Radiotherapy targeting cancer stem cells "awakens" them to induce tumour relapse and metastasis in oral cancer

Abstract

Radiotherapy is one of the most common treatments for oral cancer. However, in the clinic, recurrence and metastasis of oral cancer occur after radiotherapy, and the underlying mechanism remains unclear. Cancer stem cells (CSCs), considered the "seeds" of cancer, have been confirmed to be in a quiescent state in most established tumours, with their innate radioresistance helping them survive more easily when exposed to radiation than differentiated cancer cells. There is increasing evidence that CSCs play an important role in recurrence and metastasis post-radiotherapy in many cancers. However, little is known about how oral CSCs cause tumour recurrence and metastasis post-radiotherapy. In this review article, we will first summarise methods for the identification of oral CSCs and then focus on the characteristics of a CSC subpopulation induced by radiation, hereafter referred to as "awakened" CSCs, to highlight their response to radiotherapy and potential role in tumour recurrence and metastasis post-radiotherapy as well as potential therapeutics targeting CSCs. In addition, we explore potential therapeutic strategies targeting these "awakened" CSCs to solve the serious clinical challenges of recurrence and metastasis in oral cancer after radiotherapy.

Fig. 1

CSC hypothesis and the response of CSCs to radiotherapy. a In the CSC hypothesis, the CSC undergoes symmetrical or asymmetric division to give rise to two new CSCs or a differentiated daughter cell and another CSC. Based on the CSC model, the ability to initiate tumorigenesis and generate heterogeneity in primary tumours is fully attributed to the CSC population. b In response to radiotherapy, only if all CSCs are eliminated can tumours be permanently eradicated. Moreover, failed radiotherapy can “awaken” quiescent CSCs to enter the cell cycle, leading to tumour relapse, and induce them to transform into metastatic phenotypes, which can eventually result in tumour metastasis

Fig. 2

Potential mechanisms by which CSCs induce relapse and metastasis. CSCs have innate radioresistance. Both the CSC niche and tumour microenvironment can enhance the radioresistance of CSCs and support CSC survival during radiotherapy through the expression of multiple cytokines that contribute to increased stemness and self-renewal of CSCs and induce EMT and hypoxic conditions, resulting in higher migration and invasion of CSCs, further leading to tumour recurrence and metastasis

Fig. 3

Potential therapeutics targeting oral CSCs. Given that the surviving CSCs post-radiotherapy can lead to relapse and metastasis, a potential strategy targeting oral CSCs needs to be combined with radiotherapy for better efficacy in treating oral cancer. Some examples include treatments targeting CSC markers, CSC self-renewal pathways, CSC niche, CSC-associated EMT and hypoxia