Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications

Abstract

Strongly associated with tobacco use, heavy alcohol consumption, and with high-risk human papillomavirus (HPV) infection, head and neck squamous cell carcinoma (HNSCC) is a frequently lethal, heterogeneous disease whose pathogenesis is a multistep and multifactorial process involving genetic and epigenetic events. The majority of HNSCC patients present with locoregional advanced stage disease and are treated with combined modality strategies that can markedly impair quality of life and elicit unpredictable results. A large fraction of those who undergo locoregional treatment and achieve a complete response later develop locoregional recurrences or second field tumors. Biomarkers that are thus able to stratify risk and enable clinicians to tailor treatment plans and to personalize post-therapeutic surveillance strategies are highly desirable. To date, only HPV status is considered a reliable independent predictor of treatment response and survival in patients with HNSCC arising from the oropharyngeal site. Recent studies suggest that telomere attrition, which may be an early event in human carcinogenesis, and telomerase activation, which is detected in up to 90 % of malignancies, could be potential markers of cancer risk and disease outcome. This review examines the current state of knowledge on and discusses the implications linked to telomere dysfunction and telomerase activation in the development and clinical outcome of HNSCC.

Keywords: Field cancerization; Head and neck cancer; Human papillomavirus; Molecular biology; Recurrence; Survival; TERT; Telomerase reverse transcriptase; Telomere.

Fig. 1

Short telomeres: senescence and cancer. Telomeres, which are essential to protect chromosomes from deterioration and from end-to-end fusion, are specialized DNA structures located at the ends of chromosomes composed of (TTAGGG)n tandem repeats that are associated with capping proteins. Human adult somatic cells have a limited capacity to divide (Hayflick limit) as DNA polymerase alone cannot replicate the 3′ end of the DNA strand resulting in a progressive loss of TTAGGG telomeric sequences. Critically short telomeres trigger a DNA damage response, resulting in cellular senescence, an efficient tumor suppressor mechanism, and apoptosis. Senescence involves intact DNA damage checkpoints, such as p53 and p16/RB signaling pathways. Checkpoint-compromised cells can escape cellular senescence and apoptosis. In this context, cells can experience an increased number of divisions and can ultimately enter to breakage-fusion-bridge events and dramatic genetic instability due to telomere erosion, which most commonly leads to cell death. Rarely, the cell reactivates telomerase expression to drive telomere maintenance and replicative immortality. TERT telomerase reverse transcriptase

Fig. 2

Epithelial carcinogenesis and telomere/telomerase interplay. The inactivation of the p53 and RB pathways are the main molecular determinants in head and neck carcinogenesis. In tobacco- and alcohol-related HNSCC, the abrogation of p53 and RB pathways may occur via mutation and genetic/epigenetic alterations. In HPV-driven carcinomas, p53 and RB pathways are inactivated at the protein level by E6 and E7 HR α-HPV oncoproteins, respectively. In this context, cells can bypass cellular senescence (a condition triggered by telomere shortening in which cells remain viable but are unable to divide) and experience an increased number of cell divisions of potentially premalignant clones characterized by extremely shortened telomeres and genetic instability. Different strategies may lead to re-activation of telomerase, a ribonucleoprotein complex containing an internal RNA component and a catalytic protein, TERT, with telomere-specific reverse transcriptase activity which synthesizes de novo telomere sequences. Cells can thus escape from apoptosis and maintain short but stable telomere lengths which are the key to cell immortality. Besides providing cells with unlimited proliferation potential, telomerase interacts with other cancer-related signaling cascades, such as Wnt/β-catenin and NF-kB pathways. In this scenario, telomerase plays additional non-canonical roles that may impact cancer progression by inducing crucial factors, such as MMP9, TNF-α, IL-6, and activating cellular programs leading to increased tumor cell motility/migration/invasion capability and epithelial-to-mesenchymal transition, in a context of feed-forward loops. HR α-HPV high-risk alpha human papillomaviruses, TERT telomerase reverse transcriptase, NF-kB nuclear factor-kB, EMT epithelial-to-mesenchymal transition, MMP matrix metalloproteinase, TNF tumor necrosis factor, RB protein retinoblastoma