Residual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence

SIMPLE SUMMARY: Glioblastoma (GBM) is an aggressive and mostly incurable from of brain cancer. This is largely due to individual tumor cells invading the surrounding tissue, through which they evade surgical removal and reconstitute the tumor. Here, we define three distinct environments that GBM cells migrate into: the vascular, the neural, and the glial niches. These environments can nurture GBM recurrence through factors associated with a process called “senescence”; a cellular stress response which causes them to secrete mostly pro-tumorigenic factors. Senescence is especially relevant to late-stage brain cancer since it occurs mainly in aged people, who have senescent cells. Moreover, brain cells can become senescent in response to unresolved damage from chemo- and radio- therapies. As such, we summarize recent literature on brain senescence and discuss strategies to optimize and implement anti-senescence therapies aimed at overcoming recurrence and lethality from GBM. ABSTRACT: With a dismally low median survival of less than two years after diagnosis, Glioblastoma (GBM) is the most lethal type of brain cancer. The standard-of-care of surgical resection, followed by DNA-damaging chemo-/radiotherapy, is often non-curative. In part, this is because individual cells close to the resection border remain alive and eventually undergo renewed proliferation. These residual, therapy-resistant cells lead to rapid recurrence, against which no effective treatment exists to date. Thus, new experimental approaches need to be developed against residual disease to prevent GBM survival and recurrence. Cellular senescence is an attractive area for the development of such new approaches. Senescence can occur in healthy cells when they are irreparably damaged. Senescent cells develop a chronic secretory phenotype that is generally considered pro-tumorigenic and pro-migratory. Age is a negative prognostic factor for GBM stage, and, with age, senescence steadily increases. Moreover, chemo-/radiotherapy can provide an additional increase in senescence close to the tumor. In light of this, we will review the importance of senescence in the tumor-supportive brain parenchyma, focusing on the invasion and growth of GBM in residual disease. We will propose a future direction on the application of anti-senescence therapies against recurrent GBM.