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Dive into the research topics where Alan McIntyre is active.

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Featured researches published by Alan McIntyre.


Cancer Research | 2006

Genomic and expression profiling of human spermatocytic seminomas: primary spermatocyte as tumorigenic precursor and DMRT1 as candidate chromosome 9 gene.

L. H. J. Looijenga; Remko Hersmus; A. J. M. Gillis; Rolph Pfundt; Hans Stoop; R.J.H.L.M. van Gurp; Joris A. Veltman; H B Beverloo; E. van Drunen; A. Geurts van Kessel; R.R. Pera; Dominik Schneider; Brenda Summersgill; Janet Shipley; Alan McIntyre; P. van der Spek; E.F.P.M. Schoenmakers; J.W. Oosterhuis

Spermatocytic seminomas are solid tumors found solely in the testis of predominantly elderly individuals. We investigated these tumors using a genome-wide analysis for structural and numerical chromosomal changes through conventional karyotyping, spectral karyotyping, and array comparative genomic hybridization using a 32 K genomic tiling-path resolution BAC platform (confirmed by in situ hybridization). Our panel of five spermatocytic seminomas showed a specific pattern of chromosomal imbalances, mainly numerical in nature (range, 3-24 per tumor). Gain of chromosome 9 was the only consistent anomaly, which in one case also involved amplification of the 9p21.3-pter region. Parallel chromosome level expression profiling as well as microarray expression analyses (Affymetrix U133 plus 2.0) was also done. Unsupervised cluster analysis showed that a profile containing transcriptional data on 373 genes (difference of > or = 3.0-fold) is suitable for distinguishing these tumors from seminomas/dysgerminomas. The diagnostic markers SSX2-4 and POU5F1 (OCT3/OCT4), previously identified by us, were among the top discriminatory genes, thereby validating the experimental set-up. In addition, novel discriminatory markers suitable for diagnostic purposes were identified, including Deleted in Azospermia (DAZ). Although the seminomas/dysgerminomas were characterized by expression of stem cell-specific genes (e.g., POU5F1, PROM1/CD133, and ZFP42), spermatocytic seminomas expressed multiple cancer testis antigens, including TSP50 and CTCFL (BORIS), as well as genes known to be expressed specifically during prophase meiosis I (TCFL5, CLGN, and LDHc). This is consistent with different cells of origin, the primordial germ cell and primary spermatocyte, respectively. Based on the region of amplification defined on 9p and the associated expression plus confirmatory immunohistochemistry, DMRT1 (a male-specific transcriptional regulator) was identified as a likely candidate gene for involvement in the development of spermatocytic seminomas.


Cancer Research | 2005

Amplification and Overexpression of the KIT Gene Is Associated with Progression in the Seminoma Subtype of Testicular Germ Cell Tumors of Adolescents and Adults

Alan McIntyre; Brenda Summersgill; Beata Grygalewicz; Ad Gillis; J. Stoop; Ruud J. H. L. M. van Gurp; Nening Dennis; Cyril Fisher; Robert Huddart; Colin S. Cooper; Jeremy Clark; J. Wolter Oosterhuis; Leendert Looijenga; Janet Shipley

We have previously identified amplification at 4q12 in testicular germ cell tumors of adolescents and adults centered around the KIT gene encoding a tyrosine kinase transmembrane receptor. Analysis of primary testicular germ cell tumors totaling 190 cases revealed 21% of the seminoma subtype with an increased copy number of KIT whereas this change was rarely found in the nonseminomas. In most cases, gain of KIT did not include the immediately flanking noncoding DNA or the flanking genes KDR and PDGFRA. Increased copy number of KIT was not found in the putative precursor lesion, carcinoma in situ (CIS), adjacent to tumor with this change. KIT overexpression was found independent of gain and KIT immunostaining was stronger in selected cases with gain of KIT compared to those without. Taken together with activating mutations of KIT in exon 17 identified in 13% of seminomas, this suggests that the KIT gene product plays a role in the progression of CIS towards seminoma, the further understanding of which may lead to novel less toxic therapeutic approaches.


