9 results on '"Leigh, I."'
Search Results
2. Key differences identified between actinic keratosis and cutaneous squamous cell carcinoma by transcriptome profiling.
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Lambert, S R, Mladkova, N, Gulati, A, Hamoudi, R, Purdie, K, Cerio, R, Leigh, I, Proby, C, and Harwood, C A
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ACTINIC keratosis , *SQUAMOUS cell carcinoma , *SKIN cancer , *GENETIC transcription , *ONCOGENES , *MITOGEN-activated protein kinases ,GENETIC aspects - Abstract
Background:Cutaneous squamous cell carcinoma (cSCC) is one of the most common malignancies in fair-skinned populations worldwide and its incidence is increasing. Despite previous observations of multiple genetic abnormalities in cSCC, the oncogenic process remains elusive. The purpose of this study was to elucidate key molecular events associated with progression from premalignant actinic keratoses (AKs) to invasive cSCC by transcriptome profiling.Methods:We combined laser capture microdissection with the Affymetrix HGU133 Plus 2.0 microarrays to profile 30 cSCC and 10 AKs.Results:We identified a core set of 196 genes that are differentially expressed between AK and cSCC, and are enriched for processes including epidermal differentiation, cell migration, cell-cycle regulation and metabolism. Gene set enrichment analysis highlighted a key role for the mitogen activated protein kinase (MAPK) pathway in cSCC compared with AK. Furthermore, the histological subtype of the tumour was shown to influence the expression profile.Conclusion:These data indicate that the MAPK pathway may be pivotal to the transition from AK to cSCC, thus representing a potential target for cSCC prevention. In addition, transcriptome differences identified between cSCC subtypes have important implications for future development of targeted therapies for this malignancy. [ABSTRACT FROM AUTHOR]
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- 2014
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3. NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity.
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Wang, H, Lee, S, Nigro, C Lo, Lattanzio, L, Merlano, M, Monteverde, M, Matin, R, Purdie, K, Mladkova, N, Bergamaschi, D, Harwood, C, Syed, N, Szlosarek, P, Briasoulis, E, McHugh, A, Thompson, A, Evans, A, Leigh, I, Fleming, C, and Inman, G J
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BIOMARKERS , *MELANOMA treatment , *CELL lines , *AZACITIDINE , *GENE expression , *MELANOCYTES , *METHYLATION - Abstract
Background:Novel prognostic biomarkers and therapeutic strategies are urgently required for malignant melanoma. Ecto-5-prime-nucleotidase (NT5E; CD73) overexpression has been reported in several human cancers. The mechanism(s) underlying deregulated expression and the clinical consequences of changes in expression are not known.Methods:We used RT-PCR, qPCR, methylation-specific PCR and pyrosequencing to analyse expression and regulation of NT5E in malignant melanoma cell lines and primary and metastatic melanomas.Results:NT5E is subject to epigenetic regulation in melanoma. NT5E mRNA is downregulated by methylation-dependent transcriptional silencing in the melanoma cell lines SKMel2, SKMel23, WM35, Mel501, Mel505 and C81-61 and expression is reactivated by azacytidine. In contrast, the CpG island is unmethylated and the gene expressed in cultured normal melanocytes. In clinical cases of melanoma, methylation in the NT5E CpG island occurs in both primary and metastatic melanomas and correlates with transcriptional downregulation of NT5E mRNA. Relapse with metastatic disease, particularly to the visceral sites and brain, is more common in primary melanomas lacking NT5E methylation. Primary melanomas with methylation in NT5E show limited metastatic potential or more commonly metastasise predominantly to nodal sites rather than viscera and brain (P=0.01).Conclusion:Deregulation of NT5E expression in melanoma occurs via epigenetic changes in the NT5E CpG island. Confirmation of our results in larger clinical series would support the candidacy of NT5E as a clinical biomarker in melanoma, which could be applied in both primary and relapsed disease. Inhibition of NT5E may have therapeutic potential in melanoma, particularly in patients with more aggressive disease metastatic to viscera or the brain. [ABSTRACT FROM AUTHOR]
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- 2012
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4. Integrative mRNA profiling comparing cultured primary cells with clinical samples reveals PLK1 and C20orf20 as therapeutic targets in cutaneous squamous cell carcinoma.
