• AAV2-mediated in vivo immune gene therapy of solid tumours

      Collins, Sara A; Buhles, Alexandra; Scallan, Martina F; Harrison, Patrick T; O'Hanlon, Deirdre M; O'Sullivan, Gerald C; Tangney, Mark (2010-12-20)
      Abstract Background Many strategies have been adopted to unleash the potential of gene therapy for cancer, involving a wide range of therapeutic genes delivered by various methods. Immune therapy has become one of the major strategies adopted for cancer gene therapy and seeks to stimulate the immune system to target tumour antigens. In this study, the feasibility of AAV2 mediated immunotherapy of growing tumours was examined, in isolation and combined with anti-angiogenic therapy. Methods Immune-competent Balb/C or C57 mice bearing subcutaneous JBS fibrosarcoma or Lewis Lung Carcinoma (LLC) tumour xenografts respectively were treated by intra-tumoural administration of AAV2 vector encoding the immune up-regulating cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and the co-stimulatory molecule B7-1 to subcutaneous tumours, either alone or in combination with intra-muscular (IM) delivery of AAV2 vector encoding Nk4 14 days prior to tumour induction. Tumour growth and survival was monitored for all animals. Cured animals were re-challenged with tumourigenic doses of the original tumour type. In vivo cytotoxicity assays were used to investigate establishment of cell-mediated responses in treated animals. Results AAV2-mediated GM-CSF, B7-1 treatment resulted in a significant reduction in tumour growth and an increase in survival in both tumour models. Cured animals were resistant to re-challenge, and induction of T cell mediated anti-tumour responses were demonstrated. Adoptive transfer of splenocytes to naïve animals prevented tumour establishment. Systemic production of Nk4 induced by intra-muscular (IM) delivery of Nk4 significantly reduced subcutaneous tumour growth. However, combination of Nk4 treatment with GM-CSF, B7-1 therapy reduced the efficacy of the immune therapy. Conclusions Overall, this study demonstrates the potential for in vivo AAV2 mediated immune gene therapy, and provides data on the inter-relationship between tumour vasculature and immune cell recruitment.
    • Bacteria and tumours: causative agents or opportunistic inhabitants?

      Cummins, Joanne; Tangney, Mark (2013-03-28)
      Abstract Associations between different bacteria and various tumours have been reported in patients for decades. Studies involving characterisation of bacteria within tumour tissues have traditionally been in the context of tumourigenesis as a result of bacterial presence within healthy tissues, and in general, dogma holds that such bacteria are causative agents of malignancy (directly or indirectly). While evidence suggests that this may be the case for certain tumour types and bacterial species, it is plausible that in many cases, clinical observations of bacteria within tumours arise from spontaneous infection of established tumours. Indeed, growth of bacteria specifically within tumours following deliberate systemic administration has been demonstrated for numerous bacterial species at preclinical and clinical levels. We present the available data on links between bacteria and tumours, and propose that besides the few instances in which pathogens are playing a pathogenic role in cancer, in many instances, the prevalent relationship between solid tumours and bacteria is opportunistic rather than causative, and discuss opportunities for exploiting tumour-specific bacterial growth for cancer treatment.
    • Cancer screening in women with intellectual disabilities: An Irish perspective

      Reidy, M.; Denieffe, S.; Foran, S.; Waterford Institute of Technology (Sage, 2014-03)
    • Co-acting gene networks predict TRAIL responsiveness of tumour cells with high accuracy