Clinical Cancer Research | 2012

Carbonic Anhydrase IX Promotes Tumor Growth and Necrosis In Vivo and Inhibition Enhances Anti-VEGF Therapy

Alan McIntyre; Shalini Patiar; Simon Wigfield; Ioanna Ledaki; Helen Turley; Russell Leek; Cameron Snell; Kevin C. Gatter; William S. Sly; Richard D. Vaughan-Jones; Pawel Swietach; Adrian L. Harris

Purpose: Bevacizumab, an anti-VEGFA antibody, inhibits the developing vasculature of tumors, but resistance is common. Antiangiogenic therapy induces hypoxia and we observed increased expression of hypoxia-regulated genes, including carbonic anhydrase IX (CAIX), in response to bevacizumab treatment in xenografts. CAIX expression correlates with poor prognosis in most tumor types and with worse outcome in bevacizumab-treated patients with metastatic colorectal cancer, malignant astrocytoma, and recurrent malignant glioma. Experimental Design: We knocked down CAIX expression by short hairpin RNA in a colon cancer (HT29) and a glioblastoma (U87) cell line which have high hypoxic induction of CAIX and overexpressed CAIX in HCT116 cells which has low CAIX. We investigated the effect on growth rate in three-dimensional (3D) culture and in vivo, and examined the effect of CAIX knockdown in combination with bevacizumab. Results: CAIX expression was associated with increased growth rate in spheroids and in vivo. Surprisingly, CAIX expression was associated with increased necrosis and apoptosis in vivo and in vitro. We found that acidity inhibits CAIX activity over the pH range found in tumors (pK = 6.84), and this may be the mechanism whereby excess acid self-limits the build-up of extracellular acid. Expression of another hypoxia inducible CA isoform, CAXII, was upregulated in 3D but not two-dimensional culture in response to CAIX knockdown. CAIX knockdown enhanced the effect of bevacizumab treatment, reducing tumor growth rate in vivo. Conclusion: This work provides evidence that inhibition of the hypoxic adaptation to antiangiogenic therapy enhances bevacizumab treatment and highlights the value of developing small molecules or antibodies which inhibit CAIX for combination therapy. Clin Cancer Res; 18(11); 3100–11. ©2012 AACR.


The Journal of Pathology | 2008

Stem cell factor as a novel diagnostic marker for early malignant germ cells

Hans Stoop; Friedemann Honecker; Gjm van de Geijn; A. J. M. Gillis; Martine Cools; M de Boer; Carsten Bokemeyer; Kp Wolffenbuttel; Sls Drop; R.R. de Krijger; Nening Dennis; Brenda Summersgill; Alan McIntyre; Janet Shipley; Jw Oosterhuis; L. H. J. Looijenga

Carcinoma in situ (CIS) of the testis is the pre‐invasive stage of type II testicular germ cell tumours (TGCTs) of adolescents and adults. These tumours are the most frequently diagnosed cancer in Caucasian adolescents and young adults. In dysgenetic gonads, the precursor of type II GCTs can be either CIS or a lesion known as gonadoblastoma (GB). CIS/GB originates from a primordial germ cell (PGC)/gonocyte, ie an embryonic cell. CIS can be cured by local low‐dose irradiation, with limited side effects on hormonal function. Therefore, strategies for early diagnosis of CIS are essential. Various markers are informative to diagnose CIS in adult testis by immunohistochemistry, including c‐KIT, PLAP, AP‐2γ, NANOG, and POU5F1 (OCT3/4). OCT3/4 is the most informative and consistent in presence and expression level, resulting in intense nuclear staining. In the case of maturational delay of germ cells, frequently present in gonads of individuals at risk for type II (T)GCTs, use of these markers can result in overdiagnosis of malignant germ cells. This demonstrates the need for a more specific diagnostic marker to distinguish malignant germ cells from germ cells showing maturation delay. Here we report the novel finding that immunohistochemical detection of stem cell factor (SCF), the c‐KIT ligand, is informative in this context. This was demonstrated in over 400 cases of normal (fetal, neonatal, infantile, and adult) and pathological gonads, as well as TGCT‐derived cell lines, specifically in cases of CIS and GB. Both membrane‐bound and soluble SCF were expressed, suggestive of an autocrine loop. SCF immunohistochemistry can be a valuable diagnostic tool, in addition to OCT3/4, to screen for precursor lesions of TGCTs, especially in patients with germ cell maturation delay. Copyright


