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Review
. 2021 Jul 21:2:685236.
doi: 10.3389/froh.2021.685236. eCollection 2021.

Oral Cancer Stem Cells: Therapeutic Implications and Challenges

Linah A Shahoumi  1
Affiliations
Review

Oral Cancer Stem Cells: Therapeutic Implications and Challenges

Linah A Shahoumi. Front Oral Health. .

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.

Keywords: cancer stem cells; head and neck; self-renewal; squamous cell carcinoma; targeted therapy; tumor relapse.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The cancer stem cell microenvironment. The niche or tumor microenvironment is essential for maintenance of stemness, and this also applies to CSCs where cell–cell interactions within the niche are required to support the role of CSCs in cancer initiation and progression. The CSC microenvironment also contributes to CSCs' resistance to drugs and other cancer therapies, thereby, promoting cancer recurrence. The tumor tissue microenvironment is composed of a variety of cells, including tumor cells, cancer stem cells, inflammatory cells, and cancer-associated fibroblasts, along with blood vessels and extracellular matrix. In response to hypoxic stress and matrix, CSCs induce growth factors and cytokines including IL-6, CXCL8, and VEGF to regulate their growth via EGFR, NOTCH, WNT, and other signaling cascades. JAK, Janus kinases; STAT, signal transducer, and activator of transcription; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; mTOR, mammalian target of rapamycin; IL, Interleukin; CXCL, CXC-motif chemokine ligand.
Figure 2
Figure 2
Mechanisms involved in CSC-induced drug resistance in HNSCC. EGF binds to the EGFR receptor tyrosine kinase resulting in activation and autophosphorylation of the receptor. This activates RAS and PI3K, triggering major signaling cascades that include MEK/ERK and PI3K/AKT. NOTCH-activated NICD1, upregulates the SIRT2/ALDH1A pathway. Hedgehog ligands (Hh) bind to Patched receptors and derepress the G-protein-coupled receptor (GPCR) SMO. Hh targets ALDH+ CSCs through GLI1 expression, which is regulated by ALDH1A1. WNT proteins bind to the Fz transmembrane receptor and the LRP 5/6 to form a functional complex. β-catenin then becomes uncoupled from the degradation complex and translocates to the nucleus to promote transcription of downstream targets. TGF-β is recognized by TβR1/2 resulting in the phosphorylation of SMAD 2/3 and formation of a SMAD 2/3/4 complex. These pathways are involved in regulating multiple biological functions of CSCs, including cell proliferation, migration, invasion, self-renewal and survival. EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Fz, frizzled; JAG, Jagged ligand; DLL, Delta-like ligand; DSB, double-strand break; NICD, intracellular domain of NOTCH protein; SMO, smoothened; MAPK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinases; PATCH1, Protein patched homolog 1; TGF-β, transforming growth factor; TβR, transforming growth factor β receptor; ALDH1, Aldehyde dehydrogenase 1 family; BMI1, B lymphoma Mo-MLV insertion region 1 homolog; OCT4, Octamer-binding transcription factor 4; SOX2, Sex determining region Y-box 2; NANOG, Nanog homeobox.
Figure 3
Figure 3
Cancer stem cell-directed therapies in HNSCC. Selected anti-CSC drugs currently under clinical investigation. Their mechanisms of actions include targeting CSC-associated surface markers and CSC-associated signaling pathways, including developmental pathways, that regulate the maintenance, and survival of CSCs.
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