J H Wang

Cork University Hospital, Corcaigh, Munster, Ireland

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Publications (79)337.02 Total impact

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    ABSTRACT: Recent identification of a cancer stem cell (CSC) phenotype in solid tumors has greatly enhanced the understanding of the mechanisms responsible for cancer cell metastasis. In keeping with Pagets 'seed and soil' theory, CSCs display dependence upon stromal derived factors found within the niche in which they reside. Inflammatory mediators act as a 'fertilizer' within this niche when interacting with CSCs at the tumor stromal interface and can potentiate the metastatic ability of CSCs. Interestingly, the same components of the pro-inflammatory milieu experienced by cancer patients perioperatively are known to promote the metastagenic potential of CSCs. On the basis of this observation we discuss how surgery-induced inflammation potentiates colon CSC involvement in the metastatic process. We hypothesize that the high rates of recurrence and metastasis associated with tumor resection are potentiated by the effects of surgery-induced inflammation on CSCs. Finally we discuss potential therapeutic strategies for use in the perioperative window to protect cancer patients from the oncological effects of the pro-inflammatory milieu.
    No preview · Article · Jan 2016
  • D. Hechtl · J. H. Wang · H. P. Redmond

    No preview · Conference Paper · Apr 2015

  • No preview · Conference Paper · Apr 2015

  • No preview · Conference Paper · Apr 2015
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    N.M. Foley · J.H. Wang · H.P. Redmond

    Full-text · Article · Nov 2014 · British Journal of Surgery
  • D. Hechtl · J. H. Wang · H. P. Redmond

    No preview · Article · Sep 2014 · Irish Journal of Medical Science

  • No preview · Article · Feb 2014 · Irish Journal of Medical Science

  • No preview · Conference Paper · Mar 2013

  • No preview · Article · Nov 2012 · European Journal of Cancer
  • P. O'Leary · J.H. Wang · T.G. Cotter · H.P. Redmond

    No preview · Article · Sep 2012

  • No preview · Article · Sep 2012 · European Journal of Surgical Oncology
  • D P O'Leary · J H Wang · T G Cotter · H P Redmond
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    ABSTRACT: Reactive oxygen species (ROS) possess important cell signalling properties. This contradicts traditional thought which associated ROS activity with cell death. Emerging evidence clearly demonstrates that ROS signalling acts as a key regulator in tumour cell survival and in the cellular processes required for tumour cells to successfully metastasise and proliferate. The discovery of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) family of enzymes in the last decade has unravelled much of the mystery surrounding how ROS are generated. Tumour cells are now known to express Nox enzymes which produce ROS required for cellular signalling. Activation of Nox enzymes occurs via interaction with proinflammatory cytokines and growth factors, all of which are released following surgical trauma. As our understanding of the signalling capabilities of ROS grows, the oncological implications of ROS activity are gradually being revealed. Nox-derived ROS are known to play a central role in each step of the metastatic cascade including invasion, adhesion, angiogenesis and proliferation. This article describes how surgery creates a ROS-rich environment, which facilitates redox signalling, and also examines the role played by Nox enzymes in this process. The authors then explore current knowledge of the oncological implications of surgery-induced redox signalling, and discuss current and future therapeutic strategies targeted at ROS and Nox enzymes in cancer patients.
    No preview · Article · Dec 2011 · Gut
  • A. Ahmed · J. H. Wang · H. R. Redmond

