Miranda Pring

The Role of TGF-β in Epithelial Malignancy and its Relevance to the Pathogenesis of Oral Cancer (Part II)

The role of transforming growth factor-beta (TGF-beta) in epithelial malignancy is complex, but it is becoming clear that, in the early stages of carcinogenesis, the protein acts as a potent tumor suppressor, while later, TGF-beta can function to advance tumor progression. We review the evidence to show that the pro-oncogenic functions of TGF-beta are associated with (1) a partial loss of response to the ligand, (2) defects of components of the TGF-beta signal transduction pathway, (3) over-expression and/or activation of the latent complex, (4) epithelial-mesenchymal transition, and (5) recruitment of signaling pathways which act in concert with TGF-beta to facilitate the metastatic phenotype. These changes are viewed in the context of what is known about the pathogenesis of oral cancer and whether this knowledge can be translated into the development of new therapeutic modalities.

A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma.

This paper examines the genetic defects associated with inherited cancer syndromes and their relevance to oral cancer. Tumour suppressor genes are now thought of as either gatekeepers or caretakers according to whether they control cell growth directly by inhibiting cell proliferation and/or promoting cell death (gatekeepers) or whether they maintain the integrity of the genome by DNA repair mechanisms (caretakers). In disorders such as xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome and Fanconis anaemia, where there are defective caretaker genes, there is an increased incidence of second primary malignancies, including oral cancer. By contrast, with the exception of Li Fraumeni syndrome, abnormalities of gatekeeper genes do not predispose to oral cancer. Not only do Li Fraumeni patients develop second primary malignancies, but defects of the p53 pathway (p53 mutation, MDM2 over-expression, CDKN2A deletion) appear to be a ubiquitous feature of sporadic oral cancer as it occurs in the West. The findings suggest that genetic instability is of fundamental importance in the pathogenesis of oral cancer.

TGF-β Signal Transduction in Oro-facial Health and Non-malignant Disease (Part I)

The transforming growth factor-beta (TGF-) family of cytokines consists of multi-functional polypeptides that reg- ulate a variety of cell processes, including proliferation, differentiation, apoptosis, extracellular matrix elaboration, angiogenesis, and immune suppression, among others. In so doing, TGF- plays a key role in the control of cell behavior in both health and disease. In this report, we review what is known about the mechanisms of activation of the peptide, together with details of TGF- signal transduction pathways. This review summarizes the evidence implicating TGF- in normal physiological processes of the craniofacial complex—such as palatogenesis, tooth formation, wound healing, and scarring—and then evaluates its role in non-malignant disease processes such as scleroderma, submucous fibrosis, periodontal disease, and lichen planus.

TGF-β1 acts as a tumor suppressor of human malignant keratinocytes independently of Smad 4 expression and ligand-induced G1 arrest

This study examined the role of TGF-β1 in human keratinocyte malignancy. Two carcinoma-derived human oral keratinocyte cell lines, BICR 31 and H314, were selected on the basis of their known resistance to TGF-β1-induced G1 arrest, the presence of wild type TGF-β cell surface receptors and normal Ras. Smad 4 protein was undetectable in both cell lines, but Smad 2 and Smad 3 were expressed at levels comparable with a fully TGF-β responsive cell line, and treatment of the cells with TGF-β1 resulted in the phosphorylation of Smad 2. Treatment with exogenous TGF-β1 resulted in a failure to induce transcription from an artificial Smad-dependent promoter and a failure to down-regulate c-myc, but resulted in an up-regulation of AP-1 associated genes (Fra-1, JunB and fibronectin). Transient transfection of Smad 4 into BICR 31 restored TGF-β1-induced growth inhibition and Smad-dependent transcriptional activation. Protracted treatment of cells with exogenous TGF-β1 resulted in the attenuation of cell growth in vitro. To over-express TGF-β1, both cell lines were transfected with latent TGF-β1 cDNA; neutralization studies of conditioned media demonstrated that whilst the majority of the peptide was in the latent form, a small proportion was present as the active peptide. Cells that over-expressed endogenous TGF-β1 grew more slowly in vitro compared to both the vector-only controls and cells that did not over-express the peptide. Orthotopic transplantation of cells that over-expressed endogenous TGF-β1 to the floor of the mouth in athymic mice resulted in marked inhibition of primary tumor formation compared to controls. Expression of a dominant-negative TGF-β type II receptor in cells that over-expressed endogenous TGF-β1 resulted in enhanced cell growth in vitro and diminished the tumor suppressor effect of the ligand in vivo, indicating that the endogenous TGF-β1 was acting in an autocrine capacity. The results demonstrate that over-expression of endogenous TGF-β1 in human malignant oral keratinocytes leads to growth inhibition in vivo and tumor suppression in vitro by mechanisms that are independent of Smad 4 expression and TGF-β1-induced G1 arrest.

HPV-Related Oropharynx Cancer in the United Kingdom: An Evolution in the Understanding of Disease Etiology.

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002-2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3-54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99-1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9-2.2); 2011: 4.1 (95% CI, 4.0-4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV- cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented. Cancer Res; 76(22); 6598-606. ©2016 AACR.

