Oral Cancer Stem Cells: Therapeutic Implications and Challenges

Abstract

Head and neck squamous cell carcinoma (HNSCC) is currently one of the 10 most common malignancies worldwide, characterized by a biologically highly diverse group of tumors with non-specific biomarkers and poor prognosis. The incidence rate of HNSCC varies widely throughout the world, with an evident prevalence in developing countries such as those in Southeast Asia and Southern Africa. Tumor relapse and metastasis following traditional treatment remain major clinical problems in oral cancer management. Current evidence suggests that therapeutic resistance and metastasis of cancer are mainly driven by a unique subpopulation of tumor cells, termed cancer stem cells (CSCs), or cancer-initiating cells (CICs), which are characterized by their capacity for self-renewal, maintenance of stemness and increased tumorigenicity. Thus, more understanding of the molecular mechanisms of CSCs and their behavior may help in developing effective therapeutic interventions that inhibit tumor growth and progression. This review provides an overview of the main signaling cascades in CSCs that drive tumor repropagation and metastasis in oral cancer, with a focus on squamous cell carcinoma. Other oral non-SCC tumors, including melanoma and malignant salivary gland tumors, will also be considered. In addition, this review discusses some of the CSC-targeted therapeutic strategies that have been employed to combat disease progression, and the challenges of targeting CSCs, with the aim of improving the clinical outcomes for patients with oral malignancies. Targeting of CSCs in head and neck cancer (HNC) represents a promising approach to improve disease outcome. Some CSC-targeted therapies have already been proven to be successful in pre-clinical studies and they are now being tested in clinical trials, mainly in combination with conventional treatment regimens. However, some studies revealed that CSCs may not be the only players that control disease relapse and progression of HNC. Further, clinical research studying a combination of therapies targeted against head and neck CSCs may provide significant advances.

Diversity of the Origin of Cancer Stem Cells in Oral Squamous Cell Carcinoma and Its Clinical Implications

“…Previous studies have suggested that cancers are organized as a cellular hierarchy of various populations of cancer cells, and the hierarchy is maintained by a small subset of cancer cells, called CSCs [ 33 , 34 ]. CSCs have stemness and are also called cancer-initiating cells [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 45 ]. CSCs were identified for the first time in 1997 by Bonnet and Dick in a patient with acute myeloid leukemia [ 46 ].…”

“…CSCs have also been shown to play important roles in the development and progression of OSCC [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ]. It is reported that only a small percentage of the cell population contributes to the development of OSCC, and this population has properties corresponding to those of CSCs [ 31 , 40 ].…”

“…We have focused on the diversity of the origin of OSCC and on cancer stem cells (CSCs) [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 ] as a key plyer to explain the malignancy of OSCC. CSCs are a subset of cancer cells that occupy a very small portion of the tumor mass and have characteristics of stem cells [ 34 , 35 , 37 , 40 , 41 ].…”

CD44 Mediates Oral Squamous Cell Carcinoma-Promoting Activity of MRE11 via AKT Signaling

“…Through binding interactions of CD44 with its natural ligands, such as hyaluronic acid or other binding partners secreted in the extracellular matrix, a series of signaling cascades in OSCC cells may be activated, leading to the enhanced tumor growth, metastatic ability, and resistance to cancer treatment [ 16 ]. Therefore, targeting CD44 and its signaling pathways that involve in the cancer-promoting activities has emerged as a novel therapeutic potential for OSCC [ 17 , 18 ].…”

Treatment of Oral Cancer by a Synthetic Analogue of Capsaicin & TRPV1 Antagonist: Capsazepine

“…Among the most prevalent forms of neck and head malignancies, oral cancer mostly affects the throat, paranasal sinuses, nasopharynx, hypopharynx, salivary glands, and oral cavity. 1 Except for certain regions of France, oral cancer is rare in the industrialized world. However, it is frequent in the developing world, notably in Southeast Asia and Brazil.…”