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Watt, S A, Pourreyron, C, Purdie, K, Hogan, C, Cole, C L, Foster, N, Pratt, N, Bourdon, J-C, Appleyard, V, Murray, K, Thompson, A M, Mao, X, Mein, C, Bruckner-Tuderman, L, Evans, A, McGrath, J A, Proby, C M, Foerster, J, Leigh, I M, and South, A P
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SQUAMOUS cell carcinoma , *CANCER treatment , *SKIN cancer , *MESSENGER RNA , *HUMAN cell culture , *TUMOR growth , *GENE expression , *CLINICAL trials , *HETEROGENEITY - Abstract
Identifying therapeutic targets for cancer treatment relies on consistent changes within particular types or sub-types of malignancy. The ability to define either consistent changes or sub-types of malignancy is often masked by tumor heterogeneity. To elucidate therapeutic targets in cutaneous squamous cell carcinoma (cSCC), the most frequent skin neoplasm with malignant potential, we have developed an integrated approach to gene expression profiling beginning with primary keratinocytes in culture. Candidate drivers of cSCC development were derived by first defining a set of in vitro cancer genes and then comparing their expression in a range of clinical data sets containing normal skin, cSCC and the benign hyper-proliferative condition psoriasis. A small interfering RNA (siRNA) screen of the resulting 21 upregulated genes has yielded targets capable of reducing xenograft tumor volume in vivo. Small-molecule inhibitors for one target, Polo-like kinase-1 (PLK1), are already in clinical trials for other malignancies, and our data show efficacy in cSCC. Another target, C20orf20, is identified as being overexpressed in cSCC, and siRNA-mediated knockdown induces apoptosis in vitro and reduces tumor growth in vivo. Thus, our approach has shown established and uncharacterized drivers of tumorigenesis with potent efficacy as therapeutic targets for the treatment of cSCC. [ABSTRACT FROM AUTHOR]
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- 2011
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5. High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia.
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Purdie, K. J., Harwood, C. A., Gibbon, K., Chaplin, T., Young, B. D., Cazier, J. B., Singh, N., Leigh, I. M., and Proby, C. M.
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PAPILLOMAVIRUSES , *GENOMICS , *SQUAMOUS cell carcinoma , *GENETIC polymorphisms , *VERTEBRATE physiology , *DNA analysis , *CHROMOSOME abnormalities , *COMPARATIVE studies , *GENES , *RESEARCH methodology , *MEDICAL cooperation , *GENETIC mutation , *RESEARCH , *RESEARCH funding , *VIRUS diseases , *VULVAR tumors , *EVALUATION research , *CARCINOMA in situ , *OLIGONUCLEOTIDE arrays , *GENE expression profiling , *CERVICAL intraepithelial neoplasia , *PHYSIOLOGY ,CERVIX uteri tumors - Abstract
Background: The incidence of human papillomavirus-associated vulval neoplasia is increasing worldwide; yet the associated genetic changes remain poorly understood.Methods: We have used single-nucleotide polymorphism microarray analysis to perform the first high-resolution investigation of genome-wide allelic imbalance in vulval neoplasia. Our sample series comprised 21 high-grade vulval intraepithelial neoplasia and 6 vulval squamous cell carcinomas, with paired non-lesional samples used to adjust for normal copy number variation.Results: Overall the most common recurrent aberrations were gains at 1p and 20, with the most frequent deletions observed at 2q, 3p and 10. Copy-neutral loss of heterozygosity at 6p was a recurrent event in vulval intraepithelial neoplasia. The pattern of genetic alterations differed from the characteristic changes we previously identified in cutaneous squamous cell carcinomas. Vulval neoplasia samples did not exhibit gain at 5p, a frequent recurrent aberration in a series of cervical tumours analysed elsewhere using an identical protocol.Conclusion: This series of 27 vulval samples comprises the largest systematic genome-wide analysis of vulval neoplasia performed to date. Despite shared papillomavirus status and regional proximity, our data suggest that the frequency of certain genetic alterations may differ in vulval and cervical tumours. [ABSTRACT FROM AUTHOR]- Published
- 2010
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6. Overexpression of the Axl tyrosine kinase receptor in cutaneous SCC-derived cell lines and tumours.
