Associated Research: Oral Cancer
This programme is developing an integrated approach to understanding the mechanisms which govern transformation and disease progression in oral cancer. The group will involve CDOS and a wider group of Oral Surgeons, as well as continuing to build links with other groups both nationally and internationally.
Oral cancers are predominantly squamous cell carcinomas (SCCs). These cancers are associated with tobacco and alcohol use in developed countries and with the chewing of Paan in developing countries. We have contributed to the understanding of the former (Parkinson and Teh) by using genetic and transcriptional profiling and have formulated the hypothesis that at least two distinct patterns of progression to malignancy exist. However, virtually nothing is known about the molecular basis of Paan-associated SCCs and this type of cancer is common in large Bangladeshi community in the East End of London. In collaboration with Professor Tilakaratne in Sri Lanka we have begun to analyse the mechanism by which Paan-associated SCCs develop from the pre-neoplastic condition of oral sub-mucous fibrosis (OSMF).
Drs Waseem and Hong have established many alterations in the keratin filaments and desmosomes of early OSMF lesions, respectively and Dr. Teh has obtained a preliminary genetic profile of similar lesions. Professors Parkinson and Fortune are beginning to investigate early changes in the OSMF mesenchymal cells and have found that individuals who develop the disease may have defects in key regulators of collagen metabolism that are absent from Paan chewers that do not.
Together with Professor Tilakaratne and Professor Prime and his colleagues in Bristol they have also shown that OSMF fibroblasts at a very early stage of the disease adopt a cancer-promoting or ‘activated’ phenotype and display evidence of accelerated ageing. Whether such cells can promote neoplasia is being investigated but transcriptional profiling and immunocytochemical evidence supports the hypothesis that they are associated with poor prognosis in patients.
Professor Farida Fortune, Dr Pete Tomlins and Dr Eleni Hagi-Pavli
Histopathology is the gold standard for evaluation of oral mucosal biopsies. The technique relies upon selection of the most representative site for biopsy whereby current practice is dependent on visual inspection of the oral mucosa to determine the biopsy site. This approach has significant challenges: visual inspection of gross morphological changes is subjective; the site that is biopsied is small therefore the site representing the most serious pathology may be missed and where there are large areas of affected tissue more than one biopsy may be required. The group led by Professor Fortune has developed a new non-invasive approach using scattering attenuation microscopy (SAM) which is based upon optical coherence tomography (OCT) to improve oral cancer diagnosis, reduce the number of biopsies a patient will undergo and screen for oral cancer.
SAM uses volumetric datasets to produce quantitative 2D images of tissue. It measures attenuation of the scattering of light from cell nuclei producing a measure of the cellular changes that is indicative of oral precancer. Of patients presenting in primary care with oral cancer and pre-cancer, 15% are pre-cancerous and a further 25% present with stage 1 cancer. The remaining 60% are evenly distributed between cancer at stages 2, 3 and 4. The resulting resource cost for the 5000 oral cancer cases detected in the UK annually over 3 years costs £130m for stage 2, 3 and 4 only. (These figures are based upon published data of the distribution of disease and stage). SAM has enormous potential to decrease the costs by detecting malignant transformation at an early stage. If SAM were to identify even 10% of cancers and prevent progression to stages 2-4 it would result in an NHS saving of £17m over 3 years.
- Professor Ken Parkinson’s primary interest is in cellular aging and in particular the telomerase enzyme, which is increased in 90% of oral SCCs. The conventional role of telomerase in cancer is the addition of telomere repeats to the ends of chromosomes but it is becoming increasingly apparent that the protein component of the enzyme has other functions that include the blockade of apoptosis and terminal differentiation. Professor Parkinson’s group is attempting to dissect apart the molecular properties of the telomerase enzyme that are responsible for cancer and those that are beneficial for stem cell survival.
- Professor Ian Mackenzie’s interests centre on the hypothesis that human cancers contain a stem cell population that is ultimately responsible for tumour recurrence. In oral SCC this population resides within a fraction that is positive for the surface markers CD44 and CD133. These cells exhibit a distinct and readily recognisable morphology under certain tissue culture conditions and are more tumourigenic in immunosuppressed mice that the rest of the tumour population. Additionally, the CD44/CD133 positive population is more resistant to the induction of apoptosis by therapeutic drugs. Professor Mackenzie is currently investigating the mechanism by which these candidate cancer stem cells evade apoptosis.