Radiotherapy and Oncology | 2011

Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation

Ludwig Dubois; Sarah G.J.A. Peeters; Natasja G. Lieuwes; Nele Geusens; Anne Thiry; Simon Wigfield; Fabrizio Carta; Alan McIntyre; Andrea Scozzafava; Jean-Michel Dogné; Claudiu T. Supuran; Adrian L. Harris; Bernard Masereel; Philippe Lambin

BACKGROUND AND PURPOSE Carbonic anhydrase (CA) IX expression is increased upon hypoxia and has been proposed as a therapeutic target since it has been associated with poor prognosis, tumor progression and pH regulation. The aim of this study was to evaluate the antitumor activity of a high CAIX-affinity indanesulfonamide (11c) combined with irradiation, compared with the general CA inhibitor acetazolamide (AZA). MATERIAL AND METHODS HT-29 carcinoma cells with or without (genetic knockdown, KD) CAIX expression were incubated with 11c/AZA under different oxygen levels and proliferation, apoptosis and radiosensitivity were evaluated. 11c/AZA was administered intravenously (1×/day; 5 days) to tumor-bearing mice and tumor irradiation (10 Gy) was performed at day 3 of the injection period. Tumor growth and potential treatment toxicity were monitored (3×/week). RESULTS Treatment with 11c/AZA alone resulted in tumor regression, which was further increased in CAIX expressing cells by combining 11c with irradiation. AZA demonstrated also an additional effect in the KD tumors when combined with irradiation. CAIX inhibition in vitro significantly reduced proliferation and increased apoptosis upon hypoxia exposure without affecting intrinsic radiosensitivity. CONCLUSIONS Specific inhibition of CAIX activity enhanced the effect of tumor irradiation and might, therefore, be an attractive strategy to improve overall cancer treatment.


The Journal of Pathology | 2009

Clinical and biological significance of CXCL12 and CXCR4 expression in adult testes and germ cell tumours of adults and adolescents

Duncan C. Gilbert; Ian Chandler; Alan McIntyre; N. C. Goddard; Rhian Gabe; Robert Huddart; Janet Shipley

Interaction between the chemokine CXCL12 (SDF1) and the G‐protein coupled receptor CXCR4 is responsible for the maintenance of adult stem cell niches and is known to play an important role in utero in the migration of primordial germ cells. We demonstrate expression of CXCL12 by Sertoli cells and confirm CXCR4 expression by the germ cell population of the adult human testes. CXCR4 is also known to mediate organ‐specific patterns of metastases in a range of common cancers. We identify consistent expression of CXCR4 mRNA and protein in testicular germ cell tumours (TGCT) that accounts for their patterns of relapse in sites of known CXCL12 expression. Extragonadal primary germ cell tumours express CXCR4 and their sites of occurrence are coincident with areas of known CXCL12 expression in utero. We show that CXCL12 stimulates the invasive migration of a TGCT cell line in vitro in a CXCR4‐dependent fashion and activates ERK. Furthermore, we demonstrate that expression of CXCL12 in stage I non‐seminomas is significantly associated with organ‐confined disease post‐orchidectomy and reduced risk of relapse (p = 0.003). This may be through the loss of CXCL12 gradients that might otherwise attract cells away from the primary tumour. We propose CXCL12 expression as a potential predictor of subsequent relapse that could lead to avoiding unnecessary treatment and associated late toxicities. Our observations support a role for CXCL12/CXCR4 in the adult germ cell population and demonstrate pathological function in germ cell tumour development and metastasis that may have clinical utility. Copyright


American Journal of Pathology | 2010

The Association of CCND1 Overexpression and Cisplatin Resistance in Testicular Germ Cell Tumors and Other Cancers

