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See detailTriple negative tumors accumulate significantly less methylglyoxal specific adducts than other human breast cancer subtypes
Chiavarina, Barbara ULiege; Nokin, Marie-Julie ULiege; Durieux, Florence ULiege et al

in Oncotarget (2014)

Metabolic syndrome and type 2 diabetes are associated with increased risk of breast cancer development and progression. Methylglyoxal (MG), a glycolysis by- product, is generated through a non-enzymatic ... [more ▼]

Metabolic syndrome and type 2 diabetes are associated with increased risk of breast cancer development and progression. Methylglyoxal (MG), a glycolysis by- product, is generated through a non-enzymatic reaction from triose-phosphate intermediates. This dicarbonyl compound is highly reactive and contributes to the accumulation of advanced glycation end products. In this study, we analyzed the accumulation of Arg-pyrimidine, a MG-arginine adduct, in human breast adenocarcinoma and we observed a consistent increase of Arg-pyrimidine in cancer cells when compared with the non-tumoral counterpart. Further immunohistochemical comparative analysis of breast cancer subtypes revealed that triple negative lesions exhibited low accumulation of Arg-pyrimidine compared with other subtypes. Interestingly, the activity of glyoxalase 1 (Glo-1), an enzyme that detoxifies MG, was significantly higher in triple negative than in other subtype lesions, suggesting that these aggressive tumors are able to develop an efficient response against dicarbonyl stress. Using breast cancer cell lines, we substantiated these clinical observations by showing that, in contrast to triple positive, triple negative cells induced Glo-1 expression and activity in response to MG treatment. This is the first report that Arg- pyrimidine adduct accumulation is a consistent event in human breast cancer with a differential detection between triple negative and other breast cancer subtypes. [less ▲]

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See detailInfusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease
Hannon, Muriel ULiege; LECHANTEUR, Chantal ULiege; Lucas, Sophie et al

in Transfusion (2014), 54(February), 353-363

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See detailClinical significance of MT4-MMP and EGFR expression in Breast Cancer
Yip, Cassandre ULiege; PAYE, Alexandra ULiege; Truong, Alice ULiege et al

Scientific conference (2014, May 19)

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See detailExpression profile of undifferentiated cell transcription factor 1 in normal and cancerous human epithelia
Mouallif, Mustapha ULiege; Albert, Adelin ULiege; Zeddou, Mustapha et al

in International Journal of Experimental Pathology (2014), 95(4), 251-259

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See detailOrganized Proteomic Heterogeneity in Colorectal Cancer Liver Metastases and Implications for Therapies
Turtoi, Andrei ULiege; Blomme, Arnaud; Debois, Delphine et al

in Hepatology (Baltimore, Md.) (2014), 59(3), 924-934

Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems ... [more ▼]

Tumor heterogeneity is a major obstacle for developing effective anticancer treatments. Recent studies have pointed to large stochastic genetic heterogeneity within cancer lesions, where no pattern seems to exist that would enable a more structured targeted therapy approach. Because to date no similar information is available at the protein (phenotype) level, we employed matrix assisted laser desorption ionization (MALDI) image-guided proteomics and explored the heterogeneity of extracellular and membrane subproteome in a unique collection of eight fresh human colorectal carcinoma (CRC) liver metastases. Monitoring the spatial distribution of over 1,000 proteins, we found unexpectedly that all liver metastasis lesions displayed a reproducible, zonally delineated pattern of functional and therapeutic biomarker heterogeneity. The peritumoral region featured elevated lipid metabolism and protein synthesis, the rim of the metastasis dis- played increased cellular growth, movement, and drug metabolism, whereas the center of the lesion was characterized by elevated carbohydrate metabolism and DNA-repair activity. From the aspect of therapeutic targeting, zonal expression of known and novel biomarkers was evident, reinforcing the need to select several targets in order to achieve optimal coverage of the lesion. Finally, we highlight two novel antigens, LTBP2 and TGFBI, whose expression is a consistent feature of CRC liver metastasis. We demon- strate their in vivo antibody-based targeting and highlight their potential usefulness for clinical applications. Conclusion: The proteome heterogeneity of human CRC liver metastases has a distinct, organized pattern. This particular hallmark can now be used as part of the strategy for developing rational therapies based on multiple sets of target- able antigens. [less ▲]