      O’Reilly, Paul; Ortutay, Csaba; Gernon, Grainne; O’Connell, Enda; Seoighe, Cathal; Boyce, Susan; Serrano, Luis; Szegezdi, Eva (2014-12-19)
      Abstract Background Identification of differentially expressed genes from transcriptomic studies is one of the most common mechanisms to identify tumor biomarkers. This approach however is not well suited to identify interaction between genes whose protein products potentially influence each other, which limits its power to identify molecular wiring of tumour cells dictating response to a drug. Due to the fact that signal transduction pathways are not linear and highly interlinked, the biological response they drive may be better described by the relative amount of their components and their functional relationships than by their individual, absolute expression. Results Gene expression microarray data for 109 tumor cell lines with known sensitivity to the death ligand cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was used to identify genes with potential functional relationships determining responsiveness to TRAIL-induced apoptosis. The machine learning technique Random Forest in the statistical environment “R” with backward elimination was used to identify the key predictors of TRAIL sensitivity and differentially expressed genes were identified using the software GeneSpring. Gene co-regulation and statistical interaction was assessed with q-order partial correlation analysis and non-rejection rate. Biological (functional) interactions amongst the co-acting genes were studied with Ingenuity network analysis. Prediction accuracy was assessed by calculating the area under the receiver operator curve using an independent dataset. We show that the gene panel identified could predict TRAIL-sensitivity with a very high degree of sensitivity and specificity (AUC = 0 · 84). The genes in the panel are co-regulated and at least 40% of them functionally interact in signal transduction pathways that regulate cell death and cell survival, cellular differentiation and morphogenesis. Importantly, only 12% of the TRAIL-predictor genes were differentially expressed highlighting the importance of functional interactions in predicting the biological response. Conclusions The advantage of co-acting gene clusters is that this analysis does not depend on differential expression and is able to incorporate direct- and indirect gene interactions as well as tissue- and cell-specific characteristics. This approach (1) identified a descriptor of TRAIL sensitivity which performs significantly better as a predictor of TRAIL sensitivity than any previously reported gene signatures, (2) identified potential novel regulators of TRAIL-responsiveness and (3) provided a systematic view highlighting fundamental differences between the molecular wiring of sensitive and resistant cell types.
    • The cost of lost productivity due to premature cancer-related mortality: an economic measure of the cancer burden

      Hanly, Paul A; Sharp, Linda (2014-03-26)
      Abstract Background Most measures of the cancer burden take a public health perspective. Cancer also has a significant economic impact on society. To assess this economic burden, we estimated years of potential productive life lost (YPPLL) and costs of lost productivity due to premature cancer-related mortality in Ireland. Methods All cancers combined and the 10 sites accounting for most deaths in men and in women were considered. To compute YPPLL, deaths in 5-year age-bands between 15 and 64 years were multiplied by average working-life expectancy. Valuation of costs, using the human capital approach, involved multiplying YPPLL by age-and-gender specific gross wages, and adjusting for unemployment and workforce participation. Sensitivity analyses were conducted around retirement age and wage growth, labour force participation, employment and discount rates, and to explore the impact of including household production and caring costs. Costs were expressed in €2009. Results Total YPPLL was lower in men than women (men = 10,873; women = 12,119). Premature cancer-related mortality costs were higher in men (men: total cost = €332 million, cost/death = €290,172, cost/YPPLL = €30,558; women: total cost = €177 million, cost/death = €159,959, cost/YPPLL = €14,628). Lung cancer had the highest premature mortality cost (€84.0 million; 16.5% of total costs), followed by cancers of the colorectum (€49.6 million; 9.7%), breast (€49.4 million; 9.7%) and brain & CNS (€42.4 million: 8.3%). The total economic cost of premature cancer-related mortality in Ireland amounted to €509.5 million or 0.3% of gross domestic product. An increase of one year in the retirement age increased the total all-cancer premature mortality cost by 9.9% for men and 5.9% for women. The inclusion of household production and caring costs increased the total cost to €945.7 million. Conclusion Lost productivity costs due to cancer-related premature mortality are significant. The higher premature mortality cost in males than females reflects higher wages and rates of workforce participation. Productivity costs provide an alternative perspective on the cancer burden on society and may inform cancer control policy decisions.
    • Critical research gaps and translational priorities for the successful prevention and treatment of breast cancer

      Eccles, Suzanne A; Aboagye, Eric O; Ali, Simak; Anderson, Annie S; Armes, Jo; Berditchevski, Fedor; Blaydes, Jeremy P; Brennan, Keith; Brown, Nicola J; Bryant, Helen E; et al. (2013-10-01)
      Abstract Introduction Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice. Methods More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account. Results The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working. Conclusions With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.
    • ERBB3 is a marker of a ganglioneuroblastoma/ganglioneuroma-like expression profile in neuroblastic tumours