Elodie Noel; Marc Yeste-Velasco; Xueying Mao; Jackie Perry; Sakunthala C. Kudahetti; Ningfeng F. Li; Swee Sharp; Tracy Chaplin; Liyan Xue; Alan McIntyre; Thomas Powles; R. Tim D. Oliver; Bryan D. Young; Janet Shipley; Daniel M. Berney; Simon Joel; Yong-Jie Lu

Development of chemoresistance limits the clinical efficiency of platinum-based therapy. Although many resistance mechanisms have been demonstrated, genetic/molecular alterations responsible for drug resistance in the majority of clinical cases have not been identified. We analyzed three pairs of testicular germ cell tumor cell lines using Affymetrix expression microarrays and revealed a limited number of differentially expressed genes across the cell lines when comparing the parental and resistant cells. Among them, CCND1 was the most significantly differentially expressed gene. Analysis of testicular germ cell tumor clinical samples by quantitative reverse transcription PCR analysis revealed that overall expression of CCND1 was significantly higher in resistant cases compared with sensitive samples (P < 0.0001). We also found that CCND1 was dramatically overexpressed both in induced and intrinsically resistant samples of ovarian and prostate cancer. Finally combined CCND1 knockdown using small-interfering RNA and cisplatin treatment inhibited cell growth in vitro significantly more effectively than any of these single treatments. Therefore, deregulation of CCND1 may be a major cause of cisplatin resistance in testicular germ cell tumors and may also be implicated in ovarian and prostate cancers. CCND1 could be potentially used as a marker for treatment stratification and as a molecular target to improve the treatment of platinum-resistant tumors.


Embo Molecular Medicine | 2015

Metabolic and hypoxic adaptation to anti‐angiogenic therapy: a target for induced essentiality

Alan McIntyre; Adrian L. Harris

Anti‐angiogenic therapy has increased the progression‐free survival of many cancer patients but has had little effect on overall survival, even in colon cancer (average 6–8 weeks) due to resistance. The current licensed targeted therapies all inhibit VEGF signalling (Table ). Many mechanisms of resistance to anti‐VEGF therapy have been identified that enable cancers to bypass the angiogenic blockade. In addition, over the last decade, there has been increasing evidence for the role that the hypoxic and metabolic responses play in tumour adaptation to anti‐angiogenic therapy. The hypoxic tumour response, through the transcription factor hypoxia‐inducible factors (HIFs), induces major gene expression, metabolic and phenotypic changes, including increased invasion and metastasis. Pre‐clinical studies combining anti‐angiogenics with inhibitors of tumour hypoxic and metabolic adaptation have shown great promise, and combination clinical trials have been instigated. Understanding individual patient response and the response timing, given the opposing effects of vascular normalisation versus reduced perfusion seen with anti‐angiogenics, provides a further hurdle in the paradigm of personalised therapeutic intervention. Additional approaches for targeting the hypoxic tumour microenvironment are being investigated in pre‐clinical and clinical studies that have potential for producing synthetic lethality in combination with anti‐angiogenic therapy as a future therapeutic strategy.


Journal of Biological Chemistry | 2014

Fatty Acid-binding Protein 4, a Point of Convergence for Angiogenic and Metabolic Signaling Pathways in Endothelial Cells

Ulrike Harjes; Esther Bridges; Alan McIntyre; Barbara A. Fielding; Adrian L. Harris

