Abstract
Objective To investigate the impact of radiation-induced senescent tumor microenvironment on the proliferation and aggressiveness of GBM, as well as its underlying mechanism.
Methods Pre-irradiate astrocytes or mice for the in vitro and in vivo establishment of senescent environments. Simulate the impact of the senescent microenvironment on GBM by treating tumor cells with conditioned medium and utilizing a xenograft tumor model, followed by observation and documentation of the biological characteristics of tumor cells and survival time of mice. The anti-senescence drug was used to eliminate senescent cells in the brain of mice after radiation.
Results Astrocytes can be obviously stained by β-galactosidase staining after exposed to X-ray, and the expression of P16 and P21 genes is significantly upregulated. Cell viability assay, transwell invasion assay and wound healing assay demonstrated that GBM cells treated with senescence medium exhibited enhanced proliferation, increased migration and invasion capabilities compared to those treated with normal medium. Irradiated mice displayed larger tumor volume 20 days after tumor implantation and shorter survival times than mice in control group. Administration of navitoclax reduced tumor volume and extended survival time in mice. The transcriptome sequencing and protein detection identified IL6 as the exclusive highly expressed senescence secretion phenotype in senescence medium, which activates the JAK2-STAT3 signaling pathway in tumor cells.
Conclusion The tumor microenvironment, consisting of non-neoplastic cell senescence induced by radiotherapy and its secretory phenotype, can facilitate the proliferation and invasion of GBM, indicating the favorable role of senescent cells in the recurrence of residual GBM. This process is mediated through the activation of JAK2-STAT3 signaling pathway by SASP factor IL6. Anti-senescence drugs may emerge as a novel adjunctive therapeutic approach to delay GBM recurrence.
Competing Interest Statement
The authors have declared no competing interest.