Senescence-Derived Extracellular Molecules as Modulators of Oral Cancer Development: A Mini-Review

Abstract

Oral cancers are predominantly oral squamous cell carcinomas (OSCCs) derived from keratinocytes, and there is now very detailed knowledge of the genetics and molecular biology of the epithelial tumourigenic component of these cancers, including the identification of cancer stem or tumour-initiating cells. Several key genetic alterations have been identified including the near ubiquitous loss of the CDKN2A/p16^INK4A and p53 pathways and telomerase activation, together with frequent inactivation of the NOTCH1 canonical pathway either by somatic genetic alterations or by the presence of human papilloma virus. There is also evidence that OSCCs arise from a ‘field' of altered cells and that malignant conversion takes place pre-dominantly at the microscopic level. However, in the last decade, it has been realised that tumour development and progression are influenced by the cells of the microenvironment with cross-talk between the epithelial (tumour) and mesenchymal components. OSCCs, especially those that have bypassed cellular senescence, produce an array of proteins and metabolites that induce cellular senescence in the normal surrounding cells; indeed, senescence is a common property of cancer-associated fibroblasts (CAFs). Cellular senescence is defined as an irreversible cell cycle arrest and is associated with the release of molecules known as the senescence-associated secretory phenotype that can selectively promote the growth of pre-neoplastic keratinocytes (osteopontin) and cancer invasion (transforming growth factor β, matrix metalloproteinases, interleukin 6 and lactate). In addition, both old and new work has shown that keratinocytes harbouring NOTCH loss-of-function mutations that lead to defective keratinocyte differentiation and loss of squamous epithelial barrier function may act as a tumour-promoting stimulus for initiated cells harbouring RAS pathway mutations by activating a wound response in the tumour mesenchyme. Thus, not all keratinocytes in the tumour tissue may be tumourigenic and may instead act as promoters of tumour growth and progression analogous to the much-studied CAFs which co-evolve with the genetically altered tumourigenic cells. This new data is discussed in relation to attempts to develop novel non-invasive diagnostics and therapeutics for oral cancer.

Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-β1

“…CAF senescence (permanent proliferative arrest) and activation are characteristics particularly associated with GU-OSCCs compared to GS-OSCCs 11 and are thought to be tumour-promoting, essentially due to a unique secretome that is collectively known as the senescence-associated secretory phenotype (SASP) 12,13 . However, it is possible that GU-and GS-OSCCs are not entirely distinct entities and tumours may contain mixtures of genetically stable and unstable keratinocytes 14 (E.K.…”

Emerging role of cellular senescence in the pathogenesis of oral submucous fibrosis and its malignant transformation

“…The proteinase–antiproteinase balance is eventually dictated by the proteinase: substrate stoichiometry 1,6 . Several other paracrine mediators of senescence have been identified including IL‐1β, CCL‐2, chemokine (C‐C motif) ligand 20 ( CCL‐20 ), TGF‐β, VEGF, and platelet‐derived growth factor‐AA (PDGF‐AA) 29,31 . Among these PDGF‐AA is particularly important as it can be secreted from senescent fibroblasts and convert non‐senescent fibroblasts into profibrotic senescent fibroblasts 31 (Figure 2, blue box).…”

“…SASP has been shown to induce EMT and confer on cancer cells the ability to infiltrate and metastasize via its components such as TGF‐β, IL‐6, IL‐8, VEGF, MMPs 6,29 . The preferential proliferation of the preneoplastic keratinocytes, facilitated by the SASP component OPN 29 is considered essential for malignant induction 29 .…”

“…SASP has been shown to induce EMT and confer on cancer cells the ability to infiltrate and metastasize via its components such as TGF‐β, IL‐6, IL‐8, VEGF, MMPs 6,29 . The preferential proliferation of the preneoplastic keratinocytes, facilitated by the SASP component OPN 29 is considered essential for malignant induction 29 . The genetically unstable OSCC (GU‐OSCC) characterized by loss of TP53 and CDKN2A/P16INK4A, telomerase activation, extensive loss of heterozygosity (LOH) and inactivation of canonical NOTCH‐1 pathway differ from the genetically stable (GS‐OSCC) in their stromal component 29 .…”

Oral health in geroscience: animal models and the aging oral cavity

“…We suggest that the failure to utilize aged animals for preclinical studies of oral disease limits the clinical relevance of such studies. One goal of the Geroscience Initiative is to raise awareness of the importance of understanding the contribution of aging biology to age-related diseases (Sierra & Kohanski, 2017 Sumida & Hamakawa, 2001;Thevaranjan et al, 2017;Barrera et al, 2016;Khan et al, 2010;Yin & Chung, 2011;Parkinson et al, 2016;Lindroth & Park, 2013;Paul et al, 2015;Ballestar, 2011) R.I. Morimoto, J.E. Pessin, T.A.…”