Clearing Senescent Cells as a Way to Reduce Cancer Risk Resulting from Persistent Viral Infection

Persistent viral infection, such as by HPV, can result in cancer. Researchers here suggest that senolytic therapies to clear senescent cells can reduce that risk by removing some fraction of the cells most impacted by persistent infection. Senescent cells accumulate with age, but it is becoming clear that they are problematic in many other contexts as well. The ability to remove excess senescent cells with a single treatment via any one of the senolytic therapies under development is a powerful form of intervention that may have many applications beyond the rejuvenation of old tissues.

Senescence represents a unique cellular stress response characterized by a stable growth arrest, macromolecular alterations, and wide spectrum changes in gene expression. Classically, senescence is the end-product of progressive telomeric attrition resulting from the repetitive division of somatic cells. In addition, senescent cells accumulate in premalignant lesions, in part, as a product of oncogene hyperactivation, reflecting one element of the tumor suppressive function of senescence. Oncogenic processes that induce senescence include overexpression/hyperactivation of H-Ras, B-Raf, and cyclin E as well as inactivation of PTEN.

Oncogenic viruses, such as Human Papilloma Virus (HPV), have also been shown to induce senescence. High-risk strains of HPV drive the immortalization, and hence transformation, of cervical epithelial cells via several mechanisms, but primarily via deregulation of the cell cycle, and possibly, by facilitating escape from senescence. Despite the wide and successful utilization of HPV vaccines in reducing the incidence of cervical cancer, this measure is not effective in preventing cancer development in individuals already positive for HPV. Accordingly, in this commentary, we focus on the potential contribution of oncogene and HPV-induced senescence (OIS) in cervical cancer. We further consider the potential utility of senolytic agents for the elimination of HPV-harboring senescent cells as a strategy for reducing HPV-driven transformation and the risk of cervical cancer development.