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Green, J., Ikram, M., Vyas, J., Patel, N., Proby, C. M., Ghali, L., Leigh, I. M., O'toole, E. A., and Storey, A.
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SKIN cancer , *CANCER cells , *SQUAMOUS cell carcinoma , *PROTEIN-tyrosine kinases , *GENE expression , *POLYMERASE chain reaction , *PROTEIN metabolism , *RNA metabolism , *GENES , *IMMUNOHISTOCHEMISTRY , *PROTEINS , *RESEARCH funding , *SKIN tumors , *TRANSFERASES , *REVERSE transcriptase polymerase chain reaction , *OLIGONUCLEOTIDE arrays , *GENE expression profiling , *CANCER cell culture , *NEOPLASTIC cell transformation - Abstract
The molecular mechanisms that underlie the development of squamous cell skin cancers (SSC) are poorly understood. We have used oligonucleotide microarrays to compare the differences in cellular gene expression between a series of keratinocyte cell that mimic disease progression with the aim of identifying genes that may potentially contribute towards squamous cell carcinoma (SCC) progression in vivo, and in particular to identify markers that may serve as potential therapeutic targets for SCC treatment. Gene expression differences were corroborated by polymerase chain reaction and Western blotting. We identified Axl, a receptor tyrosine kinase with transforming potential that has also been shown to have a role in cell survival, adhesion and chemotaxis, was upregulated in vitro in SCC-derived cells compared to premalignant cells. Extending the investigation to tumour biopsies showed that the Axl protein was overexpressed in vivo in a series of SCCs. [ABSTRACT FROM AUTHOR]
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- 2006
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7. Vascular patterns in reactive lymphoid tissue and in non-Hodgkin's lymphoma.
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Passalidou, E, Stewart, M, Trivella, M, Steers, G, Pillai, G, Dogan, A, Leigh, I, Hatton, C, Harris, A, Gatter, K, and Pezzella, F
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NEOVASCULARIZATION , *LYMPHOMAS , *COMPARATIVE studies , *LYMPHATIC diseases , *LYMPHOID tissue , *RESEARCH methodology , *MEDICAL cooperation , *MEMBRANE proteins , *BASAL lamina , *RESEARCH , *EVALUATION research , *PATHOLOGIC neovascularization , *METABOLISM - Abstract
The few studies published on angiogenesis in lymphoma have raised the question of whether or not microvessel density (MVD) is associated with more aggressive disease and have reported the observation that in follicular lymphomas, vessels are mature rather than immature. We investigated MVD and the vascular phenotype within follicular or diffuse large B-cell lymphomas, reactive nodes and tonsils. Vascular phenotype was defined by the expression or loss of reactivity to the antibody LH39 (detecting the LH39 laminin epitope of the basement membrane in mature vessels) and by detection of alpha V beta 3 (expressed on immature vessels). In reactive nodes and in follicular lymphomas, MVD was higher in the paracortex than in germinal centres or in neoplastic follicles. However, in neoplastic follicles an increase in alpha V beta 3-positive endothelium suggested the activation of an angiogenic pathway different from that present in the reactive follicles. In large B-cell lymphomas, MVD was higher than in reactive and neoplastic follicles but lower than in the reactive paracortex. The number of immature vessels (LH39 negative) and of alpha V beta 3-positive vessels was higher than in reactive lymph nodes and follicular lymphoma suggesting that a switch to a different angiogenic pathway has occurred. Finally, we have demonstrated that within reactive and neoplastic follicles vascular regression is occurring, perhaps constraining the growth of reactive follicles alongside other phenomena such as apoptosis. Vascular regression was previously believed to occur in adults only in ovarian and endometrial tissue. We conclude that different types of angiogenesis are present in follicular lymphomas and large B-cell lymphomas. This has implications for possible future therapies. [ABSTRACT FROM AUTHOR]
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- 2003
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8. Vascular phenotype in angiogenic and non-angiogenic lung non-small cell carcinomas.
