The cancer of the salivary glands, known as mucoepidermoid carcinoma (MEC), is poorly understood and has few treatment options. Tumor recurrence and metastasis are 2 hallmarks of cancer, both of which are thought to be facilitated by cancer stem cells (CSCs). Researchers showed that small molecule inhibitors of MDM2-p53 interaction stimulate p53 signaling and decrease the fraction of CSC in MEC, and these inhibitors are relevant for clinical use.
In this study, they analyzed how p53 contributes to MEC CSC plasticity and self-renewal. They used gene silencing and therapeutic activation of p53 to study the effects on CSC survival/self-renewal in MEC cell lines (UM-HMC-1, -3A, -3B) by flow cytometry analysis of cell-cycle patterns and apoptosis levels. Using in vivo subcutaneous and orthotopic murine models of MEC, they assessed the impact of p53 on tumor formation (N = 51) and disease recurrence (N = 17). After removing the tumor, watched for signs of a return for 250 days. While activation of p53 does not directly cause apoptosis in MEC CSCs, it does inhibit self-renewal and other stemness features by reducing Bmi-1 expression and promoting CSC differentiation.
While upregulation of p53 inhibits tumor growth, downregulation of p53 promotes tumor development by increasing the number of CSCs. Amazingly, therapeutic activation of p53 inhibited CSC-mediated tumor recurrence. Altogether, these findings prove that p53 determines MEC stemness and raise the possibility that therapeutic activation of p53 may be of clinical benefit to individuals with salivary gland MEC.
