Natural Killer cells - role in local tumor growth and metastasis
Langers, Inge ; Renoux, Virginie ; Thiry, Marc et al
in Biologics: Targets and Therapy (2012)
Historically, the name of Natural Killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the seventies to date, accumulating data highlighted the importance of NK cells in ... [more ▼]
Historically, the name of Natural Killer (NK) cells came from their natural ability to kill tumor cells in vitro. From the seventies to date, accumulating data highlighted the importance of NK cells in host immune response against cancer and in therapy-induced anti-tumor response. The recognition and the lysis of tumor cells by NK cells are regulated by a complex balance of inhibitory and activating signals. This review summarizes NK cell mechanisms to kill cancer cells, their role in host immune responses against tumor growth or metastasis and their implications in anti-tumor immunotherapies via cytokines, antibodies or in combination with other therapies. The regulatory role of NK cells in autoimmunity is also discussed. [less ▲]Detailed reference viewed: 79 (22 ULg)
Human papillomavirus entry triggers NK cell cytotoxic activity and cytokine secretion
Renoux, Virginie ; Bastin, Renaud ; Langers, Inge et al
Poster (2012, March 28)Detailed reference viewed: 91 (50 ULg)
Barrett's metaplasia, dysplasia and esophageal ademnocarcinoma: an inadequate antitumour immunity?
Somja, Joan ; Demoulin, Stéphanie ; et al
Conference (2012, February 09)Detailed reference viewed: 22 (5 ULg)
γδ T cells could promote cancer progression of HPV-induced lesions
Van hede, Dorien ; Bastin, Renaud ; et al
Conference (2012, February 04)Detailed reference viewed: 85 (34 ULg)
Differential proteomic analysis of a human breast tumor and its matched bone metastasis identifies cell membrane and extracellular proteins associated with bone metastasis
Dumont, Bruno ; Castronovo, Vincenzo ; Peulen, Olivier et al
in Journal of Proteome Research (2012)
The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface ... [more ▼]
The classical fate of metastasizing breast cancer cells is to seed and form secondary colonies in bones. The molecules closely associated with these processes are predominantly present at the cell surface and in the extracellular space, establishing the first contacts with the target tissue. In this study, we had the rare opportunity to analyze a bone metastatic lesion and its corresponding breast primary tumor obtained simultaneously from the same patient. Using mass spectrometry, we undertook a proteomic study on cell surface and extracellular protein-enriched material. We provide a repertoire of significantly modulated proteins, some with yet unknown roles in the bone metastatic process as well as proteins notably involved in cancer cell invasiveness and in bone metabolism. The comparison of these clinical data with those previously obtained using a human osteotropic breast cancer cell line highlighted an overlapping group of proteins. Certain differentially expressed proteins are validated in the present study using immunohistochemistry on a retrospective collection of breast tumors and matched bone metastases. Our exclusive set of selected proteins supports the set-up of further investigations on both clinical samples and experimental bone metastasis models that will help to reveal the finely coordinated expression of proteins that favor the development of metastases in the bone microenvironment. [less ▲]Detailed reference viewed: 110 (19 ULg)
The c-jun N-terminal Kinase (JNK)-binding Protein (JNKBP1) Acts as a Negative Regulator of NOD2 Protein Signaling by Inhibiting Its Oligomerization Process
Lecat, Aurore ; Di Valentin, Emmanuel ; Somja, Joan et al
in Journal of Biological Chemistry (2012), 287(35), 29213-26
NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently ... [more ▼]
NOD2 is one of the best characterized member of the cytosolic NOD-like receptors (NLR) family. NOD2 is able to sense muramyl dipeptide (MDP), a specific bacterial cell wall component, and to subsequently induce various signalling pathways leading to NF- kappaB activation and autophagy, both events contributing to an efficient innate and adaptative immune response. Interestingly, loss-of-function nod2 variants were associated with a higher susceptibility for Crohn ' s disease (CD), which highlights the physiological importance of proper regulation of NOD2 activity. We performed a biochemical screen to search for new NOD2 regulators. We identified a new NOD2 partner, c-jun N-terminal kinase binding protein 1 (JNKBP1), a scaffold protein characterized by a N-terminal WD-40 domain. JNKBP1, through its WD-40 domain, binds to NOD2 following MDP activation. This interaction attenuates NOD2-mediated NF-kappaB activation and IL-8 secretion as well as NOD2 antibacterial activity. JNKBP1 exerts its repressor effect by disturbing NOD2 oligomerization and RIP2 tyrosine phosphorylation, both steps required for downstream NOD2 signalling. We furthermore showed that JNKBP1 and NOD2 are co-expressed in the human intestinal epithelium and immune cells recruited in the lamina propria, which suggests that JNKBP1 contributes to maintain NOD2-mediated intestinal immune homeostasis. [less ▲]Detailed reference viewed: 64 (42 ULg)
EVALUATION OF A NEW BIOCOMPATIBLE POLY(N-(MORPHOLINO ETHYL METHACRYLATE)-BASED COPOLYMER FOR THE DELIVERY OF Ruthenium oligonucleotides, targeting HPV16 E6 oncogene
Reschner, Anca ; ; et al
Poster (2012)Detailed reference viewed: 28 (6 ULg)
Proteomic kinetic analysis of blister fluid and serum in a patient with drug-induced toxic epidermal necrolysis. A comparison with skin immunohistochemistry.
