Oral cancer stem cells - properties and consequences

Abstract

Research on cancer stem cells (CSCs) has greatly increased in the field of medicine and pathology; however, some conceptual misunderstandings are still present among the public as well as within the general scientific community that is not yet familiar with the subject. The very first problem is the misinterpretation of CSCs as a synonym of their normal counterparts, the well-known stem cells (SCs). Particularly in Dentistry, another common mistake is the misinterpretation of oral CSCs as normal tooth-derived SCs. The present review aims to clarify important concepts related to normal SCs and CSCs, as well as discuss the relevance of CSCs to the development, metastasis and therapy resistance of oral squamous cell carcinoma.

Figure 1. Schematic view of normal stem cells (A) and cancer stem cells (B). A shows different sources of normal SCs, their biological properties of indefinite division through self-renewal and generation of differentiated cells under appropriate conditions; while embryonic stem cells are totipotent, adult stem cells are unipotent but can regain totipotent properties under in vitro conditions, originating the induced pluripotent stem cells (iPSCs). In B, adult epithelial SCs can undergo malignant transformation after cumulative genetic alterations caused by carcinogens, generating CSCs. These CSCs retain the biological properties of the self-renewal and generation of differentiated (cancer) cells, leading to cancer development and further metastasis

Figure 2. Schematic view of normal oral epithelium (A) and oral squamous cell carcinoma (B). In A, the asymmetric division of normal stem cells (SCs) found in the basal cell layer generates one daughter SC (self-renewal) and one daughter transit-amplifying cell committed to differentiation (small black box). In B, loss of balance of genes related to cell growth and death due to cumulative somatic mutations on SCs results on the development of cancer stem cells (CSCs), which retain the biological properties of self-renewal and generation of differentiated (tumour) cells (small black box). These CSC properties reflect the indefinite growth capacity and morphology heterogeneity of tumours

Figure 3. Schematic view of the primary site of oral squamous cell carcinoma (A) and metastatic lymph node (B). In A, cancer stem cells (CSCs) (round blue cells) undergo EMT (EMT CSCs) under the influence of molecules (such as TGF-β, IL6, TNF-α) from the tumour's microenvironment, assuming a complete mesenchymal (CD44^highESA^low/-ALDH-) or epithelial-mesenchymal (CD44^highESA^low/+ALDH+) phenotype. This subpopulation of EMT-CSCs is able to invade the tumour's stroma, migrate and reach blood and lymphatic circulation. Once they arrive at a metastatic lymph node (B), they revert back, through mesenchymal-epithelial transition (MET), to the proliferative non-EMT phenotype (CD44^highESAhigh) to enable the formation of a metastatic tumour at that secondary site