TMIC-44. ASTROCYTE SENESCENCE: A MODEL FOR AGE AND SEX EFFECTS ON GLIOBLASTOMA INCIDENCE

Primary brain tumor incidence rates rise more rapidly in males than females with increasing age. Both pre-neoplastic cells and stromal elements contribute to age-related increases in cancer, and cellular senescence plays a role in the transformation of pre-neoplastic cells. While senescence prevents the proliferation of damaged cells, senescent cells produce senescence-associated secretory phenotypes (SASP) which contribute to the tumor microenvironment. Certain SASP factors favor tumor suppression by inducing senescence in neighboring cells or recruiting immune cells for tumor clearance, while other factors increase tumor proliferation, resistance and relapse. Studies have demonstrated the role of senescence in the growth of solid tumors in various tissues including the liver, pancreas, and prostate. However, no studies have investigated how senescence in resident brain cells influences age-dependent increases in brain tumors. Moreover, there are no data in any tissues about sex differences in cellular senescence and its effect on age-dependent cancer rates. In the brain, astrocytes are the most abundant resident cell type with critical functions in brain structure, physiology, and homeostasis. Thus, we investigated sex differences in astrocyte senescence and whether these differences contribute to the sex disparity in brain tumor rates, specifically glioblastoma which has a male to female ratio of 1.6. Using β-galactosidase staining, we found that murine female astrocytes undergo senescence more readily after oxidative stress than their male counterparts. Furthermore, in vitro studies showed that murine GBM cells cultured in female astrocyte SASP-conditioned media show a different pattern of growth as compared to those cultured in male astrocyte SASP-conditioned media. These results indicate that there are sex differences in astrocyte senescence that influence tumor proliferation. Further investigation into the molecular mechanisms involved in male and female senescent astrocytes will allow us to better understand age-dependent brain tumor growth, which may reveal novel therapeutic targets for treatment.