; Meuwis, Marie-Alice ; Mazzucchelli, Gabriel et al
in Current Drug Safety (2012), 7(5), 339-51
Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN ... [more ▼]
Drug-induced toxic epidermal necrolysis (TEN) is a rare but potentially lethal bullous disease whose complex pathomechanisms remain uncertain. The aim of the study was an exploratory attempt to assess TEN pathobiology using a combination of immunohistochemistry and proteomics. Skin blister fluid (BF) and serum were collected in a patient in the early TEN stage at day (D) +4 of evolution and three days later (D +7). Intravenous cyclosporine A (CsA) treatment was initiated since D +4. Immunohistochemistry was performed on skin blister biopsies. In addition, proteomic analyses compared the BF protein content before and at the issue of the 3-day CsA treatment. Proteins were selected according to their prominent differential abundance in BF between D+4 and D+7, when influenced by lesional skin cells, but not in serum. Among 300 proteins, four were considered. Glutathione transferase pi was related to oxidative stress in TEN epidermis. The monocyte differentiation antigen CD14 and myeloperoxidase indicated macrophage activation. The proinflammatory S100-A8 protein probably originated from activated keratinocytes and/or macrophages. These proteomic findings were in line with immunohistochemistry and supported the prominent involvement of keratinocytes and macrophages in TEN pathomechanism. As opposed to CD14, other proteins were mainly present in BF at D+7, confirming that CsA expressed little effect, if any, on the activity of keratinocytes and macrophages in the present TEN patient. Of note, the present exploratory study using proteomic analyses in a single TEN case supports a pathogenic hypothesis without establishing any firm conclusion. [less ▲]Detailed reference viewed: 19 (5 ULg)
Drug Interactions with Normal and TEN Epidermal Keratinocytes.
; Delvenne, Philippe ; PIERARD, Gérald
in Current Drug Safety (2012), 7(5), 352-6
Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall cell mechanisms of drug ... [more ▼]
Human epidermal keratinocytes (EKs) are metabolically involved in various drug transport mechanisms, as well as in detoxification or activation processes. The overall cell mechanisms of drug metabolization, and more specifically drug processing are reviewed in normal EKs. The overall drug metabolism involves different phases corresponding to the uptake, biotransformation and anti-transport steps. In EKs, both the enzymes and transportassociated proteins are different from those involved in the hepatocyte metabolism. Some cytochrome P450 enzymes and the flavin-containing mono-oxygenases are particularly involved in EKs. Basically, EKs represent key cells likely involved during the initial stage of drug-induced toxic epidermal necrolysis (TEN). Only limited advances have been made so far in this field. Nevertheless, mitigating EKs metabolic disturbances in TEN probably represent a promising specific treatment of the disease. [less ▲]Detailed reference viewed: 11 (3 ULg)
Toxic epidermal necrolysis and antifolate drugs in cancer chemotherapy.
