References of "Castronovo, Vincenzo"
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See detailPharmacological evaluation of BM-573, a dual thromboxane A2 receptor antagonist and thromboxane synthase inhibitor, as potential anti-metastatic agent
De Leval, X.; Dassesse, T.; Benoît, V. et al

Poster (2003, December)

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See detailPharmacological evaluation of BM-573, a dual thromboxane A(2) receptor antagonist and thromboxane synthase inhibitor, as potential anti-metastatic agent
de Leval, X. J.; Dassesse, T.; Benoit, V. et al

in Blood (2003, November 16), 102(11, Part 2), 72

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See detailDentin matrix protein 1 is expressed in human lung cancer
Chaplet, Michael; de Leval, Laurence ULg; Waltregny, David ULg et al

in Journal of Bone and Mineral Research (2003), 18(8), 1506-1512

We have previously shown that breast and prostate cancers express bone matrix proteins. DMPI expression was evaluated in 59 human lung cancer samples at the protein and mRNA levels. It was detectable in ... [more ▼]

We have previously shown that breast and prostate cancers express bone matrix proteins. DMPI expression was evaluated in 59 human lung cancer samples at the protein and mRNA levels. It was detectable in 80% of the cases, suggesting a potential role for DMP1 in tumor progression and bone metastasis. Introduction: Previously, we and others have shown that bone extracellular matrix proteins such as bone sialoprotein (BSP) and osteopontin (OPN) are expressed in various types of cancer that are characterized by a high affinity for bone including breast, prostate, and lung adenocarcinoma. Based on biochemical and genetic features, BSP, OPN, dentin matrix protein 1 (DMP1), and dentin sialophosphoprotein (DSPP) have been recently classified in a unique family named SIBLING (small integrin-binding ligand, N-linked glycoprotein). Therefore, we investigated whether DMPI could also be detected in osteotropic cancers. Materials and Methods: We first used a cancer array for evaluating the relative abundance of DMP1 transcript in a broad spectrum of human cancer tissues. This screening showed that DMP1 was strongly detectable in lung tumors compared with normal corresponding tissue. In a second step, we used an immunophosphatase technique and a specific polyclonal antibody directed against DMPI to examine the expression of DMP1 in 59 human non-small cell lung cancer samples, including 29 squamous carcinoma, 20 adenocarcinoma, and 10 bronchioloalveolar carcinoma. Student's t-test was used to determine the statistical significance of immunostaining scores between the lung cancer histological groups studied and between cancer and normal lung tissues. Results: Our results show that DMP1 is detectable in 90% of the adenocarcinoma and squamous carcinoma analyzed while 8 of 10 bronchioloalveolar specimens were negative. DMP1 immunostaining intensity and extent scores were significantly higher in adenocarcinoma (p = 0.0004) and squamous carcinoma (p < 0.0001) samples compared with adjacent normal lung tissue. In situ hybridization experiments confirmed that DMP1 mRNA is localized in lung cancer cells. Conclusion: In this study, we show that a third SIBLING protein is ectopically expressed in lung cancer. The role of DMPI in lung cancer is largely unknown. Further studies are required to determine the implication of this protein, next to its sisters SIBLING proteins, in tumor progression and bone metastasis development. [less ▲]

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See detailDetection of bone sialoprotein in human (pre)neoplastic lesions of the uterine cervix
Detry, Cédric ULg; Waltregny, David ULg; Quatresooz, Pascale ULg et al

in Calcified Tissue International (2003), 73(1), 9-14

Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in the mineral compartment of developing bones. BSP is detected in a variety of human cancers, particularly those that metastasize to the ... [more ▼]

Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in the mineral compartment of developing bones. BSP is detected in a variety of human cancers, particularly those that metastasize to the skeleton. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone metastases development. Since squamous cell carcinoma (SCCs) of the uterine cervix also frequently metastasizes to bone, we investigated whether BSP is expressed in human cervical cancer. We examined BSP expression in cervical tissue samples from 47 patients, including 19 normal tissues, 20 squamous intraepithelial lesions (SILs) (9 low and 11 high grade) and 8 invasive SCCs. BSP protein expression was evaluated by the immunophosphatase technique using a BSP polyclonal antibody in paraffin-embedded cervical biopsies. The abundance of BSP protein was significantly higher in invasive SCCs and high grade SILs than in normal cervix tissue samples and low grade SILs, which showed no or a low level of anti-BSP immunoreactivity. In situ hybridization experiments performed on representative cervix invasive SCCs frozen sections revealed that BSP transcripts were detectable in these lesions. Our study demonstrates that BSP expression is a common feature in high grade SILs and invasive SCCs of the uterine cervix. The prognostic value of BSP detection in these lesions and the potential role of BSP as an angiogenic factor in this type of cancer are currently under investigation. [less ▲]