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See detailTGF-B induced protein IG-H3 is essential for the growth of human liver metastases
Castronovo, Vincenzo ULiege; Blomme, Arnaud; Delvenne, Philippe ULiege et al

in Acta Gastro-Enterologica Belgica (2014, March), 77(1), 05

Introduction : Transforming growth factor-beta-induced protein ig-h3 (TGFBI) is extracellular matrix component known to be important for cell-collagen interaction. We and others have reported elevated ... [more ▼]

Introduction : Transforming growth factor-beta-induced protein ig-h3 (TGFBI) is extracellular matrix component known to be important for cell-collagen interaction. We and others have reported elevated expression of TGFBI in sev- eral human cancers, where its role remains controversial. Aim Current study aims at clarifying the function of TGFBI to date. Methods &Results : CRC-LM and in liver metastases originating from breast, lung and pancreatic tumors. We have next focused on func- tional aspects and have silenced TGFBI expression in SW1222 human colorectal carcinoma cells. The suppression of TGFBI protein led to a marked decrease in cell migration (-70%) and proliferation (-30%) in vitro. To study the effects in vivo we have developed a novel animal model of colorectal carcinoma based on chicken chorioallantoic membrane (CAM) that mimics human CRC-LM. TGFBI silencing resulted in 50% reduction of tumor volume in the CAM tumor model. Notably, the tumors displayed a marked inhibition of vascularization, suggesting an additional anti-angiogenic effect. Indeed, SW1222 cells silenced for TGFBI expression secreted lower levels of VEGFA in vitro. Finally, we have investigated if TGFBI can be used as systemically reachable target for antibody-drug delivery. For this purpose we have The in vivo data demonstrated that TGFBI is an accessible tumor target. Conclusions : Taken together, the present study shows that TGFBI is essential for promoting the development of CRC- LM and therefore represents a promising target for designing novel therapeutic approaches. [less ▲]

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See detailStudy of the pro-tumoral effects of MT4-MMP
Yip, Cassandre ULiege; PAYE, Alexandra ULiege; Truong, Alice ULiege et al

Scientific conference (2014, January 27)

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See detailImatinib improves survival of chronic Graft-versus-host disease by inhibiting TGF-β and PDGF-R in mice
Fransolet, Gilles ULiege; Belle, Ludovic ULiege; SOMJA, Joan ULiege et al

Poster (2014, January)

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients develop the sclerodermatous ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients develop the sclerodermatous cGvHD (scl-cGvHD) form of the disease characterized by multiple organ fibrosis and loss of skin elasticity. A few studies have suggested potential benefits of imatinib, a tyrosine kinase inhibitor, as a treatment of fibrosis in scl-cGVHD due to its ability to inhibit simultaneously the PDGF receptor and TGF-β pathways (via ABL inhibition), which are both involved in fibrosis . Aim: This work investigates the impact of imatinib on fibrosis in the B10.D2 to BALB/cJ scl-cGvHD murine model. Lethally irradiated BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107 splenocytes from B10.D2 donor mice. Recipients were treated with imatinib 150 mg/kg/day (50 mg/kg in the morning followed by 100 mg/kg in the evening) by oral gavage or the same volume of sterile water. Mice health status was evaluated with a scoring system encompassing five criteria (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10 according to our local ethical committee. Results: Mice given daily 150 mg/kg imatinib had a better survival than control mice (42 versus 33 days, p = 0,0357). cGvhD scores were suggestively lower in imatinib-treated than in control mice (p ≤ 0,15). Further, histological analyses evidenced reduction in the levels of both PDGF receptor (p = 0,033) and c-Abl (p = 0,185) phosphorylation in imatinib as compared to control mice. Finally, no significant differences were observed in the number or frequency of lymphocyte subsets in the 2 groups of mice. Conclusion: Imatinib slightly decreased fibrosis and significantly improved survival in a severe scl-cGvHD murine model. [less ▲]