Background: The pro-angiogenic endothelial fatty acid-binding protein 4 (FABP4) is regulated by VEGFA. Results: VEGFA-induced FABP4 was dependent on Delta-like ligand4 (DLL4)-NOTCH signaling and FOXO1. Conclusion: DLL4-NOTCH together with Foxo1 are key regulators of FABP4. Significance: The results link NOTCH and angiogenic signaling directly to FABP4 induction and potentially to FABP4-mediated fatty acid metabolism and may provide a bypass mechanism for anti-VEGFA therapy. Fatty acid-binding protein 4 (FABP4) is an adipogenic protein and is implicated in atherosclerosis, insulin resistance, and cancer. In endothelial cells, FABP4 is induced by VEGFA, and inhibition of FABP4 blocks most of the VEGFA effects. We investigated the DLL4-NOTCH-dependent regulation of FABP4 in human umbilical vein endothelial cells by gene/protein expression and interaction analyses following inhibitor treatment and RNA interference. We found that FABP4 is directly induced by NOTCH. Stimulation of NOTCH signaling with human recombinant DLL4 led to FABP4 induction, independently of VEGFA. FABP4 induction by VEGFA was reduced by blockade of DLL4 binding to NOTCH or inhibition of NOTCH signal transduction. Chromatin immunoprecipitation of the NOTCH intracellular domain showed increased binding to two specific regions in the FABP4 promoter. The induction of FABP4 gene expression was dependent on the transcription factor FOXO1, which was essential for basal expression of FABP4, and FABP4 up-regulation following stimulation of the VEGFA and/or the NOTCH pathway. Thus, we show that the DLL4-NOTCH pathway mediates endothelial FABP4 expression. This indicates that induction of the angiogenesis-restricting DLL4-NOTCH can have pro-angiogenic effects via this pathway. It also provides a link between DLL4-NOTCH and FOXO1-mediated regulation of endothelial gene transcription, and it shows that DLL4-NOTCH is a nodal point in the integration of pro-angiogenic and metabolic signaling in endothelial cells. This may be crucial for angiogenesis in the tumor environment.


Clinical Cancer Research | 2012

Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

Roberto Tonelli; Alan McIntyre; Consuelo Camerin; Zoë S. Walters; Korinne Di Leo; Joanna Selfe; Stefania Purgato; Edoardo Missiaglia; Andrea Tortori; Jane Renshaw; Annalisa Astolfi; Kathryn R. Taylor; Salvatore Serravalle; Ryan Bishop; Cristina Nanni; Linda J. Valentijn; Andrea Faccini; Ivo Leuschner; Serena Formica; Jorge S. Reis-Filho; Valentina Ambrosini; Khin Thway; Monica Franzoni; Brenda Summersgill; Rosangela Marchelli; Patrizia Hrelia; Giorgio Cantelli-Forti; Stefano Fanti; Roberto Corradini; Andrea Pession

Purpose: Rhabdomyosarcomas are a major cause of cancer death in children, described with MYCN amplification and, in the alveolar subtype, transcription driven by the PAX3-FOXO1 fusion protein. Our aim was to determine the prevalence of N-Myc protein expression and the potential therapeutic effects of reducing expression in rhabdomyosarcomas, including use of an antigene strategy that inhibits transcription. Experimental Design: Protein expression was assessed by immunohistochemistry. MYCN expression was reduced in representative cell lines by RNA interference and an antigene peptide nucleic acid (PNA) oligonucleotide conjugated to a nuclear localization signal peptide. Associated gene expression changes, cell viability, and apoptosis were analyzed in vitro. As a paradigm for antigene therapy, the effects of systemic treatment of mice with rhabdomyosarcoma cell line xenografts were determined. Results: High N-Myc levels were significantly associated with genomic amplification, presence of the PAX3/7-FOXO1 fusion genes, and proliferative capacity. Sustained reduction of N-Myc levels in all rhabdomyosarcoma cell lines that express the protein decreased cell proliferation and increased apoptosis. Positive feedback was shown to regulate PAX3-FOXO1 and N-Myc levels in the alveolar subtype that critically decrease PAX3-FOXO1 levels on reducing N-Myc. Pharmacologic systemic administration of the antigene PNA can eliminate alveolar rhabdomyosarcoma xenografts in mice, without relapse or toxicity. Conclusion: N-Myc, with its restricted expression in non-fetal tissues, is a therapeutic target to treat rhabdomyosarcomas, and blocking gene transcription using antigene oligonucleotide strategies has therapeutic potential in the treatment of cancer and other diseases that has not been previously realized in vivo. Clin Cancer Res; 18(3); 796–807. ©2011 AACR.

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Janet Shipley

Institute of Cancer Research

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Brenda Summersgill

Institute of Cancer Research

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Duncan C. Gilbert

Royal Sussex County Hospital

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N. C. Goddard

Institute of Cancer Research

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Robert Huddart

The Royal Marsden NHS Foundation Trust

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Helen Turley

John Radcliffe Hospital

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