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See detailDépistage et détection précoce des cancers : Pourquoi? Comment? Lesquels? Qui et où? A quel prix?
Castronovo, Vincenzo ULg

in Revue Médicale de Liège (2003), 58(5), 310-3

Cancer is fighting with cardiovascular diseases for the first place as the number one killer of humans living in industrialized countries. Several factors contribute to the high incidence of cancers. The ... [more ▼]

Cancer is fighting with cardiovascular diseases for the first place as the number one killer of humans living in industrialized countries. Several factors contribute to the high incidence of cancers. The spectacular increase in life expectancy of individuals living in these areas is certainly one of the major causes that explain the steady rise of the number of patients suffering and dying from cancer. For most cancers, when the issue is fatal, it is usually after a long morbidity period often very difficult for the patient and with heavy public health consequences. Thus, a major challenge that the health professionals are facing is the reduction of malignant disease incidence. Primary prevention would be certainly the most successful strategy. However, its implementation is of extreme difficulty. Secondary prevention, non-exclusive to the primary one, represents probably the best approach to decrease morbidity and mortality linked to these diseases. Screening and early diagnosis are the two axes of such a strategy. The first one concerns the detection of a malignant lesion in an asymptomatic patient. Early diagnosis implies to consider with attention and explore any signs or symptoms that can be easily missed by the patient or the doctor and, hence, could be the first indication of a progressing cancer. The impact of cancer screening on the mortality rate due to cancer is still the subject of intense debates, while the efficacy of early diagnosis is unanimously recognized. Still, it is cancer screening that is the center of most attentions.... [less ▲]

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See detailAlimentation et cancer
Castronovo, Vincenzo ULg

in Revue Médicale de Liège (2003), 58(4), 231-9

The role of a qualitatively and quantitatively altered nutrition for the development of cancer in human is largely recognized. While the human life expectancy is continuously expanding and the World ... [more ▼]

The role of a qualitatively and quantitatively altered nutrition for the development of cancer in human is largely recognized. While the human life expectancy is continuously expanding and the World Health Organization is predicting a dramatic rise in the number of patients that will get cancer and die from it in the next decades, it is useful to attempt to understand the real impact of nutrition at the level of the oncogenesis mechanisms. Oxidative stress, methylation deficit and imbalance in the ratio of omega-3 and omega-6 fatty acids represents situations directly linked to nutrition and which contribute to an increased risk for cancer development. The understanding of the mechanisms by which nutrition affects these processes should better stimulate health professionals to consider with more attention what their patients are eating. [less ▲]

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See detailGalectin-1 accumulation in the ovary carcinoma peritumoral stroma is induced by ovary carcinoma cells and affects both cancer cell proliferation and adhesion to laminin-1 and fibronectin
van den Brule, Frédéric; Califice, Stéphane; Garnier, Frédérique et al

in Laboratory Investigation : Journal of Technical Methods & Pathology (2003), 83(3), 377-386

Galectin-1 (gal-1) is a 14-kDa laminin-binding galectin involved in several biologic events including regulation of cancer cell proliferation and adhesion to the matrix. In this study, we examined gal-1 ... [more ▼]

