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Alison M.R.,Center for Tumour Biology | Lin W.-R.,Linkou Chang Gung Memorial Hospital | Lin W.-R.,Chang Gung University
F1000Research | Year: 2016

Under normal homeostatic conditions, hepatocyte renewal is a slow process and complete turnover likely takes at least a year. Studies of hepatocyte regeneration after a two-thirds partial hepatectomy (2/3 PH) have strongly suggested that periportal hepatocytes are the driving force behind regenerative re-population, but recent murine studies have brought greater complexity to the issue. Although periportal hepatocytes are still considered pre-eminent in the response to 2/3 PH, new studies suggest that normal homeostatic renewal is driven by pericentral hepatocytes under the control of Wnts, while pericentral injury provokes the clonal expansion of a subpopulation of periportal hepatocytes expressing low levels of biliary duct genes such as Sox9 and osteopontin. Furthermore, some clarity has been given to the debate on the ability of biliary-derived hepatic progenitor cells to generate physiologically meaningful numbers of hepatocytes in injury models, demonstrating that under appropriate circumstances these cells can re-populate the whole liver. © 2016 Alison MR and Lin WR.


Morgan M.R.,Center for Tumour Biology | Morgan M.R.,University of Manchester | Jazayeri M.,Center for Tumour Biology | Ramsay A.G.,Center for Tumour Biology | And 5 more authors.
Oncogene | Year: 2011

Expression of the integrin αvΒ6 is upregulated in a variety of carcinomas where it appears to be involved in malignant progression, although the biology of this integrin is not fully explored. We have generated oral carcinoma cells that express αvΒ6 composed of wild-type αv and a mutant Β6 that lacks the unique C-terminal 11 amino acids (aa). We found that these residues, although not required for αvΒ6-dependent adhesion or migration, are essential for αvΒ6-dependent invasive activity. We have used a proteomic approach to identify novel binding partners for the Β6 subunit cytoplasmic tail and report that psoriasin (Psor) (S100A7) bound preferentially to the recombinant Β6 cytoplasmic domain, though not in the absence of the unique C-terminal 11aa. Endogenous cellular Psor co-precipitated with endogenous Β6 and colocalised with αvΒ6 at the cell membrane and intracellular vesicles. Knockdown of Psor, with small interfering RNA, had no effect on αvΒ6-dependent adhesion or migration but abrogated αvΒ6-mediated oral carcinoma cell invasion both in Transwell and, the more physiologically relevant, organotypic invasion assays, recapitulating the behaviour of the Β6-mutant cell line. Membrane-permeant Tat-peptides encoding the unique C-terminal residues of Β6, bound directly to recombinant Psor and inhibited cellular Psor binding to Β6; this blocked αvΒ6-dependent, but not αvΒ6- independent, invasion. These data identify a novel interaction between Psor and Β6 and demonstrate that it is required for αvΒ6-dependent invasion by carcinoma cells. Inhibition of this interaction may represent a novel therapeutic strategy to target carcinoma invasion. © 2011 Macmillan Publishers Limited All rights reserved.


Moutasim K.A.,University of Southampton | Jenei V.,University of Southampton | Sapienza K.,Center for Tumour Biology | Marsh D.,Center for Tumour Biology | And 10 more authors.
Journal of Pathology | Year: 2011

