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Electrical impedance spectroscopy (EIS) has been proposed as a promising noninvasive method to differentiate healthy thyroid from parathyroid tissues during thyroidectomy. However, previously reported similarities in the in vivo measured spectra of these tissues during a pilot study suggest that this separation may not be straightforward. We utilise computational modelling as a method to elucidate the distinguishing characteristics in the EIS signal and explore the features of the tissue that contribute to the observed electrical behaviour. Firstly, multiscale finite element models (or 'virtual tissue constructs') of thyroid and parathyroid tissues were developed and verified against in vivo tissue measurements. A global sensitivity analysis was performed to investigate the impact of physiological micro-, meso- and macroscale tissue morphological features of both tissue types on the computed macroscale EIS spectra and explore the separability of the two tissue types. Our results suggest that the presence of a surface fascia layer could obstruct tissue differentiation, but an analysis of the separability of simulated spectra without the surface fascia layer suggests that differentiation of the two tissue types should be possible if this layer is completely removed by the surgeon. Comprehensive in vivo measurements are required to fully determine the potential for EIS as a method in distinguishing between thyroid and parathyroid tissues. [ABSTRACT FROM AUTHOR]

We explore the possibility that defects in genes associated with the response and repair of DNA double strand breaks predispose oral potentially malignant disorders (OPMD) to undergo malignant transformation to oral squamous cell carcinoma (OSCC). Defects in the homologous recombination/Fanconi anemia (HR/FA), but not in the non-homologous end joining, causes the DNA repair pathway to appear to be consistent with features of familial conditions that are predisposed to OSCC (FA, Bloom's syndrome, Ataxia Telangiectasia); this is true for OSCC that occurs in young patients, sometimes with little/no exposure to classical risk factors. Even in Dyskeratosis Congenita, a disorder of the telomerase complex that is also predisposed to OSCC, attempts at maintaining telomere length involve a pathway with shared HR genes. Defects in the HR/FA pathway therefore appear to be pivotal in conditions that are predisposed to OSCC. There is also some evidence that abnormalities in the HR/FA pathway are associated with malignant transformation of sporadic cases OPMD and OSCC. We provide data showing overexpression of HR/FA genes in a cell-cycle-dependent manner in a series of OPMD-derived immortal keratinocyte cell lines compared to their mortal counterparts. The observations in this study argue strongly for an important role of the HA/FA DNA repair pathway in the development of OSCC. [ABSTRACT FROM AUTHOR]

A multiscale modelling approach has been applied to the simulation of the electrical properties of oral tissue, for the purpose of informing an electrical impedance-based method of oral potential malignant disorder (OPMD) diagnosis. Finite element models of individual cell types, with geometry informed by histological analysis of human oral tissue (normal, hyperplastic and dysplastic), were generated and simulated to obtain electrical parameters. These were then used in a histology-informed tissue scale model, including the electrode geometry of the ZedScan tetrapolar impedance-measurement device. The simulations offer insight into the feasibility of distinguishing moderate dysplasia from severe dysplasia or healthy tissue. For some oral sites, simulated spectra agreed with real measurements previously collected using ZedScan. However, similarities between simulated spectra for dysplastic, keratinised and non-dysplastic but hyperkeratinised tissue suggest that significant keratinisation could cause some OPMD tissues to exhibit larger than expected impedance values. This could lead to misidentification of OPMD spectra as healthy. Sources of uncertainty within the models were identified and potential remedies proposed. [ABSTRACT FROM AUTHOR]