Galectin-1 (gal-1) is a 14-kDa laminin-binding galectin involved in several biologic events including regulation of cancer cell proliferation and adhesion to the matrix. In this study, we examined gal-1 expression in 30 human epithelial ovary carcinoma samples by Western and Northern blotting and by immunohistochemistry. Gal-1 mRNA levels were increased in more than 95% of the examined ovary carcinoma samples, compared with a wedge resection of a normal ovary. Immunohistochemical analysis of the samples demonstrated gal-1 expression in cancer epithelial cells from 17 of 30 samples, with a cytoplasmic pattern. Gal-1 immunostaining was significantly increased in the stroma associated with carcinoma cells compared with the normal, noninvaded stroma (p = 0.003). This pattern of expression was confirmed by examination of 12 other frozen epithelial ovary carcinomas, using in situ hybridization. Immunohistochemical staining of the specimens demonstrated colocalization of gal-1, laminin-1, and fibronectin. In vitro experiments were conducted to elucidate the potential biologic role of gal-1 in ovarian cancer progression. Gal-1 protein expression and release was detected in AZ364, SK-OV-3, and AZ224, but not in OVCAR-3, AZ419, and AZ382, human ovary carcinoma cell lines. Incubation of 84BR fibroblasts with conditioned media harvested from the ovary carcinoma cell lines induced an increased expression of gal-1 in the cultured fibroblasts in all cases except AZ419 and SK-OV-3. High concentrations of gal-1 (100 mug/ml) induced significantly decreased cell proliferation in all cell lines, as defined by bromodeoxyuridine incorporation. Additionally, recombinant gal-1 induced a dose-dependent increase in in vitro adhesion of AZ224, SK-OV-3, and AZ382 cells to laminin-1; adhesion to fibronectin was increased by gal-1 in OVCAR-3, AZ224, and SK-OV-3. No effect was observed in the other cases. Our data contribute to define a role for gal-1 during the interactions between human ovary carcinoma cells and host fibroblasts. [less ▲]

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See detailScreening of histone deacetylase (HDAC) expression profiles in prostate cancer tissues leads to the identification of HDAC8 as a novel marker of smooth muscle differentiation
Waltregny, David ULg; Glénisson, Wendy; Tran, Syv Li et al

Conference (2003)

Background: Histone deacetylation mediated by histone deacetylases (HDAC) plays a key role in the regulation of gene expression. Inhibition of HDAC activity is associated with profound alterations in ... [more ▼]

Background: Histone deacetylation mediated by histone deacetylases (HDAC) plays a key role in the regulation of gene expression. Inhibition of HDAC activity is associated with profound alterations in cellular biology, such as cell growth arrest, apoptosis and differentiation. It has been hypothesized that altered HDAC expression and/or activity could play a role in cancer development and progression. Objectives: To investigate this possibility, we undertook a study in which we screened HDAC expression profiles in human prostate cancer. In addition, we sought to determine the specific biological effects of selected HDACs. Methods: A variety of techniques, including immunochemistry, Q-RT-PCR, and immunobloting, were used to examine the expression of several class I and class II HDACs in human prostate cancer cell lines and matched malignant and non-malignant prostate tissues. Analysis of the specific biological effects of selected HDACs was performed after knocking down their expression with the use of specific small interfering RNAs (siRNA) and/or after forcing their overexpression by transfection of the cDNAs of interest. Results: Normal prostate epithelial and stromal cells displayed distinct HDAC expression profiles, suggesting specific functions for these enzymes in the prostate. Human prostate cancer cells did not exhibit significant alterations in the abundance of any of the HDAC enzymes analyzed. One of the HDACs tested, herein referred to as HDACX, was specifically expressed, in vivo, by cells showing smooth muscle phenotype, including vascular and prostate smooth muscle cells and myoepithelial cells. HDACX expression co-localized with the expression of the specific smooth muscle marker alpha smooth muscle actin (alpha-SMA) in all human tissues tested. Nucleo-cytoplasmic fractionation experiments showed that HDACX was mainly expressed in the cytosol of human smooth muscle cells (HSMC) obtained from umbilical cord veins. Transfection experiments leading to overexpression of HDACX in mouse fibroblasts indicated that the enzyme was detected both in the cytosol and in the nucleus. By immunocytochemistry, it was observed that HDACX pattern of expression was reminiscent of actin stress fibers, suggesting that this HDAC may be involved in the regulation of the smooth muscle cell cytoskeleton. Trichostatin A (TSA), a specific global HDAC inhibitor, as well as specific HDACX siRNAs, were able to completely prevent the TGFß1-induced differentiation of fibroblasts into myofibroblasts, as assessed by alpha-SMA abundance. Forced downregulation of HDACX by siRNAs in HSMC caused a dramatic reduction in their contraction capacity, as determined with the use of hydrated collagen lattices contraction assays. Conclusions : HDACs diplay distinct expression profiles among normal prostate epithelial and stromal cells. The abundance of the HDACs analyzed in this study is not altered in prostate cancer. Further experiments are required to determine whether the activity of these enzymes is altered in prostate cancer. We have identified for the first time an HDAC that (i) is specifically expressed in cells showing smooth muscle phenotype, (ii) is required for myofibroblastic differentiation, and (iii) is involved in smooth muscle cell contraction. This HDAC may become a target for the therapy of several pathological conditions, including chronic inflammation and cancer, in which myofibroblasts play a major role. [less ▲]

