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De Boeck A.,Laboratory of Experimental Cancer Research | Hendrix A.,Laboratory of Experimental Cancer Research | Maynard D.,National Human Genome Research Institute | Van Bockstal M.,Ghent University | And 5 more authors.
Proteomics | Year: 2013

The identification of cancer-associated fibroblast (CAF)-derived proteins that mediate interactions between the tumor stroma and cancer cells is a crucial step toward the discovery of new molecular targets for therapy or molecular signatures that improve tumor classification and predict clinical outcome. CAF are α-smooth muscle actin positive, representing a myofibroblast phenotype that may differentiate from multiple precursor cells, including bone marrow-derived mesenchymal stem cells (MSC). Transforming growth factor-β1 (TGF-β1) is a crucial inducer of α-smooth muscle actin positive CAFs. In this study, we aimed to identify CAF-derived regulators of colon cancer progression by performing a high-throughput differential secretome profiling between CAF compared to noncancer-activated bone marrow-derived MSC. In addition, we explored the effect of TGF-β1 on the secretion of proteins by bone marrow-derived MSC in comparison with the protein secretion profile of CAF. TGF-β1 induced de novo secretion of 84 proteins in MSC, of which 16 proteins, including stromal-derived factor-1α and Rantes, were also present in CAF secretome. Immunohistochemistry further validated the expression of selected candidates such as tenascin C, fibronectin ED-A domain and stromal-derived factor-1 in clinical colon cancer specimens. In conclusion, this differential secretome approach enabled us to identify a series of candidate biomarkers for colon cancer that are associated with a CAF-specific phenotype. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Ogunjimi B.,University of Antwerp | Smits E.,Laboratory of Experimental Hematology | Hens N.,University of Antwerp | Hens N.,Hasselt University | And 7 more authors.
Viral Immunology | Year: 2011

Varicella-zoster virus (VZV) causes both primary varicella, and through reactivation of the virus, herpes zoster. It is hypothesized that VZV-immune adults may reduce the probability of developing herpes zoster through exposure to varicella. In this study we examine the existence of immunological boosting in VZV-immune adults after close contact with primary varicella. We followed-up 18 parents with household exposure to primary varicella for 1 y. Fifteen age-matched healthy and 20 older volunteers served as control groups. Cellular (IFN-γ ELISPOT) and humoral responses were measured. Data analyses were performed by t-tests and linear mixed models. The young control group only showed higher cellular responses than the older control group and the exposed group 1 mo after exposure. The exposed group had a strong tendency toward higher cellular responses compared to the older control group, reaching significance 1 y post-exposure. The best fitting linear mixed model predicts a decline in cellular response of 50% between 1 wk and 1 mo post-exposure, followed by an increase to attain an 80% higher level at 1 y compared to the first week post-exposure. No significant results emerged based on the humoral response of the individual parents in the exposed group, despite a general tendency toward higher antibody concentrations in the exposed versus the control groups. No significant difference in humoral immunity was found between the control groups. One year after initial re-exposure to VZV, VZV-immune adults showed a rise in cellular response as assessed by IFN-γ ELISPOT, and steady-state levels for the humoral response. Copyright 2011, Mary Ann Liebert, Inc.

Koninckx R.,Laboratory of Experimental Hematology | Koninckx R.,Hasselt University | Daniels A.,Laboratory of Experimental Hematology | Windmolders S.,Laboratory of Experimental Hematology | And 8 more authors.
Cellular and Molecular Life Sciences | Year: 2011

In the past, clinical trials transplanting bone marrow-derived mononuclear cells reported a limited improvement in cardiac function. Therefore, the search for stem cells leading to more successful stem cell therapies continues. Good candidates are the so-called cardiac stem cells (CSCs). To date, there is no clear evidence to show if these cells are intrinsic stem cells from the heart or mobilized cells from bone marrow. In this study we performed a comparative study between human mesenchymal stem cells (hMSCs), purified c-kit+ CSCs, and cardiosphere-derived cells (CDCs). Our results showed that hMSCs can be discriminated from CSCs by their differentiation capacity towards adipocytes and osteocytes and the expression of CD140b. On the other hand, cardiac progenitors display a greater cardiomyogenic differentiation capacity. Despite a different isolation protocol, no distinction could be made between c-kit + CSCs and CDCs, indicating that they probably derive from the same precursor or even are the same cells. © 2010 Springer Basel AG.