Franchimont, Claudine ; ; et al
in Current Drug Safety (2012), 7(5), 357-60
Folates are one-carbon donors essential for synthesizing purines, pyrimidines, serine, and methionine. They correspond to anionic hydrophilic molecules essential for DNA synthesis in mammalian cells. The ... [more ▼]
Folates are one-carbon donors essential for synthesizing purines, pyrimidines, serine, and methionine. They correspond to anionic hydrophilic molecules essential for DNA synthesis in mammalian cells. The latter cells lack the capacity to synthesize folates. In some patients, high dosages of antifolate drugs (eg: methotrexate, pemetrexed) used in cancer chemotherapy alter the keratinocytes, endothelial cells and Factor XIIIa+ dermal dendrocytes in a range of various severities. Such conditions clinically designed under the heading antifolate cytotoxic skin reaction (ACSR) occasionally resemble the toxic epidermal necrolysis (TEN) / Stevens-Johnson syndrome (SJS) spectrum. Whether or not the TEN/SJS presentation of ACSR is a regular condition similar to that induced by other drugs or a variant condition supported by a unique pathomechanism is unsettled. [less ▲]Detailed reference viewed: 22 (0 ULg)
Le melanome cutane: une seule maladie?
PIERARD, Gérald ; Franchimont, Claudine ; Hermanns-Lê, Trinh et al
in Revue Médicale de Liège (2012), 67(9), 458-60
For the media and the public at large, malignant melanoma is the most dreadful cancer of the skin. This statement is obvious. However, some nuances merit to be considered. The clinical presentations ... [more ▼]
For the media and the public at large, malignant melanoma is the most dreadful cancer of the skin. This statement is obvious. However, some nuances merit to be considered. The clinical presentations, histopathology and molecular genetics point to the fact that malignant melanoma is not a single monolithic pathological condition. Different types of melanomas are distinguished based on distinct origins and contrasted prognoses. The management and information for the patient should be handled individually. [less ▲]Detailed reference viewed: 22 (8 ULg)
Human papillomavirus DNA strongly correlates with a poorer prognosis in oral cavity carcinoma.
; ; et al
in Laryngoscope (2012), 122(7), 1558-65
OBJECTIVES/HYPOTHESIS: The prevalence of human papillomavirus (HPV) in a clinical series of 162 patients with oral squamous cell carcinoma (OSCC) was studied. Furthermore, we analyzed the correlation ... [more ▼]
OBJECTIVES/HYPOTHESIS: The prevalence of human papillomavirus (HPV) in a clinical series of 162 patients with oral squamous cell carcinoma (OSCC) was studied. Furthermore, we analyzed the correlation between the immunohistochemical expression of p16, p53, epidermal growth factor receptor (EGFR), and HPV status to predict survival in OSCC patients. STUDY DESIGN: Retrospective study. METHODS: Paraffin-embedded samples from OSCC patients (n = 162) were evaluated for the presence of HPV DNA using both GP5+/GP6+ consensus polymerase chain reaction (PCR) and type-specific E6/E7 PCR to detect HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67, and 68. Immunohistochemical staining for p16, p53, and EGFR was also performed. RESULTS: The type-specific E6/E7 PCR demonstrated that 65 of the 147 OSCC patients (44%) presented with high-risk (hr) HPV types and that 38 of the 147 OSCC patients (26%) presented with low-risk (lr) HPV types. Comparable p53 and EGFR expression levels were observed in the hr HPV+ group (41.5% p53+, 92% EGFR+) and the lr HPV+ group (57% p53+, 92% EGFR+). Conversely, a slight increase in the proportion of p16+ tumors was observed in the hr HPV+ group (65%) compared with the lr HPV+ group (44%). In regard to patient outcome, the presence of HPV was correlated with a worse prognosis (P = .007). CONCLUSIONS: A high prevalence of hr and lr HPV infections was detected in the OSCC patients included in the study. Moreover, hr HPV positivity was correlated with a decreased 5-year disease-free survival rate compared with HPV- and lr HPV+. [less ▲]Detailed reference viewed: 12 (0 ULg)
Occurrence of cardiovascular calcifications in normal, aging rats.
