. Here, using a stem cell fate-tracking system (OCT4promoter-reporter), we demonstrated that the radiationinduced SASP leads to changes in the tumor microenvironment, including Ly6G+ inflammatory cell recruitment and vessel formation, which result in the conversion of non-stem glioblastoma cells to GSCs. we revealed that interventions targeted toward this tumor microenvironment prevented tumor recurrence and reduced GSC dedifferentiation. The human leukemic cell line HL-60 was cultured in Roswell Park Memorial Institute medium (RPMI-1640, Lonza) supplemented with 5% FBS, 1% penicillin/streptomycin, and 2 mM L-glutamine. U87MG and LN229 cells were infected with lentivirus produced from the 293FT cell line (Life Technologies) that was transfected with a lentiviral vector (pLL-CMV-puro, pLL-CMV-IκBα mutant-puro, pLL-CMV-ID4-puro and pCDH-CMV-EF1-DsRed) and packaging vectors (3rd generation: pMDLg/pRRE, pRSV-Rev, and pMD2.G)
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