De Boeck A.,Ghent University | Pauwels P.,University of Antwerp | Hensen K.,Laboratory of Experimental Hematology | Rummens J.-L.,Laboratory of Experimental Hematology | And 9 more authors.
Gut | Year: 2013

Objective: Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumours and drive tumour progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC). Design: Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumour xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane neuregulin 1 (tNRG1), HER2 and HER3 expression was analysed in primary CRC (n=54), adjacent normal colorectal tissues (n=4), liver metastases (n=3) and adjacent normal liver tissues (n=3) by immunohistochemistry. Results: BM-MSC stimulate invasion, survival and tumorigenesis of CRC through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in CRC cells. Similarly, tumour-associated mesenchymal cells (T-MC) in CRC demonstrate high tNRG1 expression, which is significantly associated with advanced Union for International Cancer Control stage (p=0.005) and invasion depth (p=0.04) and decreased 5-year progression-free survival (p=0.01). HER2 and HER3 show membrane localisation in cancer cells of CRC tissue. Conclusion: Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis in CRC.

Hansen D.,Hasselt University | Hansen D.,Heart Center Hasselt | Linsen L.,Hasselt University | Linsen L.,Laboratory of Experimental Hematology | And 8 more authors.
Experimental Physiology | Year: 2015

New Findings: What is the central question of this study? It remains uncertain whether significant fat-free mass wasting occurs early after coronary artery bypass graft surgery, and the aetiology of this wasting in these particular conditions is unexplored. What is the main finding and its importance? Significant fat-free mass wasting is present after coronary artery bypass graft surgery, and this wasting effect is greater in younger patients and in patients with greater increments in blood cortisol-to-testosterone ratios after surgery. The magnitude and aetiology of muscle wasting early after coronary artery bypass graft (CABG) surgery remains unknown. In the present study, we assessed changes in fat-free mass early after CABG surgery and explored the possible aetiology (relationships with postsurgical changes in blood hormones, insulin resistance, subject characteristics and inflammation) for these changes. Fat-free mass was assessed before and 23 (range: 25) days after CABG surgery in 25 subjects. Blood testosterone, cortisol, insulin-like growth factor-1, growth hormone, sex hormone-binding globulin, glucose, insulin, C-peptide and C-reactive protein concentrations were determined, and free androgen index, cortisol-to-testosterone ratio and HOMA-IR index were all calculated before surgery, during the first 3 days after surgery and at reassessment of body composition. Relationships between changes in fat-free mass and changes in blood parameters after surgery or subject characteristics were studied. After surgery, free androgen index and blood sex hormone-binding globulin, testosterone and insulin-like growth factor-1 concentrations decreased significantly, while HOMA-IR index, cortisol-to-testosterone ratio, blood growth hormone, insulin and C-reactive protein concentrations increased significantly (P < 0.0025, observed α > 0.80). Whole-body fat-free mass decreased significantly [by -1.9 (range: 9.1) kg, P < 0.0025, observed α = 0.99] after surgery. According to regression analysis, greater absolute loss of fat-free mass was observed after CABG surgery in subjects who were younger, who experienced a greater increase in blood cortisol-to-testosterone ratio after surgery and/or who underwent earlier reassessment of body composition (P < 0.05). Significant decrements in fat-free mass were observed early after CABG surgery, especially in younger subjects and/or subjects with elevated blood cortisol-to-testosterone ratios after surgery. Interventions to preserve fat-free mass soon after CABG surgery are thus warranted. © 2015 The Physiological Society.

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