    No preview · Article · Sep 2011 · European Journal of Cancer
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    ABSTRACT: Tumour stroma gene expression in biopsy specimens may obscure the expression of tumour parenchyma, hampering the predictive power of microarrays. We aimed to assess the utility of fluorescence-activated cell sorting (FACS) for generating cell populations for gene expression analysis and to compare the gene expression of FACS-purified tumour parenchyma to that of whole tumour biopsies. Single cell suspensions were generated from colorectal tumour biopsies and tumour parenchyma was separated using FACS. Fluorescence-activated cell sorting allowed reliable estimation and purification of cell populations, generating parenchymal purity above 90%. RNA from FACS-purified and corresponding whole tumour biopsies was hybridised to Affymetrix oligonucleotide microarrays. Whole tumour and parenchymal samples demonstrated differential gene expression, with 289 genes significantly overexpressed in the whole tumour, many of which were consistent with stromal gene expression (e.g., COL6A3, COL1A2, POSTN, TIMP2). Genes characteristic of colorectal carcinoma were overexpressed in the FACS-purified cells (e.g., HOX2D and RHOB). We found FACS to be a robust method for generating samples for gene expression analysis, allowing simultaneous assessment of parenchymal and stromal compartments. Gross stromal contamination may affect the interpretation of cancer gene expression microarray experiments, with implications for hypotheses generation and the stability of expression signatures used for predicting clinical outcomes.
    Full-text · Article · Jun 2009 · British Journal of Cancer
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    S D Killeen · J H Wang · E J Andrews · H P Redmond
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    ABSTRACT: Perioperative exposure to lipopolysaccharide (LPS) is associated with accelerated metastatic colorectal tumour growth. LPS directly affects cells through Toll-like receptor 4 (TLR-4) and the transcription factor NF-kappaB. The urokinase plasminogen activator (u-PA) system is intimately implicated in tumour cell extracellular matrix (ECM) interactions fundamental to tumour progression. Thus we sought to determine if LPS directly induces accelerated tumour cell ECM adhesion and invasion through activation of the u-PA system and to elucidate the cellular pathways involved. Human colorectal tumour cell lines were stimulated with LPS. u-PA concentration, u-PA activity, active u-PA, surface urokinase plasminogen activator receptor (u-PAR) and TLR-4 expression were assessed by ELISA, colorimetric assay, western blot analysis and flow cytometry respectively. In vitro tumour cell vitronectin adhesion and ECM invasion were analysed by vitronectin adhesion assay and ECM invasion chambers. u-PA and u-PAR function was inhibited with anti u-PA antibodies or the selective u-PA inhibitors amiloride or WXC-340, TLR-4 by TLR-4-blocking antibodies and NF-kappaB by the selective NF-kappaB inhibitor SN-50. LPS upregulates u-PA and u-PAR in a dose-dependent manner, enhancing in vitro tumour cell vitronectin adhesion and ECM invasion by >40% (P<0.01). These effects were ameliorated by u-PA and u-PAR inhibition. LPS activates NF-kappaB through TLR-4. TLR-4 and NF-kappaB inhibition ameliorated LPS-enhanced u-PA and u-PAR expression, tumour cell vitronectin adhesion and ECM invasion. LPS promotes tumour cell ECM adhesion and invasion through activation of the u-PA system in a TLR-4- and NF-kappaB-dependent manner.
    Full-text · Article · May 2009 · British Journal of Cancer
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    ABSTRACT: Background: Surgical trauma potentiates tumour growth. Endothelial progenitor cells (EPC), derived from bone-marrow, enhance tumour angiogenesis and growth. We hypothesized that laparotomy and laparoscopy differentially affect the mobilization of EPCs and hence tumour angiogenesis.Methods: C57BL/6 mice, bearing Lewis lung (3LL) flank tumours, were randomized to laparotomy, laparoscopy (CO2 pneumoperitoneum), and anaesthetic-only treatment groups (n = 12 per group). Bone marrow EPC were detected by flow cytometry using stem cell antigen (SCA-1) at 6, 24 and 48 h after treatment. Differentiated EPC were identified, at the same time points, in splenic homogenates by dual staining for lectin/UEA-1 and acetylated low density lipoprotein uptake. These findings were correlated with changes in tumour volume and microvessel density for each group. In addition, EPC uptake in tumours was evaluated using CM-Dil-labelling. This was further correlated with tumour growth and angiogenesis.Results: Laparotomy induced an 11-fold (P = <0.001) increase in bone marrow EPC, compared with anaesthetic-only control (table) at 24 h. Laparoscopy significantly (P = <0.001) attenuated EPC mobilization compared with laparotomy. This correlated with reduced tumour growth and angiogenesis. Following laparotomy, increased EPC were demonstrated lining tumour microvessels. This phenomenon was significantly (P = <0.001) attenuated in the laparoscopy group.Conclusions: Laparotomy is associated with significant mobilization of EPC for perioperative tumour angiogenesis and growth. Laparoscopy attenuates this effect. These findings identify a novel pathway by which open surgery promotes tumour angiogenesis.
    Full-text · Article · Jan 2009 · British Journal of Surgery
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    ABSTRACT: Periprosthetic osteolysis precipitates aseptic loosening of components, increases the risk of periprosthetic fracture and, through massive bone loss, complicates revision surgery and ultimately is the primary cause for failure of joint arthroplasty. The anti-inflammatory properties of HMG-CoA reductase inhibitors belonging to the statin family are well recognized. We investigated a possible role for status in initiating the first stage of the osteolytic cycle, namely monocytic activation. We used an in vitro model of the human monocyte/macrophage inflammatory response to poly-methylmethacrylate (PMMA) particles after pretreat-ing cells with cerivastatin, a potent member of the statin family. Cell activation based upon production of TNF-alpha and MCP-1 cytokines was analyzed and the intracellular Raf-MEK-ERK signal transduction pathway was evaluated using western blot analysis, to identify its role in cell activation and in any cerivastatin effects observed. We found that pretreatment with cerivastatin significantly abrogates the production of inflammatory cytokines TNF-alpha and MCP-1 by human monocytes in response to polymethylmethacrylate particle activation. This inflammatory activation and attenuation appear to be mediated through the intracellular Raf-MEK-ERK pathway. We propose that by intervening at the upstream activation stage, subsequent osteoclast activation and osteolysis can be suppressed. We believe that the anti-inflammatory properties of statins may potentially play a prophylactic role in the setting of aseptic loosening, and in so doing increase implant longevity.
