Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma

Abstract

An understanding of the process by which tumor cells destroy the basement membrane of the surface epithelium, invade, and metastasize is essential to the development of novel treatment of head and neck squamous cell carcinoma (HNSCC). In recent years, there has been increased interest in the role of epithelial-mesenchymal transition (EMT) in invasion. EMT is a process that describes the development of motile, mesenchymal-like cells from non-motile parent epithelial cells. There are 3 known types of EMT that mediate development, wound healing, and carcinogenesis. This review summarizes studies of known EMT biomarkers in the context of HNSCC progression. The biomarkers discussed come from a wide range of proteins, including cell-surface proteins (E-cadherin, N-cadherin, and Integrins), cytoskeletal proteins (α-Smooth Muscle Actin, Vimentin, and β-catenin), extracellular matrix proteins (Collagens, Fibronectin, and Laminin), and transcription factors (SNAIL1, SNAIL2, TWIST, and LEF-1). Overall, the findings of these studies suggest that EMT mediates HNSCC progression. The mechanistic role of the EMT markers that have been associated with HNSCC should be more clearly defined if new anti-HNSCC therapies to block EMT progression are to be developed.

Figure 1.

Head and neck squamous cell carcinoma (HNSCC) progression. Normal epithelium consists of cells with low mitotic activity and an intact basement membrane. In dysplasia, abnormal cells appear near the basement membrane, and in carcinoma in situ (full-thickness dysplasia), the abnormal cells are present throughout the full thickness of the epithelium. In carcinoma, the basement membrane is disrupted, and tumor cells invade the connective tissue.

Figure 2.

Epithelial-to-mesenchymal transition (EMT) to mesenchymal-to-epithelial transition (MET). Epithelial-like cells display tight cell-cell contacts and maintain polarity, whereas mesenchymal-like cells are more motile and display more contact with the extracellular matrix. Proteins associated with the epithelial-like or the mesenchymal-like states are referred to as biomarkers. As cells progress through EMT and MET, the levels of proteins associated with each state are altered, reflecting the phenotypic switch between the 2 states.

Figure 3.

Three types of Epithelial-to-mesenchymal transition (EMT). Type 1 EMT occurs in development, for example, when gastrulation epithelial cells transition to motile mesenchymal cells. Type 2 EMT occurs when secondary epithelial or endothelial cells move to interstitial spaces in wound healing or chronic inflammation, resulting in fibrosis. Type 3 EMT occurs when epithelial tumor cells migrate beyond a primary tumor and metastasize.

Figure 4.

Proteins involved in Epithelial-to-mesenchymal transition (EMT). Several proteins have been identified as biomarkers of EMT. These proteins include cell-surface proteins, cytoskeletal proteins, extracellular matrix proteins, and transcription factors.

Figure 5.

Targeted therapies against epithelial-to-mesenchymal transition (EMT) pathways. EMT progression involves many signaling pathways that may be targeted in the clinical setting, which include monoclonal antibodies (mAB) and small molecule inhibitors (boxed).