Oral submucous fibrosis (OSF) is a premalignant, fibrosing disorder of the mouth, pharynx, and oesophagus, with a malignant transformation rate of 7-13%. OSF is strongly associated with areca (betel) nut chewing and worldwide, over 5 million people are affected. As αvβ6 integrin is capable of promoting both tissue fibrosis and carcinoma invasion, we examined its expression in fibroepithelial hyperplasia and OSF. αvβ6 was markedly up-regulated in OSF, with high expression detected in 22 of 41 cases (p < 0.001). We investigated the functional role of αvβ6 using oral keratinocyte-derived cells genetically modified to express high αvβ6 (VB6), and also NTERT-immortalized oral keratinocytes, which express low αvβ6 (OKF6/TERT-1). VB6 cells showed significant αvβ6- dependent activation of TGF-β1, which induced transdifferentiation of oral fibroblasts into myofibroblasts and resulted in up-regulation of genes associated with tissue fibrosis. These experimental in vitro findings were confirmed using human clinical samples, where we showed that the stroma of OSF contained myofibroblasts and that TGF-β1-dependent Smad signalling was detectable both in keratinocytes and in myofibroblasts. We also found that arecoline, the major alkaloid of areca nuts, up-regulated keratinocyte αvβ6 expression. This was modulated through the M4 muscarinic acetylcholine receptor and was suppressed by the M4 antagonist, tropicamide. Arecoline-dependent αvβ6 up-regulation promoted keratinocyte migration and induced invasion, raising the possibility that this mechanism may support malignant transformation. Over 80% of OSF-related oral cancers examined had moderate/high αvβ6 expression. These data suggest that the pathogenesis of OSF may be epithelial-driven and involve arecoline-dependent up-regulation of αvβ6 integrin. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Marsh D.,Center for Tumour Biology | Marsh D.,University College London | Moutasim K.A.,University of Southampton | Vallath S.,Center for Tumour Biology | And 12 more authors.
Journal of Pathology | Year: 2011

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvβ6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvβ6-dependent TGF-β1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Baker A.-M.,Center for Tumour Biology | Graham T.A.,University of California at San Francisco | Wright N.A.,Center for Tumour Biology
Journal of Pathology | Year: 2013

Classically, the risk of cancer progression in premalignant conditions of the gastrointestinal tract is assessed by examining the degree of histological dysplasia. However, there are many putative pro-cancer genetic changes that have occurred in histologically normal tissue well before the onset of dysplasia. Here we summarize the evidence for such pre-tumour clones and the existing technology that can be used to locate these clones and characterize them at the genetic level. We also discuss the mechanisms by which pre-tumour clones may spread through large areas of normal tissue, and highlight emerging theories on how multiple clones compete and interact within the gastrointestinal mucosa. It is important to gain an understanding of these processes, as it is envisaged that certain pre-tumour changes may be powerful predictive markers, with the potential to identify patients at high risk of developing cancer at a much earlier stage. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Catchpole S.,King's College London | Spencer-Dene B.,Cancer Research UK Research Institute | Spencer-Dene B.,Imperial College London | Hall D.,King's College London | And 8 more authors.
International Journal of Oncology | Year: 2011

The four members of the JARID1/KDM5 family of proteins, a sub-group of the larger ARID (AT rich DNA binding domain) family, have been shown to demethylate trimethylated lysine 4 on histone 3 (H3K4me3), a chromatin mark associated with actively transcribed genes. In some lower organisms a single homologue of JARID1 is found, and functions of the four proteins found in mice and humans may be specific or overlapping. To investigate the function of the JARID1B protein we examined the effects of deletion of the gene in mice. Systemic knock out of Jarid1b resulted in early embryonic lethality, whereas mice not expressing the related Jarid1A gene are viable and fertile. A second mouse strain expressing a Jarid1b gene with the ARID domain deleted was viable and fertile but displayed a mammary phenotype, where terminal end bud development and side branching was delayed at puberty and in early pregnancy. Since development of terminal end buds are completely dependent on signalling from the estrogen receptor (ERα), we investigated the expression of a target gene (progesterone receptor) in the ΔARID mouse and found levels to be reduced as compared to wild-type. JARID1B is widely expressed in ER+ breast cancers and breast cancer cell lines, and interaction with ERα was demonstrated by co-immunoprecipitations in cells transfected with tagged ERα and JARID1B genes. Down-regulation of expression of JARID1B using shRNAi in MCF-7 cells resulted in a dramatic decrease in E2 stimulated tumour growth in nude mice. The data demonstrate a specific role for Jarid1B in early embryonic development, in the development and differentiation of the normal mammary gland, and in estrogen induced growth of ER+ breast cancer. Copyright © 2011 Spandidos Publications Ltd. All rights reserved.