      Wilzén, Annica; Krona, Cecilia; Sveinbjörnsson, Baldur; Kristiansson, Erik; Dalevi, Daniel; Øra, Ingrid; De Preter, Katleen; Stallings, Raymond L; Maris, John; Versteeg, Rogier; et al. (2013-07-08)
      Abstract Background Neuroblastoma (NB) tumours are commonly divided into three cytogenetic subgroups. However, by unsupervised principal components analysis of gene expression profiles we recently identified four distinct subgroups, r1-r4. In the current study we characterized these different subgroups in more detail, with a specific focus on the fourth divergent tumour subgroup (r4). Methods Expression microarray data from four international studies corresponding to 148 neuroblastic tumour cases were subject to division into four expression subgroups using a previously described 6-gene signature. Differentially expressed genes between groups were identified using Significance Analysis of Microarray (SAM). Next, gene expression network modelling was performed to map signalling pathways and cellular processes representing each subgroup. Findings were validated at the protein level by immunohistochemistry and immunoblot analyses. Results We identified several significantly up-regulated genes in the r4 subgroup of which the tyrosine kinase receptor ERBB3 was most prominent (fold change: 132–240). By gene set enrichment analysis (GSEA) the constructed gene network of ERBB3 (n = 38 network partners) was significantly enriched in the r4 subgroup in all four independent data sets. ERBB3 was also positively correlated to the ErbB family members EGFR and ERBB2 in all data sets, and a concurrent overexpression was seen in the r4 subgroup. Further studies of histopathology categories using a fifth data set of 110 neuroblastic tumours, showed a striking similarity between the expression profile of r4 to ganglioneuroblastoma (GNB) and ganglioneuroma (GN) tumours. In contrast, the NB histopathological subtype was dominated by mitotic regulating genes, characterizing unfavourable NB subgroups in particular. The high ErbB3 expression in GN tumour types was verified at the protein level, and showed mainly expression in the mature ganglion cells. Conclusions Conclusively, this study demonstrates the importance of performing unsupervised clustering and subtype discovery of data sets prior to analyses to avoid a mixture of tumour subtypes, which may otherwise give distorted results and lead to incorrect conclusions. The current study identifies ERBB3 as a clear-cut marker of a GNB/GN-like expression profile, and we suggest a 7-gene expression signature (including ERBB3) as a complement to histopathology analysis of neuroblastic tumours. Further studies of ErbB3 and other ErbB family members and their role in neuroblastic differentiation and pathogenesis are warranted.
    • Exercise in cancer care in Ireland: a survey of oncology nurses and physiotherapists

      O'Hanlon, É.; Kennedy, N.; Department of Clinical Therapies, Faculty of Education and Health Sciences, University of Limerick, Limerick, Ireland (European Journal of Cancer Care, 2014-05)
    • Exercise in cancer care in Ireland: a survey of oncology nurses and physiotherapists

      O’Hanlon, Éadaoin; Kennedy, Noralee; Dept of Clinical Therapies, University of Limerick (European Journal of Cancer Care, 2014-06)
    • Exercise Rehabilitation Services Provided by Physiotherapy Departments in Cancer Care in Ireland

      Mulcahy, S; Prendergast, J; Foley, G; O Hare, A; Murphy, E; Guinan, E.M; Hussey, J; Trinity College Dublin (Irish Medical Journal, 2018-10)
    • Exploring the Interface of Oncology and Palliative Care in Ireland

      Coleman, K.; Brady, C.; O’Reilly, S.; O’ Brien, T. (Irish Medical Journal, 2019-07)
    • Expression of neuroepithelial transforming gene 1 is enhanced in oesophageal cancer and mediates an invasive tumour cell phenotype

      Lahiff, Conor; Cotter, Eoin; Casey, Rory; Doran, Peter; Pidgeon, Graham; Reynolds, John; MacMathuna, Padraic; Murray, David (2013-08-14)
      Abstract Introduction Neuroepithelial Transforming Gene 1 (NET1) is a well characterised oncoprotein and a proven marker of an aggressive phenotype in a number of cancers, including gastric adenocarcinoma. We aimed to investigate whether NET1 plays a functional role in oesophageal cancer (OAC) and its pre-malignant phenotype Barrett’s oesophagus. Methods Baseline NET1 mRNA levels were determined by qPCR across a panel of six cell lines, including normal oesophageal, Barrett’s and OAC derived cells. Quantification of NET1 protein in OAC cells was performed using Western blot and immunofluorescence. NET1 expression was modulated by treating with lysophosphatidic acid (LPA) and NET1-specific siRNA. The functional effects of NET1 knockdown were assessed in vitro using proliferation, migration and invasion assays. Results NET1 expression was increased in Barrett’s and in OAC-derived cells in comparison to normal oesophageal cells. The highest expression was observed in OE33 a Barrett’s-related OAC cell line. NET1 protein and mRNA expression was enhanced by LPA treatment in OAC and furthermore LPA treatment caused increased proliferation, migration and invasion in a NET1-dependent manner. NET1 knockdown resulted in reduced OAC cell proliferation and invasion. Conclusions As found in other malignancies, NET1 expression is elevated in OAC and its pre-malignant phenotype, Barrett’s oesophagus. NET1 promotes OAC cell invasion and proliferation and it mediates LPA-induced OAC cell migration.
    • Factors affecting receipt of a medical card in a cohort of colorectal cancer patients, 2002-2006