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See detailLipides, dépression et suicide
Colin, A.; Reggers, Jean ULg; Castronovo, Vincenzo ULg et al

in Encéphale (L') (2003), 29(1, JAN-FEB), 49-58

Polyunsatured fatty acids are made out of a hydrocarbonated chain of variable length with several double bonds. The position of the first double bond (omega; omega) differentiates polyunsatured omega3 ... [more ▼]

Polyunsatured fatty acids are made out of a hydrocarbonated chain of variable length with several double bonds. The position of the first double bond (omega; omega) differentiates polyunsatured omega3 fatty acids (for example : alpha-linolenic acid or alpha-LNA) and polyunsatured omega6 fatty acids (for example : linoleic acid or LA). These two classes of fatty acids are said to be essential because they cannot be synthetised by the organism and have to be taken from alimentation. The omega3 are present in linseed oil, nuts, soya beans, wheat and cold water fish whereas omega6 are present in maize, sunflower and sesame oil. Fatty acids are part of phospholipids and, consequently, of all biological membranes. The membrane fluidity, of crucial importance for its functionning, depends on its lipidic components. Phospholipids composed of chains of polyunsatured fatty acids increase the membrane fluidity because, by bending some chains, double bonds prevent them from compacting themselves perfectly. Membrane fluidity is also determined by the phospholipids/free cholesterol ratio, as cholesterol increases membrane viscosity. A diet based on a high proportion of essential polyunsatured fatty acids (fluid) would allow a higher incorporation of cholesterol (rigid) in the membranes to balance their fluidity, which would contribute to lower blood cholesterol levels. Brain membranes have a very high content in essential polyunsatured fatty acids for which they depend on alimentation. Any dietary lack of essential polyunsatured fatty acids has consequences on cerebral development, modifying the activity of enzymes of the cerebral membranes and decreasing efficiency in learning tasks. Epidemiological data - The prevalence of depression seems to increase continuously since the beginning of the century. Though different factors most probably contribute to this evolution, it has been suggested that it could be related to an evolution of alimentary patterns in the Western world, in which polyunsatured omega fatty acids contained in fish, game and vegetables have been largely replaced by polyunsatured omega6 fatty acids of cereal oils. Some epidemiological data support the hypothesis of a relation between lower depression and/or suicide rates and a higher consumption of fish. These data do not however prove a relation of causality. Cholesterol and depression - Several cohort studies (on nondepressed subjects) have assessed the relationship between plasma cholesterol and depressive symptoms with contradictory results. Though some results found a significant relationship between a decrease of total cholesterol and high scores of depression, some other did not. Studies among patients suffering from major depression signalled more constantly an association between low cholesterol and major depression. Besides, some trials showed that clinical recovery maybe associated with a significant increase of total cholesterol. Cholesterol and suicidal behaviour - The hypothesis that a low cholesterol level may represent a suicidal risk factor was discovered accidentally following a series of epidemiological studies which revealed an increase of the suicidal risk among subjects with a low cholesterol level. Though some contradictory studies do exist, this relationship has been confirmed by several subsequent cohort studies. These findings have challenged the vast public health programs aimed at promoting the decrease of cholesterol, and even suggested to suspend the administration of lipid lowering drugs. Recent clinical studies on populations treated whith lipid lowering drugs showed nevertheless a lack of significant increase of mortality, either by suicide or accident. In addition, several controlled studies among psychiatric patients revealed a decrease of the concentrations of plasma cholesterol among patients who had attempted suicide in comparison with other patients. Polyunsaturated fatty acids and depression - In major depression, all studies revealed a significant decrease of the polyunsaturated omega3 fatty acids and/or an increase of the omega6/omega3 ratio in plasma and/or in the membranes of the red cells. In addition, two studies found a higher severity of depression when the level of polyunsaturated omega fatty acids or the ratio omega3/omega6 was low. Parallel to these modifications, other biochemical perturbations have been reported in major depression, particularly an activation of the inflammatory response system, resulting in an increase of the pro-inflammatory cytokines (interleukins: IL-1beta, IL-6 and interferon gamma) and eicosanoids (among others, prostaglandin E2) in the blood and the CSF of depressed patients. These substances cause a peroxidation and, consequently a catabolism of membrane phospholipids, among others those containing polyunsaturated fatty acids. The cytokines and eicosanoids derive from polyunsaturated fatty acids and have opposite physiological functions according to their omega or omega6 precursor. Arachidonic acid (omega6) is, among others, precursor of pro-inflammatoty prostaglandin E2 (PGE2), whereas polyunsaturated W fatty acids inhibit the formation of PGE2. It has been shown that a dietary increase of polyunsaturated W fatty acids reduced strongly the production of IL-1beta, IL-2, IL-6 and TNF-alpha (tumor necrosis factor-alpha). In contrast, diets with a higher supply of linoleic acid (omega6) increased significantly the production of pro-inflammatory cytokines, like TNF-alpha. Therefore, polyunsaturated omega3 fatty acids could be associated at different levels in the pathophysiology of major depression, on the one hand through their role in the membrane fluidity which influences diverse steps of neurotransmission and, on the other hand, through their function as precursor of pro-inflammatory cytokines and eicosanoids disturbing neurotransmission. In addition, antidepressants could exhibit an immunoregulating effect by reducing the release of pro-inflammatory cytokines, by increasing the release of endogenous antagonists of pro-inflammatory cytokines like IL-10 and, finally, by acting like inhibitors of cyclo-oxygenase. Therapeutic use of fatty acids - Data available concerning the administration of supplements of DHA (docosahexanoic acid) or other polyunsaturated fatty acids omega3 are limited. In a double blind placebo-controlled study on 30 patients with bipolar disorder, the addition of polyunsaturated omega3 fatty acids was associated with a longer period of remission. Moreover, nearly all the other prognosis measures were better in the omega3 group. Very recently, a controlled trial showed the benefits of adding an omega3 fatty acid, eicosopentanoic acid, among depressed patients. After 4 weeks, six of the 10 patients receiving the fatty acid were considered as responders in comparison with only one of the ten patients receiving placebo. Conclusions Some epidemiological, experimental and clinical data favour the hypothesis that polyunsaturated fatty acids could play a role in the pathogenesis and/or the treatment of depression. More studies however are needed in order to better precise the actual implication of those biochemical factors among the various aspects of depressive illness. [less ▲]