Simple Summary: The early treatment of oral cancer is a high priority, as improvements in this area could lead to greater cure rates and reduced disability due to extensive surgery. Oral cancer is very difficult to detect in over 70% of cases as it develops unseen until quite advanced, sometimes rapidly. It has become apparent that there are at least two types of epithelial cells (keratinocytes) found in oral tissue on the road to cancer (premalignant). One type secretes molecules called prostaglandins but the other does not and the former may stimulate the latter to progress to malignancy, either by stimulating their proliferation or encouraging the influx of blood vessels to feed them. Additionally, we have identified regulators of prostaglandin secretion in premalignant oral cells that could be targeted in future therapies, such as inducers of cellular senescence, drugs which kill senescent cells (senolytics), steroid metabolism, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase. Potentially pre-malignant oral lesions (PPOLs) are composed of keratinocytes that are either mortal (MPPOL) or immortal (IPPOL) in vitro. We report here that MPPOL, but not generally IPPOL, keratinocytes upregulate various extracellular tumor-promoting cytokines (interleukins 6 and 8) and prostaglandins E1 (ePGE1) and E2 (ePGE2) relative to normal oral keratinocytes (NOKs). ePGE upregulation in MPPOL was independent of PGE receptor status and was associated with some but not all markers of cellular senescence. Nevertheless, ePGE upregulation was dependent on the senescence program, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase and was partially regulated by hydrocortisone. Following senescence in the absence of p16INK4A, ePGEs accumulated in parallel with a subset of tumor promoting cytokine and metalloproteinase (MMP) transcripts, all of which were ablated by ectopic telomerase. Surprisingly, ataxia telangiectasia mutated (ATM) function was not required for ePGE upregulation and was increased in expression in IPPOL keratinocytes in line with its recently reported role in telomerase function. Only ePGE1 was dependent on p53 function, suggesting that ePGEs 1 and 2 are regulated differently in oral keratinocytes. We show here that ePGE2 stimulates IPPOL keratinocyte proliferation in vitro. Therefore, we propose that MPPOL keratinocytes promote the progression of IPPOL to oral SCC in a pre-cancerous field by supplying PGEs, interleukins and MMPs in a paracrine manner. Our results suggest that the therapeutic targeting of COX-2 might be enhanced by strategies that target keratinocyte senescence. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cavity is the most common site of head and neck cancer which is ranked as the eighth most common cancer worldwide. Oral cancer treatment is often associated with significant morbidity and is sometimes ineffective. These cancers, mainly due to tobacco and alcohol consumption, can develop from oral potentially malignant disorders, the most common of which is oral leukoplakia. Some of these oral potentially malignant disorders disappear, while others will transform to oral cancer. Patients may also develop cancer in the field of cancerization. Unfortunately, except for the surgical excision of lesions with dysplasia, there is no effective intervention to effectively prevent transformation or cancer development in the field of cancerization. Moreover, no standardized biomarker has been clearly identified as sufficient to predict malignant transformation. In this article, several experts discuss the main challenges in oral cancer prevention, in particular the need (i) to define new a new classification system integrating cellular and molecular features aiming (ii) at better identifying patients at high risk of malignant transformation, and (iii) at developing treatment strategies to prevent their malignant transformation of oral potentially malignant disorders. Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation. [ABSTRACT FROM AUTHOR]