    Preview · Article · Mar 2008 · Acta Orthopaedica
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    ABSTRACT: The urokinase plasminogen activator (u-PA) is intimately associated with tumour invasion and metastases. Surgery facilitates accelerated metastatic tumour growth in murine models, a phenomenon related to elevated perioperative bacterial lipopolysaccaride (LPS) and inflammatory cytokine levels. The objectives of the study were to examine the role of u-PA in cytokine-enhanced tumour cell invasion in vitro and surgery-induced accelerated metastatic tumour growth in vivo and to assess the potential benefit of a novel selective u-PA inhibitor WXC-340 in this setting. CT-26 murine colorectal carcinoma cells were stimulated with LPS, tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Cell supernatant u-PA expression and activity were determined using a colorimetric assay and Western blot analysis, respectively. Baseline and cytokine-stimulated in vitro invasion were assessed using ECmatrix invasion chambers. Two established murine models of accelerated metastatic tumour growth were used to investigate the consequences of u-PA inhibition on postoperative metastatic tumour burden. The effect of u-PA inhibition in vitro and in vivo was examined using the novel selective u-PA inhibitor, WXC-340. Proinflammatory cytokine stimulation significantly enhanced in vitro u-PA expression, activity and extracellular matrix invasion by approximately 50% compared to controls (P<0.05). This was abrogated by WXC-340. In vivo WXC-340 almost completely ameliorated both LPS- and surgery-induced, metastatic tumour growth compared to controls (P>0.05). In conclusion, u-PA cascade is actively involved in cytokine-mediated enhanced tumour cell invasion and LPS and surgery-induced metastatic tumour growth. Perioperative u-PA inhibition with WXC-340 may represent a novel therapeutic paradigm.
    Full-text · Article · Feb 2007 · British Journal of Cancer
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    ABSTRACT: Post-natal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells migrate, differentiate and incorporate into the nacent endothelium and thereby contribute to physiological and pathological neurovascularisation, has stimulated much interest. Its contribution to neovascularisation of tumours, wound healing and revascularisation associated with ischaemia of skeletal and cardiac muscles is well established. We evaluated the responses of endothelial precursor cells in bone marrow to musculoskeletal trauma in mice. Bone marrow from six C57 Black 6 mice subjected to a standardised, closed fracture of the femur, was analysed for the combined expression of cell-surface markers stem cell antigen 1 (sca-1(+)) and stem cell factor receptor, CD117 (c-kit(+)) in order to identify the endothelial precursor cell population. Immunomagnetically-enriched sca-1(+) mononuclear cell (MNC(sca-1+)) populations were then cultured and examined for functional vascular endothelial differentiation. Bone marrow MNC(sca-1+,c-kit+) counts increased almost twofold within 48 hours of the event, compared with baseline levels, before decreasing by 72 hours. Sca-1(+) mononuclear cell populations in culture from samples of bone marrow at 48 hours bound together Ulex Europus-1, and incorporated fluorescent 1,1'-dioctadecyl- 3,3,3,'3'-tetramethylindocarbocyanine perchlorate-labelled acetylated low-density lipoprotein intracellularily, both characteristics of mature endothelium. Our findings suggest that a systemic provascular response of bone marrow is initiated by musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of neovascularisation and the healing of fractures.
    Preview · Article · Feb 2007 · The Bone & Joint Journal
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    ABSTRACT: Postnatal vasculogenesis, the process by which vascular committed bone marrow stem cells or endothelial precursor cells (EPC) migrate, differentiate, and incorporate into the nacent endothelium contributing to physiological and pathological neovascularization, has stimulated much interest. Its contribution to tumor nonvascularization, wound healing, and revascularization associated with skeletal and cardiac muscles ischaemia is established. We evaluated the mobilization of EPCs in response to musculoskeletal trauma. Blood from patients (n = 15) following AO type 42a1 closed diaphyseal tibial fractures was analyzed for CD34 and AC133 cell surface marker expression. Immunomagnetically enriched CD34+ mononuclear cell (MNC(CD34+)) populations were cultured and examined for phenotypic and functional vascular endothelial differentiation. Circulating MNC(CD34+) levels increased sevenfold by day 3 postinjury. Circulating MNC(AC133+) increased 2.5-fold. Enriched MNC(CD34+) populations from day 3 samples in culture exhibited cell cluster formation with sprouting spindles. These cells bound UEA-1 and incorporated fluorescent DiI-Ac-LDL intracellularily. Our findings suggest a systemic provascular response is initiated in response to musculoskeletal trauma. Its therapeutic manipulation may have implications for the potential enhancement of fracture healing.
    Full-text · Article · Jan 2007 · Journal of Orthopaedic Research

Publication Stats

2k Citations
337.02 Total Impact Points

Institutions

  • 1998-2014
    • Cork University Hospital
      • Department of Radiology
      Corcaigh, Munster, Ireland
  • 2000-2009
    • University College Cork
      • • Department of Biochemistry
      • • Department of Surgery
      Corcaigh, Munster, Ireland
  • 1994-2002
    • Beaumont Hospital
      Dublin, Leinster, Ireland
  • 2001
    • National University of Ireland, Galway
      Gaillimh, Connaught, Ireland