      McDevitt, J; Sharp, L; MacDonald, D; Dwane, F; Comber, H (Irish Medical Journal, 2013-04)
    • Healthcare utilisation among cancer survivors over 50 years of age

      Coughlan, D; Doherty, E; Frick, K; Ward, P; O’Neill, C (Irish Medical Journal, 2016-02)
    • Immunotherapy- A double Edged Sword; A case of Fatal Myocarditis and Complete Response

      Peters, N; Greally, M; Breen, K; Fabre, A; Blazkova, S (Irish Medical Journal, 2019-05)
    • Increasing late stage colorectal cancer and rectal cancer mortality demonstrates the need for screening: a population based study in Ireland, 1994-2010

      Clarke, Nicholas; McDevitt, Joseph; Kearney, Patricia M; Sharp, Linda (2014-05-13)
      Abstract Background This paper describes trends in colorectal cancer incidence, survival and mortality from 1994 to 2010 in Ireland prior to the introduction of population-based screening. Methods We examined incidence (National Cancer Registry Ireland (NCRI) and mortality (Central Statistics Office) from 1994 to 2010. Age standardised rates (ASR) for incidence and mortality have been calculated, weighted by the European standard population. Annual percentage change was calculated in addition to testing for linear trends in treatment and case fraction of early and late stage disease. Relative survival was calculated considering deaths from all causes. Results The colorectal cancer ASR was 63.7 per 100,000 in males and 38.7 per 100,000 in females in 2010. There was little change in the ASR over time in either sex, or when colon and rectal cancers were considered separately; however the number of incident cancers increased significantly during 1994-2010 (1752 to 2298). The case fractions of late stage (III/IV) colon and rectal cancers rose significantly over time. One and 5 year relative survival improved for both sexes between the periods 1994-2008. Colorectal cancer mortality ASRs decreased annually from 1994-2009 by 1.8% (95% CI -2.2, -1.4). Rectal cancer mortality ASRs rose annually by 2.4% (95% CI 1.1, 3.6) and 2.8% (95% CI 1.2, 4.4) in males and females respectively. Conclusions Increases in late-stage disease and rectal cancer mortality demonstrate an urgent need for colorectal cancer screening. However, the narrow age range at which screening is initially being rolled-out in Ireland means that the full potential for reductions in late-stage cancers and incidence and mortality are unlikely to be achieved. While it is possible that the observed increase in rectal cancer mortality may be partly an artefact of cause of death misclassification, it could also be explained by variations in treatment and adherence to best practice guidelines; further investigation is warranted.
    • An integrated analysis of the SOX2 microRNA response program in human pluripotent and nullipotent stem cell lines

      Vencken, Sebastian F; Sethupathy, Praveen; Blackshields, Gordon; Spillane, Cathy; Elbaruni, Salah; Sheils, Orla; Gallagher, Michael F; O’Leary, John J (2014-08-25)
      Abstract Background SOX2 is a core component of the transcriptional network responsible for maintaining embryonal carcinoma cells (ECCs) in a pluripotent, undifferentiated state of self-renewal. As such, SOX2 is an oncogenic transcription factor and crucial cancer stem cell (CSC) biomarker in embryonal carcinoma and, as more recently found, in the stem-like cancer cell component of many other malignancies. SOX2 is furthermore a crucial factor in the maintenance of adult stem cell phenotypes and has additional roles in cell fate determination. The SOX2-linked microRNA (miRNA) transcriptome and regulome has not yet been fully defined in human pluripotent cells or CSCs. To improve our understanding of the SOX2-linked miRNA regulatory network as a contribution to the phenotype of these cell types, we used high-throughput differential miRNA and gene expression analysis combined with existing genome-wide SOX2 chromatin immunoprecipitation (ChIP) data to map the SOX2 miRNA transcriptome in two human embryonal carcinoma cell (hECC) lines. Results Whole-microRNAome and genome analysis of SOX2-silenced hECCs revealed many miRNAs regulated by SOX2, including several with highly characterised functions in both cancer and embryonic stem cell (ESC) biology. We subsequently performed genome-wide differential expression analysis and applied a Monte Carlo simulation algorithm and target prediction to identify a SOX2-linked miRNA regulome, which was strongly enriched with epithelial-to-mesenchymal transition (EMT) markers. Additionally, several deregulated miRNAs important to EMT processes had SOX2 binding sites in their promoter regions. Conclusion In ESC-like CSCs, SOX2 regulates a large miRNA network that regulates and interlinks the expression of crucial genes involved in EMT.
    • Investigation of nanoscale structural alterations of cell nucleus as an early sign of cancer