- Dr Teh’s research aims to translate basic science into clinical applications and towards personalised medicine based on a combination of patient’s genetic (eg., SNP, LOH, CNV), epigenetic (DNA methylation/histone marks) and gene expression (mRNA levels) signatures. He believes that the key to successful cancer treatment and cure is early detection of cancer formation and personalised treatment based on individual’s molecular profile. Hence, he aims to delineate the mechanisms and identify molecular markers of early cancer initiation by employing his expertise in various molecular and cell culture techniques such as high-resolution DNA microarray ‘SNP fingerprinting’ technique, epigenomics (genome-wide methylome mapping, methylation specific qPCR), adult stem cell cultures, 3D organotypic tissue regeneration, retroviral gene delivery, RNA interference gene silencing, absolute real-time quantitative PCR, and bioinformatics.
Dr Teh is currently investigating the mechanism of oncogene-induced epigenetic modifications that perturbs the molecular program regulating stem cell renewal, differentiation and senescence. The stable and heritable properties of epigenetic ‘fingerprints’ render these signatures potentially important for clinical translation into diagnostic biomarkers.
- Dr Wan is interested in modulation of structure and function of intercellular junctions in cancer, in particular the desmosomes which confer strong adhesion in tissues that experience extensive mechanical stress. Loss of desmosomal proteins and modulation of desmosome structure are frequently seen in squamous cell carcinoma of head and neck. It is now widely accepted that desmosomes play a suppression role in epithelial cell invasion and metastasis. However, the function of desmosomal proteins are not only restricted to cell-cell adhesion but also involved in intracellular signaling in many biological processes.
Wan has found that desmosomal proteins including Desmoglein 3 are low in their expression levels in adult keratinocyte stem cells or progenitors, suggesting strongly that desmosomal proteins may participate in the regulation of cell proliferation, differentiation and tissue morphogenesis. Wan is currently investigating the role of Desmoglein 3 in such biological processes in addition to desmosome adhesion and has identified a novel cellular function of this protein in the regulation of cell-cell adhesion and cell differentaition. This study will enhance our understanding the pathogenesis of cancer and other desmosome related diseases such as pemphigus.
- Dr. Ahmad Waseem is interested in keratin expression as diagnostic and prognostic markers of oral squamous carcinoma. Keratin proteins are expressed in all epithelial tissues in a differentiation specific fashion. The normal pattern of keratin expression changes dramatically when the tissue becomes cancerous. In the early stages of cancer development i.e. in dysplasia, the oral epithelium acquires a phenotype similar to that of skin in terms of keratin expression. Once the oral tissue becomes cancerous, the expression of differentiation-specific keratins is suppressed with concomitant induction of embryonic keratins (such as keratin K8 and K18). When the cancer starts to metastasize the cancerous epithelial cells suppress most keratins and start to express vimentin, a marker of mesenchymal tissue.
This switch from keratin to vimentin expression is a type of epithelial-mesenchymal transition (EMT) associated with tissue invasion. We have shown that suppression of vimentin in cells derived from highly metastatic head and neck cancer can restore epithelial phenotype and suppress invasion in vitro as well as in vivo models. Waseem is currently investigating the mechanism of keratin switching in oral squamous cell carcinoma and the role of vimentin in bringing about EMT during metastasis. This study will provide important insights into the role of keratins in the development and spread of oral cancer.
Professor Eric Ken Parkinson
Professor of Head & Neck Cancer
+44 20 7882 7185 (Phone)
+44 20 7882 7153 (Fax)
Research Centre for Clinical & Diagnostic Oral Sciences
Barts & The London
Queen Mary's School of Medicine & Dentistry
4 Newark Street
London E1 2AT
- Dr Alan Cruchley - Senior Lecturer in Oral Pathology (non clinical)
- Professor Farida Fortune - Head of Clinical and Diagnostic Oral Sciences
- Dr Eleni Hagi-Pavli - Senior Lecturer in Oral Sciences
- Professor Ian Mackenzie - Professor of Stem Cell Science
- Professor Kim Piper - Consultant Oral Pathologist and Hon Professor, Senior Tutor for Dental Admissions
- Dr Muy-Teck Teh - Senior Lecturer in Head and Neck Cancer
- Dr Pete Tomlins - Senior Lecturer in Dental Biometrics (non-clinical)
- Dr Hong Wan - Senior Lecturer
- Dr Ahmad Waseem - Professor of Molecular and Cellular Biology