Epithelial-to-Mesenchymal Transition and Neoangiogenesis in Laryngeal Squamous Cell Carcinoma

Abstract

The mechanism of epithelial-mesenchymal transition (EMT) is fundamental for carcinogenesis, tumor progression, cancer cell invasion, metastasis, recurrence, and therapy resistance, comprising important events, such as cellular junction degradation, downregulation of epithelial phenotype markers, overexpression of mesenchymal markers, and increase in cellular motility. The same factors that drive epithelial cells toward a mesenchymal phenotype may also drive endothelial cells toward a proangiogenic phenotype. The aim of this exploratory study was to investigate a potential interplay between EMT and angiogenesis (quantified through CD105 expression) in laryngeal carcinoma (LSCC). CD105-assessed microvessel density (MVD) and EMT markers (E-cadherin, N-cadherin, Snail, Slug, Zeb1, and Zeb2) were assessed on 37 consecutive LSCC cases. The univariate Cox regression model identified pN+ status (p = 0.0343) and Slug expression (p = 0.0268) as predictive of disease-free survival (DFS). A trend toward significance emerged for CD105-assessed MVD (p = 0.0869) and N-cadherin expression (p = 0.0911). In the multivariate Cox model, pN-status, Slug, and N-cadherin expressions retained their significant values in predicting DFS (p = 0.0346, p = 0.0430, and p = 0.0214, respectively). Our data support the hypothesis of a mutual concurrence of EMT and angiogenesis in driving LSCC cells toward an aggressive phenotype. To better characterize the predictive performance of prognostic models based on EMT and angiogenesis, further large-scale prospective studies are required.

Keywords: CD105; N-cadherin; Slug; angiogenesis; epithelial–mesenchymal transition; laryngeal squamous cell carcinoma; prognosis.

Figure 1

Representative cases of positive immunohistochemistry stain. Cancer cells showing strong membrane immunoreaction for E-cadherin (A) and N-cadherin (B); nuclear expression for Snail (C), Slug (D), Zeb1 (E), and Zeb2 (F). Note that Zeb1 and Zeb2 resulted in a patchy stain pattern in all cases (arrowheads). A, B, C, D, E, F: Original magnification: 100×.

Figure 2

Representative cases with matched microvessel stain with CD105. (A) Squamous cell carcinoma with moderate differentiation and high MVD as shown by CD105 stain (B). (C) Squamous cell carcinoma with moderate differentiation and low MVD as shown by CD105 stain (D). A, C: Hematoxylin and eosin stain. A, B, C, D: Original magnification: 100×.

Figure 3

Time-dependent AUCs and 95% confidence intervals.