Residual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence

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.

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

“…Indeed, LAV-BPIFB4 treatment downregulates senescence both in cancer cells in vitro and in T lymphocytes from GBM patients, a key event which may support a dual activity of LAV-BPIFB4 in the cancer microenvironment. We demonstrated that LAV-BPIFB4 can specifically counterbalance the therapy-induced senescence ( Figure 1 and Figure 3 ), a state which is responsible for a chronic secretory phenotype that is generally considered pro-tumorigenic and promigratory, especially in GBM residual disease [ 46 ].…”

Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5β1 Integrin

“…Senescence is considered a favourable response to chemotherapy as it blocks tumoral cell proliferation. This view has been challenged as the irreversibility of drug-induced senescence remains under debate and the pro-tumorigenic properties of the senescent-associated secretory phenotype (SASP) are clearly demonstrated [ 52 , 53 ]. It has already been demonstrated that TMZ induces senescence rather than apoptosis in glioma cells [ 44 , 54 , 55 ].…”

Cell aging-related genes can be used to characterize clinical prognoses and further stratify diffuse gliomas

“…It has been found that conditioned medium from aging astrocytes in vitro can promote the proliferation of glioma cell lines by increasing c-Myc; more importantly, this conditioned medium can improve the survival of TMZ-treated glioma cells 24 . Additionally, although residual glioma cells are very different from the original tumor, they secrete factors that are part of the aging-associated secretory phenotype (SASP), which maintains residual gliomas through therapy and drives drug resistance and recurrence 25 . Altogether, these results indicate that cellular senescence is likely to cause gliomas and residual tumors.…”