; ; et al
in Experimental Gerontology (2012), 47(8), 614-9
BACKGROUND: Cardiovascular calcification is an independent predictor of morbidity and mortality and increases with age. Animal models are frequently used to investigate the underlying pathophysiology ... [more ▼]
BACKGROUND: Cardiovascular calcification is an independent predictor of morbidity and mortality and increases with age. Animal models are frequently used to investigate the underlying pathophysiology. Only scarce data regarding the effect of aging on calcifications in these animal models are available. The aim of this study is to investigate the occurrence of cardiovascular calcifications in normal, aging rats. METHODS: A mixed inbred/outbred population of 44 male Lewis/Wistar rats was studied. Group 1 of three-month-old rats, group 2 twelve-month-old, group 3 twenty-four-month-old and group 4 thirty-month-old rats. Calibrated integrated backscatter (cIB) values and blood parameters (creatinine, parathyroid hormone (PTH)) were measured, followed by ex-vivo micro-CT and histology as reference methods. RESULTS: Cardiovascular calcifications developed with age, as demonstrated by significantly increasing cIB values of the aortic valve and myocardium. This was confirmed by a significant increase in the calcified volume on ex-vivo micro-CT and in the histological calcium score. There was also a significantly higher level of creatinine and PTH with age. CONCLUSIONS: As in humans, cardiovascular calcifications progressively increase with age in the normal rat. Therefore the aging rat model could be used for studying calcifying cardiovascular disease. cIB might have a value in future studies for the early detection of subclinical calcifications in humans. [less ▲]Detailed reference viewed: 10 (0 ULg)
Proinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers: Implications for chronic obstructive pulmonary disease therapy.
Herfs, Michael ; Hubert, Pascale ; POIRRIER, Anne-Lise et al
in American Journal of Respiratory Cell and Molecular Biology (2012), 47(1), 67-79
Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this ... [more ▼]
Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia is still unclear. In the present study, we investigated the implication of cigarette smoke-mediated pro-inflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. By using immunohistological techniques, we showed a higher epithelial expression of TNFalpha, IL-1beta and IL-6 as well as an activation of NF-kappaB and AP-1/MAPK signalling pathways in the respiratory tract of smoking patients compared to the normal ciliated epithelium of non-smoking patients. In addition, we demonstrated that these signalling pathways strongly influence the proliferation and the differentiation state of in vitro generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks and demonstrated that anti-TNFalpha (etanercept), anti-IL-1beta (anakinra) and/or anti-IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and squamous metaplasia development. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, administration of pro-inflammatory cytokine antagonists may have clinical application in the management of COPD patients. [less ▲]Detailed reference viewed: 69 (21 ULg)
Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome.
Hermanns-Lê, Trinh ; REGINSTER, Marie-Annick ; Franchimont, Claudine et al
in Journal of Biomedicine & Biotechnology (2012), 2012
The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural ... [more ▼]
The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH. [less ▲]Detailed reference viewed: 14 (3 ULg)
Miconazole , a pharmacological barrier to skin fungal infections.
Pierard, Gérald ; Hermanns-Lê, Trinh ; Delvenne, Philippe et al
in Expert Opinion on Pharmacotherapy (2012), 13(8), 1187-94
Introduction: Miconazole (MCZ) is a time-honored antifungal of the imidazole class. MCZ exerts a multipronged effect on fungi. It inhibits the cytochrome P450 complex, including the 14alpha-demethylase ... [more ▼]
Introduction: Miconazole (MCZ) is a time-honored antifungal of the imidazole class. MCZ exerts a multipronged effect on fungi. It inhibits the cytochrome P450 complex, including the 14alpha-demethylase enzyme required for ergosterol biosynthesis, in fungal cell membranes. In addition, intracellular accumulation of toxic methylated sterols occurs and the synthesis of triglycerides and phospholipids is altered. Disturbances in oxidative and peroxidative enzyme activities lead to an intracellular toxic concentration of hydrogen peroxide. As a result, intracellular organelle destruction then leads to cell necrosis. Farnesol synthesis stimulated in Candida spp. prevents the yeast-to-mycelium formation. MCZ is further active against Gram-positive bacteria. Areas covered: This review aims at revisiting the MCZ antifungal activity in dermatomycoses. Expert opinion: MCZ's wide spectrum of activity appears noteworthy. The full pharmacological profile of MCZ indicates its fungistatic profile through its effect on ergosterol biosynthesis. In addition, it exhibits a fungicidal effect against a number of fungal species, due to hydrogen peroxide accumulation. MCZ is characterized by high safety, efficacy and versatility, and a unique, multifaceted nature of activity in the treatment of dermatomycoses. [less ▲]Detailed reference viewed: 61 (5 ULg)
Ustekinumab in psoriasis immunopathology with emphasis on the Th17-IL23 axis. A primer.
