MRC Cancer Cell Unit

Cambridge, United Kingdom

MRC Cancer Cell Unit

Cambridge, United Kingdom
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Weaver J.M.J.,MRC Cancer Cell Unit | Ross-Innes C.S.,MRC Cancer Cell Unit | Fitzgerald R.C.,MRC Cancer Cell Unit
Nature Reviews Gastroenterology and Hepatology | Year: 2014

Oesophageal adenocarcinoma (OAC) is the eighth most common cancer type worldwide with a dismal 5-year survival. Barrett oesophagus, the replacement of the normal squamous epithelia with glandular cells, is the first step in the pathway towards OAC. Although most patients with OAC present de novo, the presence of the easily detectable OAC precursor lesion, Barrett oesophagus, enables the possibility of early detection of high-risk patients who are more likely to progress. Currently, identification of high-risk patients depends on histopathological assessment of dysplasia with no regards to molecular pathogenesis. In the future, screening and risk stratification initiatives for Barrett oesophagus that incorporate molecular profiles might permit improved early diagnosis and intervention strategies with the possibility of preventing OAC. For the majority of patients presenting de novo at an advanced stage, combining so-called -omics datasets with current clinical staging algorithms might enable OACs to be better classified according to distinct molecular programmes, thereby leading to better targeted treatment strategies as well as cancer monitoring regimes. This Review discusses how the latest advances in -omics technologies have improved our understanding of the development and biology of OAC, and how this development might alter patient management in the future. © 2014 Macmillan Publishers Limited. All rights reserved.


Fels Elliott D.R.,University of Cambridge | Fitzgerald R.C.,MRC Cancer Cell Unit
Current Opinion in Gastroenterology | Year: 2013

PURPOSE OF REVIEW: There is a clinical need for biomarkers that can improve diagnostic accuracy and risk stratification of esophageal lesions. Here we review the current literature and highlight the most important, recent advancements in biomarkers as a supplement to histopathology for management of patients with Barrett's esophagus. RECENT FINDINGS: A prospective cohort study in Northern Ireland shows that a small panel of biomarkers (low-grade dysplasia, abnormal DNA ploidy and Aspergillus oryzae lectin) can identify patients at high risk for developing high-grade dysplasia or cancer. Recent research in molecular imaging shows promise for molecular probes in endoscopy, using fluorescently labeled peptides or lectins to identify dysplastic areas of Barrett's epithelium. Based on the current literature, p53 immunostaining is starting to be adopted by some centers as an adjunct to histopathology diagnosis for dysplasia. SUMMARY: The evidence base for the use of biomarkers is increasing and it appears that panels may have superior diagnostic and predictive power over single, candidate biomarkers. Prior to clinical implementation, biomarkers must overcome significant barriers including the need for large-scale prospective validation trials, and the limited ability of clinical laboratories to process and analyze complex biomarker assays. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.


Doupe D.P.,MRC Cancer Cell Unit | Klein A.M.,University of Cambridge | Klein A.M.,Harvard University | Simons B.D.,MRC Cancer Cell Unit | And 2 more authors.
Developmental Cell | Year: 2010

Typical murine epidermis has a patterned structure, seen clearly in ear skin, with regular columns of differentiated cells overlying the proliferative basal layer. It has been proposed that each column is a clonal epidermal proliferative unit maintained by a central stem cell and its transit amplifying cell progeny. An alternative hypothesis is that proliferating basal cells have random fate, the probability of generating cycling or differentiated cells being balanced so homeostasis is achieved. The stochastic model seems irreconcilable with an ordered tissue. Here we use lineage tracing to reveal that basal cells generate clones with highly irregular shapes that contribute progeny to multiple columns. Basal cell fate and cell cycle time is random. Cell columns form due to the properties of postmitotic cells. We conclude that the ordered architecture of the epidermis is maintained by a stochastic progenitor cell population, providing a simple and robust mechanism of homeostasis. © 2010 Elsevier Inc. All rights reserved.


Spechler S.J.,University of Texas Southwestern Medical Center | Fitzgerald R.C.,MRC Cancer Cell Unit | Prasad G.A.,Rochester College | Wang K.K.,Rochester College
Gastroenterology | Year: 2010

This report is an adjunct to the American Gastroenterological Association Institute's medical position statement and technical review on the management of Barrett's esophagus, which will be published in the near future. Those documents will consider a number of broad questions on the diagnosis, clinical features, and management of patients with Barrett's esophagus, and the reader is referred to the technical review for an in-depth discussion of those topics. In this report, we review historical, molecular, and endoscopic therapeutic aspects of Barrett's esophagus that are of interest to clinicians and researchers. © 2010 AGA Institute.


Lao-Sirieix P.,MRC Cancer Cell Unit | Fitzgerald R.C.,MRC Cancer Cell Unit
Biochemical Society Transactions | Year: 2010

Most epithelial cancers occur on the background of chronic exposure to damaging agents which is reflected in the long lag phase from development of a pre-invasive lesion to the development of a carcinoma. Luminal refluxate has long been recognized to be associated with Barrett's oesophagus, although causal mechanisms have not been clearly defined. Recently, obesity and dietary nitric oxide have also been implicated in the disease pathogenesis. We have demonstrated that acid can alter cell kinetics and, together with nitric oxide, can induce double-stranded DNA breaks. Aside from exposure to luminal factors, the stromal microenvironment may also be important. There is increasing evidence to suggest that inflammatory pathways such as TGF (transforming growth factor) β may play a role in Barrett's oesophagus carcinogenesis. Hence stromal-epithelial-luminal interactions may influence cell behaviour. As sequelae to this, it is possible that the niches created by the micro-environment may influence genetic epithelial diversity observed within the Barrett's oesophagus segment. ©The Authors.