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See detailp53-dependent downregulation of metastasis-associated laminin receptor
Modugno, Michele; Tagliabue, Elda; Ardini, Elena et al

in Oncogene (2002), 21(49), 7478-7487

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild ... [more ▼]

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression. [less ▲]

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See detailNovel antiangiogenic effects of the bisphosphonate compound zoledronic acid
Wood, J.; Bonjean, K.; Ruetz, S. et al

in Journal of Pharmacology and Experimental Therapeutics (2002), 302(3), 1055-1061

Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation ... [more ▼]

Bisphosphonate drugs inhibit osteoclastic bone resorption and are widely used to treat skeletal complications in patients with tumor-induced osteolysis. We now show that zoledronic acid, a new generation bisphosphonate with a heterocyclic imidazole substituent, is also a potent inhibitor of angiogenesis. In vitro, zoledronic acid inhibits proliferation of human endothelial cells stimulated with fetal calf serum, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (IC50 values 4.1, 4.2, and 6.9 muM, respectively), and modulates endothelial cell adhesion and migration. In cultured aortic rings and in the chicken egg chorioallantoic membrane assay, zoledronic acid reduces vessel sprouting. When administered systemically to mice, zoledronic acid potently inhibits the angiogenesis induced by subcutaneous implants impregnated with bFGF [ED50, 3 mug/kg (7.5 nmol/kg) s.c.]. These findings indicate that zoledronic acid has marked antiangiogenic properties that could augment its efficacy in the treatment of malignant bone disease and extend its potential clinical use to other diseases with an angiogenic component. [less ▲]

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See detailOverexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation
Waltregny, David ULg; Alami, Younes; Clausse, Nathalie et al

in Prostate (2002), 50(3), 162-169

BACKGROUND. Homeobox (HOX)-containing proteins have been identified as regulators controlling the coordinated expression of genes involved in development and differentiation. Recent data also suggest a ... [more ▼]