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Passalidou, E., Trivella, M., Singh, N, Ferguson, M, Hu, J, Cesario, A, Granone, P, Nicholson, A G, Goldstraw, P, Ratcliffe, C, Tetlow, M, Leigh, I, Harris, A L, Gatter, K C, and Pezzella, F
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LUNG cancer , *NEOVASCULARIZATION - Abstract
We have previously described a group of non-small cell lung carcinomas without morphological evidence of neo-angiogenesis. In these tumours neoplastic cells fill up the alveoli and the only vessels present appear to belong to the trapped alveolar septa. In the present study we have characterised the phenotype of the vessels present in these non-angiogenic tumours, in normal lung and in angiogenic non-small cell lung carcinomas. The vessels, identified by the expression of CD31, were scored as mature when expressing the epitope LH39 in the basal membrane and as newly formed when expressing alphaVbeta3 on the endothelial cells and/or lacking LH39 expression. In the nine putative non-angiogenic cases examined, the vascular phenotype of all the vessels was the same as that of alveolar vessels in normal lung: LH39 positive and alphaVbeta3 variable or negative. Instead in 104 angiogenic tumours examined, only a minority of vessels (mean 13.1%; range 0--60%) expressed LH39, while alphaVbeta3 (in 45 cases) was strongly expressed on many vessels (mean 55.5%; range 5--90%). We conclude that in putative non-angiogenic tumours the vascular phenotype is that of normal vessels and there is no neo-angiogenesis. This type of cancer may be resistant to some anti-angiogenic therapy and different strategies need to be developed. [ABSTRACT FROM AUTHOR]
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- 2002
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9. Relationship of vascular maturation in breast cancer blood vessels to vascular density and metastasis, assessed by expression of a novel basement membrane component, LH39.
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Kakolyris, S, Fox, S B, Koukourakis, M, Giatromanolaki, A, Brown, N, Leek, R D, Taylor, M, Leigh, I M, Gatter, K C, and Harris, A L
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NEOVASCULARIZATION , *BREAST cancer - Abstract
Angiogenesis, the formation of new vessels, has been demonstrated to be an indicator of prognosis in breast cancer patients. The extent of differentiation of the tumour vessels may affect access of peripheral white cells and egress or invasion of tumour cells. This has not been assessed in relation to tumour microvessel density or other variables and may be a marker of vascular remodelling. LH39 is a monoclonal antibody recognizing an epitope located at the lamina lucida of mature small veins and capillaries but not in newly formed vessels. To study vascular differentiation in breast tumours, we examined the vascular maturation index (VMI) in 12 normal and 50 breast carcinomas and this was correlated with different clinicopathological variables including angiogenesis. Mature vessels were defined by staining with antibodies to both LH39 and to CD31, using double immunohistochemistry, whereas immature vessels stained only for CD31. VMI was defined as the % fraction of mature vessels (LH39-positive) / total number of vessels (CD31-positive). The VMI was significantly higher in normal (54-68.5%; median 66.5%) than in tumours (0-47%; median 8.8%) (P = 0.0005). There was a significant inverse correlation between the tumour VMI and nodal status (Fisher's exact test,P = 0.01) and between high VMI and low thymidine phosphorylase (TP) expression (Mann-WhitneyU-test,P = 0.01). No significant association between VMI and tumour size, oestrogen receptor, epidermal growth factor receptor, grade, angiogenesis, patient age, or E-selectin was seen. There was a significant reduction in relapse-free survival (P = 0.01) with high angiogenesis. These findings show that the VMI gives new information on the mechanism of tumour angiogenesis independently from microvessel quantitation, there is a wide variation in the differentiation of tumour vasculature but the degree of capillary differentiation is not associated with quantitative angiogenesis. The VMI identifies a subset of patients... [ABSTRACT FROM AUTHOR]
- Published
- 2000
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