Mechanisms involved in cancer stem cell resistance in head and neck squamous cell carcinoma

Abstract

Despite scientific advances in the Oncology field, cancer remains a leading cause of death worldwide. Molecular and cellular heterogeneity of head and neck squamous cell carcinoma (HNSCC) is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment. Cancer stem cells (CSCs) are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis, leading to poor prognosis in different types of cancer. CSCs exhibit a high level of plasticity, quickly adapting to the tumor microenvironment changes, and are intrinsically resistant to current chemo and radiotherapies. The mechanisms of CSC-mediated therapy resistance are not fully understood. However, they include different strategies used by CSCs to overcome challenges imposed by treatment, such as activation of DNA repair system, anti-apoptotic mechanisms, acquisition of quiescent state and Epithelial-mesenchymal transition, increased drug efflux capacity, hypoxic environment, protection by the CSC niche, overexpression of stemness related genes, and immune surveillance. Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients. This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC, supporting the use of possible strategies to overcome therapy failure.

Keywords: Head and neck squamous cell carcinoma; cancer stem cell; chemotherapy; radiotherapy; therapy resistance.

Figure 1

Mechanisms related to CSCs radioresistance in HNSCC. Radiation can activate stemness pathways such as Sox-2 and Oct3/4 and induce CSC phenotype in non-stem cancer cells. Radiation promotes an arrest of CSCs in the G2/M phase and activates Chk2 and Chk1, which delays cell cycle progression and allows DNA repair. Overexpression of CSC marker ALDH1 leads to increased rates of sub-lethal damage repair (SLDR), enabling efficient cell repair and reducing tumor control capabilities. CSCs upregulate anti-apoptotic proteins such as Bcl-2 and X-linked inhibitors of apoptosis (XIAP). Hypoxia upregulates CSCs genes (Sox2 and Nanog) and is essential in protecting the CSCs niche from radiation effects. GDF15 (growth differentiation factor 15) participates in ROS suppression in HNSCC, contributing to radioresistance and acquisition of the CSC phenotype.

Figure 2

Mechanisms related to CSCs’ chemoresistance in HNSCC. Overexpression of Bmi1, Sox2, Sox8, Oct4, Slug, Snail, Nanog, and TSPAN1 genes leads to the acquisition of drug resistance and stemness, EMT, and metastasis. CSCs activate signaling pathways such as the NOTCH1, FGF2, and Wnt/β-catenin to promote chemoresistance and stemness. Increased expression of ABC transporters, mainly ABCG2, the activation of EMT, cell cycle deregulation, increased autophagy, and activation of epigenetic mechanisms, such as up-regulation of miR-10, are involved with CSC’s chemoresistance in HNSCC.