BACKGROUND. Homeobox (HOX)-containing proteins have been identified as regulators controlling the coordinated expression of genes involved in development and differentiation. Recent data also suggest a possible involvement of HOX genes in malignant transformation and/or progression. We have previously shown that HOXC8 expression was selectively turned on in human cervix cancer cells compared with normal keratinocytes, suggesting that HOXC8 may be involved in the process leading to the transformation of cervix keratinocytes [Alami et al.: Biochem Biophys Res Commun 257:738-745,1999]. METHODS. RT-PCR and in situ hybridization experiments were performed to investigate the expression and cell type localization of HOXC8 transcripts in human prostate cancer cell lines and tissues. In situ hybridization was performed with the use of an HOXC8 anti-sense digoxigenin-labeled probe to investigate HOXC8 mRNA expression in 27 prostate cancer tissue specimens. RESULTS. Out of the three human prostate cancer cell lines tested, DU-145 and PC3 but not LNCaP cells expressed detectable amount of HOXC8 transcripts. Results from in situ hybridization experiments demonstrated that HOXC8 gene was expressed mainly in malignant epithelial cells. Furthermore, the staining intensity in epithelial cells was significantly increased in high Gleason score carcinomas (scores 7-9, n = 12; labeling intensity 2 + to 3 +) compared with the one observed in low and intermediate Gleason score tumors (scores 3-6, n = 15; labeling intensity 0 and 1 +) (ANOVA test, P < 0.0001). CONCLUSIONS. Our data showing that HOXC8 overexpression is associated with the loss of tumor differentiation in human prostate cancer suggests that HOXC8 may play a role in the acquisition of the invasive and metastatic phenotype of this malignancy. (C) 2002 Wiley-Liss, Inc. [less ▲]

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See detailHistone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling
Deroanne, Christophe ULg; Bonjean, Karine; Servotte, Sandrine et al

in Oncogene (2002), 21(3), 427-436

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to ... [more ▼]

Angiogenesis is a complex biological process involving the coordinated modulation of many genes. Histone deacetylases (HDAC) are a growing family of enzymes that mediate the availability of chromatin to the transcriptional machinery. Trichostatin-A (TSA) and suberoylanilide hydroxamic acid (SAHA), two HDAC inhibitors known to relieve gene silencing, were evaluated as potential antiangiogenic agents. TSA and SAHA were shown to prevent vascular endothelial growth factor (VEGF)-stimulated human umbilical cord endothelial cells (HUVEC) from invading a type I collagen gel and forming capillary-like structures. SAHA and TSA inhibited the VEGF-induced formation of a CD31-positive capillary-like network in embryoid bodies and inhibited the VEGF-induced angiogenesis in the CAM assay. TSA also prevented, in a dose-response relationship, the sprouting of capillaries from rat aortic rings. TSA inhibited in a dose-dependent and reversible fashion the VEGF-induced expression of VEGF receptors, VEGFR1, VEGFR2, and neuropilin-1. TSA and SAHA upregulated the expression by HUVEC of semaphorin III, a recently described VEGF competitor, at both mRNA and protein levels. This effect was specific to endothelial cells and was not observed in human fibroblasts neither in vascular smooth muscle cells. These observations provide a conspicuous demonstration that HDAC inhibitors are potent anti-angiogenic factors altering VEGF signaling. [less ▲]

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See detailS-acetyl-glutathione selectively induces apoptosis in human lymphoma cells through a GSH-independent mechanism
Locigno, Roberto; Pincemail, Joël ULg; Henno, Audrey et al

in International Journal of Oncology (2002), 20(1), 69-75

Reduced apoptosis is associated to cancer development. Agents able to restore the programmed cell death responsiveness of cancer cells are foreseen as potential effective cancer therapies. In this study ... [more ▼]

