Oral epithelial stem cells - implications in normal development and cancer metastasis

Abstract

Oral mucosa is continuously exposed to environmental forces and has to be constantly renewed. Accordingly, the oral mucosa epithelium contains a large reservoir of epithelial stem cells necessary for tissue homeostasis. Despite considerable scientific advances in stem cell behavior in a number of tissues, fewer studies have been devoted to the stem cells in the oral epithelium. Most of oral mucosa stem cells studies are focused on identifying cancer stem cells (CSC) in oral squamous cell carcinomas (OSCCs) among other head and neck cancers. OSCCs are the most prevalent epithelial tumors of the head and neck region, marked by their aggressiveness and invasiveness. Due to their highly tumorigenic properties, it has been suggested that CSC may be the critical population of cancer cells in the development of OSCC metastasis. This review presents a brief overview of epithelium stem cells with implications in oral health, and the clinical implications of the CSC concept in OSCC metastatic dissemination.

Keywords: Cancer stem cells; Epithelial stem cells; Invasion; Metastasis; Oral mucosa; Oral squamous cell carcinoma.

Figure 1. Markers of epithelial stem cells during normal development and in relation with poor clinical outcome in patients with OSCC

Representative photomicrographs of primary human oral carcinomas immune-stained for markers that are associated with poor clinical outcome in patients with oral carcinomas: Aurora B (a–d, h), Survivin (e, i), beta-catenin (j–k), EGFR (l–m), Ki67 (f–g) and CD44 (n–p). a, Aurora B expression in mitotically active cells in the basal layer of severe oral dysplasia; note the limits with basal membrane outlined by star. b–c, increased and aberrant mitoses overexpressing Aurora B, in aggressive OSCC at invasive front; b1–c1, metaphases; b2, early anaphase; c2, late anaphase; b3–c3, late anaphase-cytokinesis; b4–c4, anomalous cytokineses. Aurora B overexpression is coupled with survivin up-regulation in the invasion fronts of OSCC giving raise to aberrant mitoses (d, Aurora B; e, survivin). High proliferative index of aggressive and invasive cells with perivascular (f) and perineural (g) localization positive for Ki-67, is coupled with Aurora B (h) and Survivin (i) over-expression. Beta-catenin expression in the invasive front (j) and a metastatic embolus (k) of OSCC. EGFR expression in the invasive cells front (l–m). CD44 expression in the basal layer of normal human oral mucosa (n), salivary gland (o) and dental root epithelia (p). All the samples were obtained with the signed informed consent of patients under approved protocols by the Ethical Committees of the Universities of Foggia and Marseille.

Figure 2. Putative cancer stem cells markers in oral carcinomas

Representative photomicrographs (magnification 20x) of human derived oral squamous cell carcinomas cells immune-stained for CD44 (A), Lgr5 (B), CD15 (C), beta-catenin (D), Bmi-1 (E) and Ki67 (F). Larger size mesenchymal-like CSC co-exist with normal size CSC that retain the epithelial characteristics (yellow arrow). DAPI (blue) identified nuclei.