QUATRESOOZ, Pascale ; Hermanns-Lê, Trinh ; Pierard, Gérald et al
in Journal of Biomedicine & Biotechnology (2012), 2012(147413),
Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL)-12 and IL-23 is beyond doubt, as well ... [more ▼]
Psoriasis is a chronic relapsing immunoinflammatory dermatosis that is commonly associated with systemic comorbidities. The pathogenic importance of interleukin (IL)-12 and IL-23 is beyond doubt, as well as the involvement of T helper cells (Th)1 and Th17 cells. There is upregulation of the p40 subunit shared by IL-12 and IL-23 and of the IL-23 p19 subunit, but not an increased expression of the IL-12 p35 subunit. This indicates that IL-23 appears more involved than IL-12 in the pathogenesis of psoriatic plaques. Ustekinumab is a fully human monoclonal antibody of the immunoglobulin (Ig) G1 class targeting the p40 subunit common to both IL-12 and IL-23, thus inhibiting both IL-12 and IL-23 receptor-mediated signalling. Ustekinumab is part of the recent biologic therapies active in psoriasis, autoimmune arthritides, and inflammatory bowel diseases. [less ▲]Detailed reference viewed: 27 (3 ULg)
Malignant melanoma and its stromal nonimmune microecosystem.
PIERARD, Gérald ; Franchimont, Claudine ; Delvenne, Philippe
in Journal of Oncology (2012), 2012
In recent years, rapid advances were reached in the understanding of a series of biologic signals influencing cutaneous malignant melanoma (CMM) cells. CMM is in close contact with a peculiar dermal ... [more ▼]
In recent years, rapid advances were reached in the understanding of a series of biologic signals influencing cutaneous malignant melanoma (CMM) cells. CMM is in close contact with a peculiar dermal extracellular matrix (ECM). Stromal cells store and release various structural ECM components. The impact on CMM growth and progression is mediated through strong and long-lasting effects of ECM products. This paper summarizes some peculiar aspects of the peri-CMM stroma showing intracytoplasmic loads in Factor XIIIa, CD34, versican, and alpha (IV) collagen chains. The restricted peri-CMM skin territory exhibiting such changes corresponds to the area showing neoangiogenesis and extravascular unicellular metastatic spread. The latter inconspicuous migratory CMM cells possibly correspond to CMM stem cells or to CMM cells with aberrant HOX gene expression. Their presence is associated with an increased risk for metastases in the regional sentinel lymph nodes. In conclusion, the CMM-stroma connection appears crucial to the growth regulation, invasiveness and initial metastatic spread of CMM cells. Although much remains to be learned in this field, the active intervention of the peri-CMM stroma is likely involved in the inconspicuous early metastatic migration of CMM cells. [less ▲]Detailed reference viewed: 22 (14 ULg)
Overexpression of GRP94 in breast cancer cells resistant to oxidative stress promotes high levels of cancer cell proliferation and migration: implications for tumor recurrence.
; ; Guénin, Samuel et al
in Free Radical Biology & Medicine (2012), 52(6), 993-1002
Targeting the altered redox status of cancer cells is emerging as an interesting approach to potentiate chemotherapy. However, to maximize the effectiveness of this strategy and define the correct ... [more ▼]
Targeting the altered redox status of cancer cells is emerging as an interesting approach to potentiate chemotherapy. However, to maximize the effectiveness of this strategy and define the correct chemotherapeutic associations, it is important to understand the biological consequences of chronically exposing cancer cells to reactive oxygen species (ROS). Using an H(2)O(2)-generating system, we selected a ROS-resistant MCF-7 breast cancer cell line, namely Resox cells. By exploring different survival pathways that are usually induced during oxidative stress, we identified a constitutive overexpression of the endoplasmic reticulum chaperone, GRP94, in these cells, whereas levels of its cytoplasmic homolog HSP90, or GRP78, were not modified. This overexpression was not mediated by constitutive unfolded protein response (UPR) activation. The increase in GRP94 is tightly linked to an increase in cell proliferation and migration capacities, as shown by GRP94-silencing experiments. Interestingly, we also observed that GRP94 silencing inhibits migration and proliferation of the highly aggressive MDA-MB-231 cells. By immunohistochemistry, we showed that GRP94 expression was higher in recurrent human breast cancers than in their paired primary neoplasias. Similar to the situation in the Resox cells, this increase was not associated with an increase in UPR activation in recurrent tumors. In conclusion, this study suggests that GRP94 overexpression may be a hallmark of aggressiveness and recurrence in breast cancers. [less ▲]Detailed reference viewed: 30 (6 ULg)