Lao-Sirieix P.,MRC Cancer Cell Unit | Fitzgerald R.C.,MRC Cancer Cell Unit
Nature Reviews Clinical Oncology | Year: 2012

Oesophageal cancer is a global health problem with high mortality due to the advanced nature of the disease at presentation; therefore, detection at an early stage significantly improves outcome. Oesophageal squamous-cell cancer is preceded by dysplasia and oesophageal adenocarcinoma is preceded by Barrett's oesophagus, which progresses to cancer via intermediate dysplastic stages. Screening to detect these preneoplastic lesions has the potential to substantially reduce mortality and morbidity. However, the risks and benefits of such programmes to individuals and to society need to be carefully weighed. Endoscopic screening is invasive, costly and error prone owing to sampling bias and the subjective diagnosis of dysplasia. Non-endoscopic cell-sampling methods are less invasive and more cost effective than endoscopy, but the sensitivity and specificity of cytological assessment of atypia has been disappointing. The use of biomarkers to analyse samples collected using pan-oesophageal cell-collection devices may improve diagnostic accuracy; however, further work is required to confirm this. The psychological and economic implications of screening as well as the feasibility of implementing such programmes must also be considered. © 2012 Macmillan Publishers Limited. All rights reserved.


Alcolea M.P.,MRC Cancer Cell Unit | Jones P.H.,MRC Cancer Cell Unit
Nature Reviews Cancer | Year: 2013

For tumours to develop, mutations must disrupt tissue homeostasis in favour of deregulated proliferation. Genetic lineage tracing has uncovered the behaviour of proliferating cells that underpins the maintenance of epithelial tissues and the barriers that are broken in neoplastic transformation. In this Review, we focus on new insights revealed by quantifying the behaviour of normal, preneoplastic and tumour cells in epithelia in transgenic mice and consider their potential importance in humans.© 2013 Macmillan Publishers Limited. All rights reserved.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 879.23K | Year: 2011

Lung cancer is the leading cause of cancer-related death worldwide. Most patients present with locally advanced inoperable or metastatic disease and despite advances in treatment median survival at this stage remains low. While new therapies for the treatment of advanced lung cancer are showing promising results recent studies suggest that tumours harbouring Kras mutations (30-50% of non-small cell lung cancers) may be particularly difficult to treat. Therefore, novel therapeutic strategies aimed at Kras mutant lung tumours are urgently in need. Our lab is interested in the mechanisms responsible for the progression of lung tumours harbouring Kras mutations. By understanding the processes that enable tumours to develop we aim to find new vulnerable points for therapeutic intervention. Using mouse lung tumour models we recently showed that a Kras-mutation is sufficient to drive the initial expansion of tumour cells but progression to malignancy is associated with the acquisition of new mutations. We will now identify these additional requirements by mapping all mutations associated with benign and malignant disease using state-of-the-art whole genome sequencing technology. Furthermore, we will test the relevance of such mutations for tumour progression in vivo using mouse lung tumour models. Finally, we will use our models to test the therapeutic potential of targeting these mutations in established lung tumours with mutant Kras.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 571.67K | Year: 2011

There is much excitement about using our immune system to fight cancer instead of toxic drugs. Although successful in the laboratory, transition to the clinic is proving more difficult. These problems likely arise because tumours create a protective microenvironment, to which our immune system is ineffective. Non-cancerous cells in the tumour form a supportive network known as the tumour stroma. We do not yet fully understand how the stroma promotes tumour development, or how it contributes to the related immune dysfunction. Tumours induce the growth of lymphatic vessels within the stroma. There, lymphatics drain fluid from the tumour, but also act as the route by which tumour cells spread. Additionally, lymphatics connect a tumour to our immune system. So, how, although connected to our defences, can a tumour evade immune destruction? We believe that rather than simply providing structural support to a developing tumour, the stroma has a much more active role in establishing the protective microenvironment and ultimately making a tumour more difficult to treat. Our research uses state of the art in vitro and in vivo systems to determine how the stroma, the cells it interacts with, and the physical forces experienced by these, impact tumour development; and ultimately, how we can exploit these feature to more effectively treat cancer.


Grant
Agency: GTR | Branch: MRC | Program: | Phase: Intramural | Award Amount: 450.76K | Year: 2012

Cancer is currently viewed as a genetic disease whereby well-characterised gene mutations are sufficient to drive unrestrained growth and proliferation. In order to support proliferation, cancer cells utilise a specific set of nutrients, among which glucose and glutamine are the most important. It has been shown that inherent dysfunctions of glucose and glutamine metabolism in some circumstances predispose to cancer formation. However, how altered metabolism drives tumorigenesis in not fully understood. In this project, we intend to investigate the role of genes involved in cell metabolism in cancer formation. We will start by studying the role of these genes in altering cell metabolism using cell culture models. Then, we will move into animal models to define how each candidate gene triggers tumorigenesis in vivo. Our goal is to find metabolic pathways required for the survival of these mutant tumours in order to determine potential anti-cancer drug targets. Furthermore, we aim to detect early signs of these metabolic changes in body fluids such as urine and blood, in order to discover novel biomarkers for the early detection of cancer.

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