Over recent decades, the field of cellular senescence has attracted considerable attention due to its association with aging, the development of age-related diseases and cancer. Senescent cells are unable to proliferate, as the pathways responsible for initiating the cell cycle are irreversibly inhibited. Nevertheless, senescent cells accumulate in tissues and develop a pro-inflammatory secretome, known as the senescence-associated secretory phenotype (SASP), which can have serious deleterious effects if not properly regulated. There is increasing evidence suggesting senescent cells contribute to different stages of carcinogenesis in different anatomical sites, mainly due to the paracrine effects of the SASP. Thus, a new therapeutic field, known as senotherapeutics, has developed. In this review, we aim to discuss the molecular mechanisms underlying the senescence response and its relationship with cancer development, focusing on the link between senescence-related inflammation and cancer. We will also discuss different approaches to target senescent cells that might be of use for cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients may develop white or red patches of the lining of the mouth with an increased risk of developing oral cancer. Treatment with Vitamin A derivatives (retinoids) results in some improvement in these lesions, but this is not maintained, and there are side effects. We know that the cells of the mouth lose cellular receptors for retinoids as these lesions develop, initially by a reversible alteration to the DNA (DNA methylation). Drugs, such as 5-AZA-CdR, which reduce DNA methylation, may restore sensitivity to the effects of retinoids. Treatment of a panel of cells from mouth precancer white patches with retinoids, 5-AZA-CdR and a combination results in varied responses: some cells re-sensitise to retinoids, whereas in others, the main effects on cell division rate and cell lifespan seem related to the effects of 5-AZA-CdR alone. These findings help us to understand the varied responses to retinoids in the clinical setting. Loss of RARβ2 expression by promoter methylation is an early event in oral carcinogenesis. Understanding the mechanisms and consequences of RARβ loss may aid in understanding the disappointing results of retinoid chemoprevention trials. This study aimed to describe the effects of all-trans retinoic acid (ATRA) and the de-methylating agent 5-Aza-2′ deoxycytidine (5-AZA-CdR) on a panel of immortal potentially malignant oral lesion (PMOL) cell cultures. RARβ expression was assessed in PMOL tissues by immunohistochemistry. Cells were treated with ATRA ± 5-AZA-CdR, and the effects on the cell cycle and senescence were assessed. In PMOL tissues, RARβ expression was variable, but lower in biopsies which gave rise to immortal cell cultures. Treatment of iPMOL cells with ATRA resulted in little change in RARβ expression, but the addition of 5-AZA-CdR resulted in significant increases. The effects on the cell cycle and senescence were variable and may be related to 5-AZA-CdR, as this has wider effects on the cell cycle. Overall, the response of iPMOL cells to ATRA and 5-AZA-CdR treatment was variable and is dependent on several factors, including RARβ-promoter methylation. These findings may help to explain the lack of consistent effect of retinoids in PMOLs seen in chemoprevention trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone metastasis is a debilitating, incurable complication that occurs in breast cancer patients with a variable period of latency after treatment of the primary tumor. The seeding of individual cancer cells in the bone marrow from the primary tumor occurs early in disease progression. How disseminated cancer cells are able to remain dormant in the bone marrow and then reactivate decades later to form destructive bone lesions is not fully understood. We have used model systems to identify bone resident cell types, and molecular mediators, that influence the survival and fate of disseminated breast cancer cells. The identification of such cellular and molecular support mechanisms can inform the design of new therapeutic strategies aimed at eliminating indolent cancer cells from the bone marrow, preventing progression to overt metastases. Metastatic breast cancer in bone is incurable and there is an urgent need to develop new therapeutic approaches to improve survival. Key to this is understanding the mechanisms governing cancer cell survival and growth in bone, which involves interplay between malignant and accessory cell types. Here, we performed a cellular and molecular comparison of the bone microenvironment in mouse models representing either metastatic indolence or growth, to identify mechanisms regulating cancer cell survival and fate. In vivo, we show that regardless of their fate, breast cancer cells in bone occupy niches rich in osteoblastic cells. As the number of osteoblasts in bone declines, so does the ability to sustain large numbers of breast cancer cells and support metastatic outgrowth. In vitro, osteoblasts protected breast cancer cells from death induced by cell stress and signaling via gap junctions was found to provide important juxtacrine protective mechanisms between osteoblasts and both MDA-MB-231 (TNBC) and MCF7 (ER+) breast cancer cells. Combined with mathematical modelling, these findings indicate that the fate of DTCs is not controlled through the association with specific vessel subtypes. Instead, numbers of osteoblasts dictate availability of protective niches which breast cancer cells can colonize prior to stimulation of metastatic outgrowth. [ABSTRACT FROM AUTHOR]

The HOX genes are a group of homeodomain-containing transcription factors that play important regulatory roles in early development, including the establishment of cell and tissue identity. HOX expression is generally reduced in adult cells but is frequently re-established as an early event in tumour formation and supports an oncogenic phenotype. HOX transcription factors are also involved in cell cycle regulation and DNA repair, along with normal adult physiological process including stem cell renewal. There have been extensive studies on the mechanism by which HOX proteins regulate transcription, with particular emphasis on their interaction with cofactors such as Pre-B-cell Leukaemia Homeobox (PBX) and Myeloid Ecotropic Viral Integration Site 1 (MEIS). However, significantly less is known of how the activity of HOX proteins is regulated. There is growing evidence that phosphorylation may play an important role in this context, and in this review, we draw together a number of important studies published over the last 20 years, and discuss the relevance of phosphorylation in the regulation and function of HOX proteins in development, evolution, cell cycle regulation, and cancer. [ABSTRACT FROM AUTHOR]