Mechanisms of Invasion in Head and Neck Cancer

Abstract

Context: The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5-year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed.

Objectives: To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion.

Data sources: A literature review of peer-reviewed articles in PubMed on HNSCC invasion.

Conclusions: Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation.

Figure 1.. Signaling pathways in HNSCC invasion involving the EGFR.

Epidermal growth factor receptor (EGFR), activated by EGFR ligands, can activate ERK/AP1, PI3K/Akt, or Src activity, which all lead to increased invasion in head and neck cancer. EGFR can be cross-activated by GCPRs, whose downstream signaling leads to the release of EGFR ligands from their transmembrane precursors through activity by the ADAM family of proteases.

Figure 2.. Proteins that contribute to invadopodium structure and function.

Invadopodia are actin-rich structures that specialize in mediating the degradation of the ECM. Their formation can be induced by EGFR signaling. The key components of the core structure are cortactin, Tks5, N-WASP, Arp2/3, Nck-1 and −2, and cofilin. Adhesion rings, made up of adhesion proteins such as integrins and ILKs, are important for the formation and stabilization of invadopodia. Proteases, such as MMP2 and MMP9, are secreted at invadopodia. MT1-MMP can be transported by exosomes, which are secreted from multi-vesicular endosomes.

Figure 3.. Invadopodial matrix degradation assay.

UMSCC1 cells, a human oral cavity squamous cell carcinoma cell line, were plated onto an Alexa Fluor-405 labeled gelatin matrix. After 4 hours the cells were fixed and stained for cortactin and Tks5, two invadopodia markers. Representative images of the degraded fluorescent matrix (A) Tks5 (B) and cortactin (C) and the merged (D) (cortactin: red, Tks5: green, matrix: blue) staining at 60X magnification. The merged image shows colocalization of Tks5- and cortactin-rich structures associated with degradation holes in the Alexa Fluor-405 matrix.