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See detailVulvar Skin Disorders throughout Lifetime: About Some Representative Dermatoses
DOYEN, Jean ULiege; Demoulin, Stéphanie ULiege; DELBECQUE, Katty ULiege et al

in BioMed Research International (2014)

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See detailMyoferlin is a Key Regulator of HER Receptor Family Function in Breast Cancer
Costanza, Brunella ULiege; Blomme, Arnaud; Bellahcene, Akeila ULiege et al

Scientific conference (2014)

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See detailNational Belgian registration of gestational trophoblastic disease - a Belgian gynaecological oncology group (BGOG) initiative
Han, Sileny; Noel, Jean-Christophe; Moerman, Philippe et al

Poster (2014)

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See detailComparison of two FFPE preparation methods using label-free shotgun proteomics: Application to tissues of diverticulitis patients.
QUESADA CALVO, Florence ULiege; Bertrand, Virginie ULiege; Longuespée, Rémi ULiege et al

in Journal of proteomics (2014), 112C

Formalin-fixed paraffin-embedded (FFPE) specimens of patients are useful sources of materials for clinical research and have recently gained interest for use in the discovery of clinical proteomic ... [more ▼]

Formalin-fixed paraffin-embedded (FFPE) specimens of patients are useful sources of materials for clinical research and have recently gained interest for use in the discovery of clinical proteomic biomarkers. However, the critical step in this field is the ability to obtain an efficient and repeatable extraction using the limited quantities of material available for research in hospital biobanks. This work describes the evaluation of the peptide/protein extraction using FFPE sections treated by the following two methods before shotgun proteomic analysis: a commercial solution (FFPE-FASP) (filter aided sample preparation) and an antigen retrieval-derived protocol (On Slice AR). Their efficiencies and repeatabilities are compared using data-independent differential quantitative label-free analysis. FFPE-FASP was shown to be globally better both qualitatively and quantitatively than On Slice AR. FFPE-FASP was tested on several samples, and differential analysis was used to compare the tissues of diverticulitis patients (healthy and inflammatory tissues). In this differential proteomic analysis using retrospective clinical FFPE material, FFPE-FASP was reproducible and provided a high number of confident protein identifications, highlighting potential protein biomarkers. BIOLOGICAL SIGNIFICANCE: In clinical proteomics, FFPE is an important resource for retrospective analysis and for the discovery of biomarkers. The challenge for FFPE shotgun proteomic analysis is preparation by an efficient and reproducible protocol, which includes protein extraction and digestion. In this study, we analyzed two different methods and evaluated their repeatabilities and efficiencies. We illustrated the reproducibility of the most efficient method, FFPE-FASP, by a pilot study on diverticulitis tissue and on FFPE samples amount accessible in hospital biobanks. These data showed that FFPE is suitable for use in clinical proteomics, especially when the FFPE-FASP method is combined with label-free shotgun proteomics as described in the workflow presented in this work. [less ▲]

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See detailVieillissement et cancer: coincidence ou relation etiologique?
Duray, A.; Demoulin, Stéphanie ULiege; Petermans, Jean ULiege et al

in Revue medicale de Liege (2014), 69(5-6), 276-81

In Belgium and in other countries, the Cancer Registry data show an increased incidence of cancers related to age, the majority of tumors being diagnosed beyond 60 years. However, the mechanisms ... [more ▼]

