Essentials of oral cancer

Abstract

Oral cancer is one of the 10 most common cancers in the world, with a delayed clinical detection, poor prognosis, without specific biomarkers for the disease and expensive therapeutic alternatives. This review aims to present the fundamental aspects of this cancer, focused on squamous cell carcinoma of the oral cavity (OSCC), moving from its definition and epidemiological aspects, addressing the oral carcinogenesis, oral potentially malignant disorders, epithelial precursor lesions and experimental methods for its study, therapies and future challenges. Oral cancer is a preventable disease, risk factors and natural history is already being known, where biomedical sciences and dentistry in particular are likely to improve their poor clinical indicators.

Keywords: Mouth neoplasms; carcinogenesis; neoplasm staging; oral cancer; oral squamous cell carcinoma; tumor microenvironment.

Figure 1

OSCC multistep progress. The development of squamous cell carcinoma of the oral cavity is considered a complex multistep process. Normal oral mucosal keratinocytes are chronically exposed to risk factors, which can break the homeostasis and generate genetic instability. Key genetic alterations occurring in TP53, NOTCH1 (Notch homolog 1, translocation-associated [Drosophila]), EGFR (epidermal growth factor receptor), CDKN2A (cyclin-dependent kinase inhibitor 2a) genes STAT3 (signal transducer and activator of transcription 3), Cyclin D1, Rb (retinoblastoma) plus LOH (loss of heterozygosity). The proliferation and uncontrolled growth, along with a battery discharge granted adaptive advantages over the surrounding cells, which promote local invasion and orchestrate a collaboration of the surrounding stromal cells. Among the factors secreted by tumor cells are MMP2 (matrix metalloproteinase 2), MMP9 (matrix metalloproteinase 9), MMP13 (matrix metalloproteinase 13), ROS (reactive oxygen species), VEGF (vascular endothelial growth factor), CXCL1 (chemokine [CXC motif] ligand 1), CXCL8 (chemokine [CXC motif] ligand 8), PDGF (platelet-derived growth factor), IL-8 (inteleukin 8), FGF-2 (fibroblast growth factor 2), TGF-β (transforming growth factor-β), TNF-α (tumor necrosis factor-α), IL-1 (inteleukin 1), GMCSF (granulocye-macrophage colony-stimulating factor). This microenvironment promotes cell adhesion loss (ex. E-cadherin) and facilitates epithelium mesenchymal transition (EMT), Vimentin and N-cadherin can be expressed in these cells. CAFs markers (tumor-associated fibroblasts) are α-SMA (α-smooth muscle actin) and integrin α6. Endothelins can contribute to pro-migratory paracrine signaling between CAFs and oral cancer cells. It also promotes CXCL1 and CXCL8 endothelial cell proliferation and survival. Endothelial cells produce factors like EGF, which increase migration.

Figure 2

Opportunities for biomarkers in oral cancer. The “natural history” of oral cancer allows the study of different phases in the progression of malignancy. One opportunity is given by the generation of an etiologic field -influenced by risk factors “exposome” and their interactions “interactome” that promotes a state of susceptibility. The passage of this state to canzerisable field gives another opportunity for research. With the diagnosis may emerge prognostic and predictive biomarkers. Figure modified from Rivera C. Opportunities for biomarkers with potential clinical use in oral cancer. Medwave. 2015 Jul 20;15(6):e6186. doi: 10.5867/medwave.2015.06.6186.