Epithelial-to-Mesenchymal Transition in the Pathogenesis and Therapy of Head and Neck Cancer

Abstract

Head and neck cancer (HNC) is one of the most prevalent human malignancies worldwide, with a high morbidity and mortality. Implementation of interdisciplinary treatment modalities has improved the quality of life, but only minor changes in overall survival have been achieved over the past decades. Main causes for treatment failure are an aggressive and invasive tumor growth in combination with a high degree of intrinsic or acquired treatment resistance. A subset of tumor cells gain these properties during malignant progression by reactivating a complex program of epithelia-to-mesenchymal transition (EMT), which is integral in embryonic development, wound healing, and stem cell behavior. EMT is mediated by a core set of key transcription factors, which are under the control of a large range of developmental signals and extracellular cues. Unraveling molecular principles that drive EMT provides new concepts to better understand tumor cell plasticity and response to established as well as new treatment modalities, and has the potential to identify new drug targets for a more effective, less toxic, and individualized therapy of HNC patients. Here, we review the most recent findings on the clinical relevance of a mesenchymal-like phenotype for HNC patients, including more rare cases of mucosal melanoma and adenoid cystic carcinoma.

Keywords: biomarkers; epithelial-to-mesenchymal transition; head and neck cancer; mesenchymal-to-epithelial transition.

Figure 1

Scheme of EMT (epithelial-to-mesenchymal transition) as a program with dynamic transitional states, which are characterized by metastable intermediates. For metastatic colonization, a reversal of EMT known as mesenchymal-to-epithelial transition (MET) supports tumor cell expansion as an important prerequisite for metastatic growth. Phenotypic hallmarks of EMT are loss of cell-cell junctions, loss of apical-basal polarity, and acquisition of migratory and invasive properties. Those changes are induced by loss of E-cadherin and increased levels of biomarkers like vimentin and fibronectin. EMT-TF: EMT-transcription factor.

Figure 2

(A) Several well-established mesenchymal marker genes (e.g., VIM and FN1) are elevated in primary HNSCC with low SOX2 expression according to TCGA (The Cancer Genome Atlas; https://cancergenome.nih.gov) (B) Inverse expression pattern between KLK6 and mesenchymal markers as well as key regulators of EMT in primary HNSCC of the TCGA cohort; (C) High expression of SOX2 contributes—among others—to the pathogenesis of HNSCC by promoting tumor cell proliferation. In advanced tumor stages, SOX2 might interfere with tumor cell plasticity and activation of mesenchymal transition by stabilization of the epithelial phenotype including stemness-like traits. KLK6 (kallikrein-related peptidase 6).