      Liu, Yang; Uttam, Shikhar; Alexandrov, Sergey; Bista, Rajan K (2014-02-10)
      Abstract Background The cell and tissue structural properties assessed with a conventional bright-field light microscope play a key role in cancer diagnosis, but they sometimes have limited accuracy in detecting early-stage cancers or predicting future risk of cancer progression for individual patients (i.e., prognosis) if no frank cancer is found. The recent development in optical microscopy techniques now permit the nanoscale structural imaging and quantitative structural analysis of tissue and cells, which offers a new opportunity to investigate the structural properties of cell and tissue below 200 – 250 nm as an early sign of carcinogenesis, prior to the presence of microscale morphological abnormalities. Identification of nanoscale structural signatures is significant for earlier and more accurate cancer detection and prognosis. Results Our group has recently developed two simple spectral-domain optical microscopy techniques for assessing 3D nanoscale structural alterations – spectral-encoding of spatial frequency microscopy and spatial-domain low-coherence quantitative phase microscopy. These two techniques use the scattered light from biological cells and tissue and share a common experimental approach of assessing the Fourier space by various wavelengths to quantify the 3D structural information of the scattering object at the nanoscale sensitivity with a simple reflectance-mode light microscopy setup without the need for high-NA optics. This review paper discusses the physical principles and validation of these two techniques to interrogate nanoscale structural properties, as well as the use of these methods to probe nanoscale nuclear architectural alterations during carcinogenesis in cancer cell lines and well-annotated human tissue during carcinogenesis. Conclusions The analysis of nanoscale structural characteristics has shown promise in detecting cancer before the microscopically visible changes become evident and proof-of-concept studies have shown its feasibility as an earlier or more sensitive marker for cancer detection or diagnosis. Further biophysical investigation of specific 3D nanoscale structural characteristics in carcinogenesis, especially with well-annotated human cells and tissue, is much needed in cancer research.
    • The magnitude and characteristics of the population of cancer survivors: using population-based estimates of cancer prevalence to inform service planning for survivorship care

      Sharp, Linda; Deady, Sandra; Gallagher, Pamela; Molcho, Michal; Pearce, Alison; Alforque Thomas, Audrey; Timmons, Aileen; Comber, Harry (2014-10-15)
      Abstract Background Rising cancer incidence and survival mean that the number of cancer survivors is growing. Accumulating evidence suggests many survivors have long-term medical and supportive care needs, and that these needs vary by survivors’ socio-demographic and clinical characteristics. To illustrate how cancer registry data may be useful in survivorship care service planning, we generated population-based estimates of cancer prevalence in Ireland and described socio-demographic and clinical characteristics of the survivor population. Methods Details of people diagnosed with invasive cancer (ICD10 C00-C96) during 1994–2011, and who were still alive on 31/12/2011, were abstracted from the National Cancer Registry, and tabulated by cancer site, sex, current age, marital status, initial treatment, and time since diagnosis. Associations were investigated using chi-square tests. Results After excluding non-melanoma skin cancers, 17-year cancer prevalence in Ireland was 112,610 (females: 58,054 (52%) males: 54,556 (48%)). The four most prevalent cancers among females were breast (26,066), colorectum (6,598), melanoma (4,593) and uterus (3,505) and among males were prostate (23,966), colorectum (8,207), lymphoma (3,236) and melanoma (2,774). At the end of 2011, 39% of female survivors were aged <60 and 35% were ≥70 compared to 25% and 46% of males (p < 0.001). More than half of survivors of bladder, colorectal and prostate cancer were ≥70. Cancers with the highest percentages of younger (<40) survivors were: testis (50%); leukaemia (females: 28%; males: 22%); cervix (20%); and lymphoma (females: 19%; males: 20%). Fewer female (57%) than male (64%) survivors were married but the percentage single was similar (17-18%). More female (25%) than male survivors (18%; p < 0.001) were ≥10 years from diagnosis. Overall, 69% of survivors had undergone cancer-directed surgery, and 39%, 32% and 18% had received radiotherapy, chemotherapy and hormone therapy, respectively. These frequencies were higher among females than males (surgery: 82%, 54%; radiotherapy: 42%, 35%; chemotherapy: 40%, 22%; hormone therapy: 23%, 13%). Conclusions These results reveal the socio-demographic and clinical heterogeneity of the survivor population, and highlight groups which may have specific medical and supportive care needs. These types of population-based estimates may help decision-makers, planners and service providers to develop follow-up and after-care services to effectively meet survivors’ needs.