In Belgium and in other countries, the Cancer Registry data show an increased incidence of cancers related to age, the majority of tumors being diagnosed beyond 60 years. However, the mechanisms responsible for this increase are not clear. Cancer could be chronologically associated with aging because of the long latency period between the exposition to carcinogenic agents and the appearance of clinical signs. Aging could also predispose directly to cancer by different mechanisms (impaired immune response, increased oxidative stress, shortening of telomeres, accumulation of senescent cells). In this review, we propose to describe different hypotheses which could explain the increased incidence of cancers in the elderly. [less ▲]

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See detailDeltaNp63 isoform-mediated beta-defensin family up-regulation is associated with (lymph)angiogenesis and poor prognosis in patients with squamous cell carcinoma.
Suarez-Carmona, Meggy ULiege; Hubert, Pascale ULiege; Gonzalez, Arnaud ULiege et al

in Oncotarget (2014), 5(7), 1856-1868

Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype ... [more ▼]

Beside a role in normal development/differentiation, high p63 immunoreactivity is also frequently observed in squamous cell carcinoma (SCC). Due to the complexity of the gene, the role of each p63 isotype in tumorigenesis is still confusing. Constitutively produced or induced in inflammatory conditions, human beta-defensins (HbetaDs) are cationic peptides involved in host defenses against bacteria, viruses and fungi. Here, we investigated both the role of p63 proteins in the regulation of HbetaDs and the implication of these antimicrobial peptides in tumor (lymph)angiogenesis. Thus, in contrast to TAp63 isotypes, we observed that DeltaNp63 proteins (alpha, beta, gamma) induce HbetaD1, 2 and 4 expression. Similar results were observed in cancer tissues and cell lines. We next demonstrated that DeltaNp63-overexpressing SCC are associated with both a poor prognosis and a high tumor vascularisation and lymphangiogenesis. Moreover, we showed that HbetaDs exert a chemotactic activity for (lymphatic) endothelial cells in a CCR6-dependent manner. The ability of HbetaDs to enhance (lymph)angiogenesis in vivo was also evaluated. We observed that HbetaDs increase the vessel number and induce a significant increase in relative vascular area compared to negative control. Taken together, the results of this study suggest that DeltaNp63-regulated HbetaD could promote tumor (lymph)angiogenesis in SCC microenvironment. [less ▲]

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See detailAccessibilome of human glioblastoma: collagen-VI-alpha-1 is a new target and a marker of poor outcome
Turtoi, Andrei ULiege; Blomme, Arnaud ULiege; BIANCHI, Elettra ULiege et al

in Journal of Proteome Research (2014), 13(12), 5660-5669

Functional targeted therapy has unfortunately failed to improve the outcome of glioblastoma patients. Success stories evidenced by the use of antibody-drug conjugates in other tumor types are encouraging ... [more ▼]

Functional targeted therapy has unfortunately failed to improve the outcome of glioblastoma patients. Success stories evidenced by the use of antibody-drug conjugates in other tumor types are encouraging, but targets specific to glioblastoma and accessible through the bloodstream remain scarce. In the current work, we have identified and characterized novel and accessible proteins using an innovative proteomic approach on six human glioblastomas; the corresponding data have been deposited in the PRIDE database identifier PXD001398. Among several clusters of uniquely expressed proteins, we highlight collagen-VI-alpha-1 (COL6A1) as a highly expressed tumor biomarker with low levels in most normal tissues. Immunohistochemical analysis of glioma samples from 61 patients demonstrated that COL6A1 is a significant and consistent feature of high-grade glioma. Deposits of COL6A1 were evidenced in the perivascular regions of the tumor-associated vasculature and in glioma cells found in pseudopalisade structures. Retrospective analysis of public gene-expression data sets from over 300 glioma patients demonstrated a significant correlation of poor patient outcome and high COL6A1 expression. In a proof-of-concept study, we use chicken chorioallantoic membrane in vivo model to show that COL6A1 is a reachable target for IV-injected antibodies. The present data warrant further development of human COL6A1 antibodies for assessing the quantitative biodistribution in the preclinical tumor models. [less ▲]

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