Alison M.R.,Center for Tumour Biology | Lin W.-R.,Chang Gung University
Journal of Pathology | Year: 2016

The liver's ability to regenerate is indisputable; for example, after a two-thirds partial hepatectomy in rats all residual hepatocytes can divide, questioning the need for a specific stem cell population. On the other hand, there is a potential stem cell compartment in the canals of Hering, giving rise to ductular reactions composed of hepatic progenitor cells (HPCs) when the liver's ability to regenerate is hindered by replicative senescence, but the functional relevance of this response has been questioned. Several papers have now clarified regenerative mechanisms operative in the mouse liver, suggesting that the liver is possibly unrivalled in its versatility to replace lost tissue. Under homeostatic conditions a perivenous population of clonogenic hepatocytes operates, whereas during chronic damage a minor population of periportal clonogenic hepatocytes come to the fore, while the ability of HPCs to completely replace the liver parenchyma has now been shown. © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Novitskaya V.,University of Birmingham | Romanska H.,University of Birmingham | Dawoud M.,Center for Tumour Biology | Jones J.L.,Center for Tumour Biology | Berditchevski F.,University of Birmingham
Cancer Research | Year: 2010

Tetraspanin CD151 is associated with laminin-binding integrins (i.e., α 3β 1, α 6β 1, and α 6β 4) and regulates tumor cell migration and invasion. Here, we examined the role of CD151 in proliferation of mammary epithelial cells using in vitro and in vivo models. Depletion of CD151 suppressed growth of HB2 cells, a nontumorigenic breast epithelial cell line, in three-dimensional (3D) extracellular matrices (ECM) and in Matrigel-based xenografts. Whereas the presence of α 3β 1 (but not α 6 integrins) was necessary to support growth of HB2 cells in 3D ECM, the pro-proliferative activity of CD151 did not require direct interaction with integrins. Furthermore, depletion of CD151 potentiated formation of the internal lumen and partial restoration of polarity when HB2 cells were cultured in 3D ECM. This correlated with a decrease in phosphorylation levels of extracellular signal-regulated kinase 1/2 and cAkt in CD151-negative cells and increase in activation of caspase-3. Accordingly, the number of CD151-positive colonies with internal lumen was increased by ∼5-fold when cells were cultured in the presence of MAP/ ERK kinase (U0126) and phosphoinositide 3-kinase (LY29004) inhibitors. To establish the physiologic relevance of pro-proliferative and morphogenetic activities of CD151, we analyzed the expression of this tetraspanin in ductal carcinoma in situ (DCIS), which is characterized by neoplastic proliferation of mammary epithelial cells. Strong homogeneous membrane expression of CD151 was found to be associated with a high grade of DCIS (P = 0.004). Taken together, these results strongly suggest that CD151 complexes play a crucial role in the development of hyperproliferative diseases in the mammary gland. ©2010 AACR.


Cross W.C.H.,Center for Tumour Biology | Graham T.A.,Center for Tumour Biology | Wright N.A.,Center for Tumour Biology
Journal of Pathology | Year: 2016

Evolutionary theories are themselves subject to evolution. Clonal evolution – the model that describes the initiation and progression of cancer – is entering a period of profound change, brought about largely by technological developments in genome analysis. A flurry of recent publications, using modern mathematical and bioinformatics techniques, have revealed both punctuated and neutral evolution phenomena that are poorly explained by the conventional graduated perspectives. In this review, we propose that a hybrid model, inspired by the evolutionary model of punctuated equilibrium, could better explain these recent observations. We also discuss the conceptual changes and clinical implications of variable evolutionary tempos. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


PubMed | Center for Tumour Biology
Type: Journal Article | Journal: The Journal of pathology | Year: 2016

Evolutionary theories are themselves subject to evolution. Clonal evolution - the model that describes the initiation and progression of cancer - is entering a period of profound change, brought about largely by technological developments in genome analysis. A flurry of recent publications, using modern mathematical and bioinformatics techniques, have revealed both punctuated and neutral evolution phenomena that are poorly explained by the conventional graduated perspectives. In this review, we propose that a hybrid model, inspired by the evolutionary model of punctuated equilibrium, could better explain these recent observations. We also discuss the conceptual changes and clinical implications of variable evolutionary tempos. Copyright 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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