Hallmarks of Cancer Applied to Oral and Oropharyngeal Carcinogenesis: A Scoping Review of the Evidence Gaps Found in Published Systematic Reviews

Abstract

In 2000 and 2011, Hanahan and Weinberg published two papers in which they defined the characteristics that cells must fulfil in order to be considered neoplastic cells in all types of tumours that affect humans, which the authors called "hallmarks of cancer". These papers have represented a milestone in our understanding of the biology of many types of cancers and have made it possible to reach high levels of scientific evidence in relation to the prognostic impact that these hallmarks have on different tumour types. However, to date, there is no study that globally analyses evidence-based knowledge on the importance of these hallmarks in oral and oropharyngeal squamous cell carcinomas. For this reason, we set out to conduct this scoping review of systematic reviews with the aim of detecting evidence gaps in relation to the relevance of the cancer hallmarks proposed by Hanahan and Weinberg in oral and oropharyngeal cancer, and oral potentially malignant disorders, and to point out future lines of research in this field.

Keywords: biomarkers; hallmarks of cancer; meta-analysis; oral cancer; oral potentially malignant disorders; oropharyngeal cancer; scoping review; systematic review.

Figure 1

Flow diagram of the identification and selection process of the studies included in this scoping review of systematic reviews.

Figure 2

Graphic representation of the most relevant pathways regulating sustaining proliferative signalling in oral squamous cell carcinomas. (A) Tyrosine kinase receptors (e.g., EGFR or ErbB2) may be activated on the cell membrane by extracellular growth factors (e.g., EGF) or by constitutive mutations of the genes that encode them. Consequently, (B) Ras is downstream activated through the stimulation of these receptors, although Ras can be also activated by mutations, representing an influential central point in oral carcinogenesis, able to stimulate two important downstream oncogenic pathways: PI3K (pathway graphically represented in purple colour) and/or MAPK (pathway graphically represented in pink colour). (C) The PI3K pathway (PI3K-Akt-mTor, green), which can be blocked by its potent supressor PTEN (C), regulates the downstream translation of CCND1 mRNA via mTor (C). This pathway can also be constitutively activated by PI3K mutations (C). In parallel, (D) the endpoint of the MAPK pathway (Raf-MEK-Erk; in pink colour), which can also be activated by the constitutive mutation of Raf (D), is the Erk-mediated transcriptional activation of CCND1 (D). A third key pathway in the oncogenic activation of cyclin D1 is (E) NF-kB (in blue colour), which can be activated by IKK, as a consequence of PI3K pathway activation. (F) CCND1 transcriptional activation mediated by ERK, and mTor-mediated translation of its messenger RNA, are both essential for the ribosomal synthesis of cyclin D1, which forms complexes with its binding partners, CDK4/6, that finally translocate to the nucleus. (G) Nuclear Cyclin D1-CDK4/6 complexes subsequently activate the retinoblastoma pathway, in which the release of transcription factors E2F is induced by the translocation of a phosphate group, (H) with progression from G1 to S phase of the cell cycle. Activation of the retinoblastoma pathway can be prevented (I) through the potent inhibition of Cyclin D1-CDK4/6 by the product of tumour suppressor gene CDKN2A (i.e., p16INK4), blocking cell cycle advance; or alternatively by the tumour suppressor p53 (J), which plays an important role arresting the cell cycle progression, repairing the damaged DNA or finally promoting apoptosis, in an effort to prevent sustaining proliferation in cancer cells.

Figure 3

(a) Immunohistochemical image of cyclin D1 expression in OSCC. Note the nuclear expression of cyclin D1 at the periphery of the well-differentiated tumour nests (40× magnification). (b). Expression of ki67 in oral cancer and adjacent non-tumour epithelium. Note how the cellular proliferative activity of the well-differentiated tumour nests is very similar to that observed in the non-tumour oral epithelium (40× magnification). (c). Immunohistochemical overexpression of p53 protein in oral cancer and adjacent non-tumour epithelium. Note the early overexpression of p53 in premalignant epithelium (20× magnification). (d). Detail of Figure 3c. Note the overexpression of p53 in the premalignant epithelium adjacent to the carcinoma in which in the right area (red arrow) protein expression is observed in the basal layer, while in the left area (black arrow) protein overexpression is observed in the basal and suprabasal layers of the epithelium, which also shows a morphological alteration compatible with epithelial dysplasia (40× magnification). (e). Immunohistochemical expression of bcl-2 in the periphery of well-differentiated tumour nests (40× magnification). (f). Cytoplasmic cyclin D1 expression. Note that some cells show an amoeboid form of invasion probably due to the development of actin-based structures (lamellipodia and invadopodia) (40×, 200× and 40×, magnification, respectively).

Figure 4

Graphic representation of the reprogramming energetic metabolism in oral squamous cell carcinomas, modified from Vander Heiden et al. [239]. Energetic metabolism in mammalian cells depends essentially, but not exclusively, on the consumption of glucose. The type of energy metabolism adapted by cells is primarily influenced by the availability of oxygen in the surrounding environment and by their proliferative state. Quiescent cells from oral differentiated tissues, in the presence of oxygen, adopt a type of metabolism called oxidative phosphorylation, converting glucose through glycolysis into pyruvate, which is subsequently converted into CO₂ in the mitochondria through the tricarboxylic acid cycle (TCA). In this process, the cofactor NADH (nicotinamide adenine dinucleotide reduced) is produced, which is relevant for maximising energy production in the form of ATP (adenosine 5’-triphosphate). During oxidative phosphorylation, a small amount of glucose is metabolised to lactate production. The net result of this energy programme is the production of 32 molecules of ATP for each molecule of glucose. In hypoxic situations, quiescent cells develop a type of metabolism known as anaerobic glycolysis, which shifts glucose metabolism towards lactate production, resulting in a much lower energy yield compared to oxidative phosphorylation, resulting in 2 molecules of ATP for each molecule of glucose metabolised. On the other hand, oral proliferative tissues and oral cancer cells develop an apparently paradoxical type of metabolism, called aerobic glycolysis (also known as the Warburg effect), whereby, even in the presence of oxygen, most of the glucose (85%) is derived to produce lactate, while a small percentage (5%) is metabolised in the mitochondria to produce CO₂ and a small amount of ATP—4 molecules of ATP for each molecule of glucose.

Figure 5

Bar and pie charts graphically summarizing the evidence derived from the research on hallmarks of oral and oropharyngeal carcinogenesis across secondary-level systematic reviews and meta-analyses. Hallmarks of cancer were ordered by absolute counts (left, bar chart) and relative frequencies by calculating raw proportions, expressed as percentages (right, pie chart).