TGF-β inhibits metastasis in late stage human squamous cell carcinoma of the skin by a mechanism that does not involve Id1

It is now generally accepted that TGF-β acts as a pro-metastatic factor in advanced human breast cancer. However, it is well documented, that TGF-β is context dependent, and whether the TGF-β pathway switches to promote metastasis during the progression of squamous cell carcinoma (SCC) is unknown. This study examined the role of TGF-β signalling in SCC using a series of genetically related keratinocyte cell lines representing later stages of the disease, stably transduced with a dominant negative TβRII cDNA (dnTβRII). We demonstrated that clones expressing dnTβRII lost their growth inhibitory response to TGF-βin vitro, while ligand expression remained unchanged. Following transplantation of transduced cells to athymic mice in vivo, we showed that attenuation of the TGF-β signal resulted in a loss of differentiation and increased metastasis. In human tissue samples loss of TGF-β signal transduction as measured by pSmad2 activity also correlated with a loss of differentiation. Id1, previously shown to be down regulated by TGF-β, an inhibitor of differentiation and associated with metastasis, was weakly expressed in focal areas of a small number of human tumours but expression did not correlate with low levels of pSmad2. Our data demonstrate that TGF-β does not switch to promote metastasis in late stage human SCC of the skin and that inhibition of TGF-β signalling results in a loss of differentiation and increased metastasis in the later stages of this disease.

Establishing a large prospective clinical cohort in people with head and neck cancer as a biomedical resource: head and neck 5000

BackgroundHead and neck cancer is an important cause of ill health. Survival appears to be improving but the reasons for this are unclear. They could include evolving aetiology, modifications in care, improvements in treatment or changes in lifestyle behaviour. Observational studies are required to explore survival trends and identify outcome predictors.MethodsWe are identifying people with a new diagnosis of head and neck cancer. We obtain consent that includes agreement to collect longitudinal data, store samples and record linkage. Prior to treatment we give participants three questionnaires on health and lifestyle, quality of life and sexual history. We collect blood and saliva samples, complete a clinical data capture form and request a formalin fixed tissue sample. At four and twelve months we complete further data capture forms and send participants further quality of life questionnaires.DiscussionThis large clinical cohort of people with head and neck cancer brings together clinical data, patient-reported outcomes and biological samples in a single co-ordinated resource for translational and prognostic research.

Recruitment, response rates and characteristics of 5511 people enrolled in a prospective clinical cohort study: head and neck 5000.

*School of Oral and Dental Sciences, National Institute for Health Research (NIHR) Biomedical Research Unit in Nutrition, Diet and Lifestyle, UniversityHospitals Bristol NHSFoundation Trust, School ofOral andDental Sciences, University of Bristol, Surgical Research Team, University Hospitals Bristol NHS Foundation Trust, School of Social and Community Medicine, University of Bristol, Bristol, UK National Cancer Research Institute Consumer Liaison Group (NCRI CLG), Independent Cancer Patients Voice (ICPV), London, UK **MRC Integrative Epidemiology Unit and Avon Longitudinal Study of Parents and Children, School of Social and CommunityMedicine, School of Clinical Sciences, University of Bristol, Bristol, Cochrane Oral Health Group, School of Dentistry, University of Manchester, Manchester, Royal Marsden Hospital and the Institute for Cancer Research, London, Leeds Institute for Cancer and Pathology, University of Leeds, Leeds, ***Evidence-Based Practice Research Centre (EPRC), Faculty of Health and Social Care, Edge Hill University, Ormskirk, Lancashire, UK

Isolated submandibular metastasis from a contralateral thyroid papillary microcarcinoma: An unusual case

Papillary carcinoma is the most common form of thyroid cancer. It is a relatively indolent disease, which commonly remains clinically silent until its incidental histological diagnosis in surgical material or at autopsy. A tumour less than 10 mm in size is termed a papillary microcarcinoma. Papillary microcarcinoma may present with clinical symptoms, most commonly jugulodigastric and pretracheal lymphadenopathy with or without palpable thyroid nodules. Isolated submandibular metastases are rare. We present the case of a submandibular metastasis arising from a solitary 3 mm papillary microcarcinoma of the thyroid on the contralateral side in a 46-year-old woman. We describe the ultrasound and MRI characteristics of the submandibular mass. The ultrasound findings in particular were suggestive of a thyroid malignancy and prompted detailed examination of the thyroid gland. Clinical and radiological examination of the thyroid was normal. To the best of our knowledge, we present the first report of a papillary microcarcinoma of the thyroid presenting as a contralateral and isolated submandibular mass.

Mammary analogue secretory carcinoma of the salivary glands: a diagnostic dilemma

Mammary analogue secretory carcinoma (MASC) is a recently identified salivary gland neoplasm that can mimic other salivary gland tumours such as acinic cell carcinoma and cystadenocarcinoma. It is distinguished from these by differences in immunohistochemical profile and the identification of an ETV6-NTRK3 translocation (12;15)(p13;q25), which is also found in secretory carcinomas of the breast. Previous publications have suggested that MASC tumours have similar biological behaviour to acinic cell carcinoma. We report two cases of MASC that affected the upper lip, and showed an infiltrative and locally aggressive growth pattern that required several operations to ensure clearance of microscopic tumour cells.