Reduced apoptosis is associated to cancer development. Agents able to restore the programmed cell death responsiveness of cancer cells are foreseen as potential effective cancer therapies. In this study, we report that a glutathione-S-derivative, S-acetyl-glutathione (Sag), induces significant apoptosis in three human lymphoma cell lines, including Daudi, Raji and Jurkat cells while it had no or little effect on either Hut-78 lymphoma cells or the normal BT lymphocytes. We used Annexin-V FACS analysis and DNA laddering to demonstrate that Sag activated apoptosis in the three sensitive cell lines in a dose- and time-dependent-fashion. Using mercury orange staining and FACS analysis, we showed that Sag generated an intracellular GSH depletion in Daudi, Raji and Jurkat cells but not in Hut-78 or the normal BT cells. These data provide direct evidence that Sag specifically activates programmed cell death in lymphoma cells through, at least in part, a depletion of intracellular GSH rather than an increase, as previously suggested. Because of its selective effect on cancer cells, Sag appears as a promising new lymphoma cell apoptosis inducer with potential clinical value for lymphoma patients. [less ▲]

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See detailThe role of bone sialoprotein and other members of the SIBLING family in bone metastases formation
Castronovo, Vincenzo ULg; Waltregny, David ULg; Fisher, Larry et al

in 3rd International Conference on Osteopontin and SIBLING (Small Integrin-Binding Ligand, N-linked Glycoprotein) Proteins (2002)

Bone metastasis is a major health and social-economic problem in well-developed countries because they are frequent and generate major morbidity in cancer patients. Although virtually all cancer cells can ... [more ▼]

Bone metastasis is a major health and social-economic problem in well-developed countries because they are frequent and generate major morbidity in cancer patients. Although virtually all cancer cells can metastasize to bone, the majority of bone metastases are due to a few types of cancers that exhibit a high osteotropism. These include carcinoma of the breast, lung, prostate, thyroid, kidney, and multiple myeloma. The exact molecular mechanisms by which certain cancer cells preferentially implant to specific sites are not yet fully understood. [less ▲]

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See detailReduced Glutathione System: Role in Cancer Development, Prevention and Treatment (Review)
Locigno, R.; Castronovo, Vincenzo ULg

in International Journal of Oncology (2001), 19(2), 221-36

Reduced glutathione (GSH), a ubiquitous thiol-containing tripeptide, is unanimously recognized to play a central role in cell biology. It is highly implicated in the cellular defense against xenobiotics ... [more ▼]

Reduced glutathione (GSH), a ubiquitous thiol-containing tripeptide, is unanimously recognized to play a central role in cell biology. It is highly implicated in the cellular defense against xenobiotics and naturally occurring deleterious compounds such as free radicals and hydroperoxides. Consequently, GSH is an essential actor in several human diseases including cancer and cardio-vascular diseases. Its implication in oncogenesis has led to the development of new strategies to improve both prevention and treatment of cancer. The present review proposes an in depth analysis or our current knowledge of the relations between GSH and cancer. [less ▲]

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See detailGenetic Imbalances in Preleukemic Thymuses
Verlaet, Myriam ULg; Deregowski, Valérie; Denis, Ghislaine et al

in Biochemical and Biophysical Research Communications (2001), 283(1), 12-8

To understand the molecular mechanisms involved in preleukemia, the suppression subtractive hybridization method was used in a murine radiation-induced thymic lymphoma model. Seventeen mRNAs overexpressed ... [more ▼]

To understand the molecular mechanisms involved in preleukemia, the suppression subtractive hybridization method was used in a murine radiation-induced thymic lymphoma model. Seventeen mRNAs overexpressed in preleukemic thymuses were identified: mouse laminin binding protein (p40/37LBP), E25 protein, Rattus norvegicus clone BB.1.4.1, profilin, poly(A) binding protein (PABP), mouse high mobility group protein 1, topoisomerase I, clusterin, proteasome RC1 subunit, rat prostatein C3 and C1 subunits; two ESTs and four unknown genes. The overexpression of PABP, clusterin, profilin, and the p40/37LBP mRNAs was confirmed in preleukemic thymuses and can be related to some cellular events observed during the preleukemic period, i.e., alterations of cell cycle and apoptosis properties. The p40/37LBP and 67-kDa laminin receptor proteins were upregulated during the preleukemic period. The data suggest that additional studies on p40/37LBP and 67-kDa laminin receptor regulation are required to evaluate their potential role in the lymphoma prevention by TNF-alpha and IFN-gamma. [less ▲]

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See detailIncreased Expression of Galectin-1 in Carcinoma-Associated Stroma Predicts Poor Outcome in Prostate Carcinoma Patients
van den Brule, Frederic; Waltregny, David ULg; Castronovo, Vincenzo ULg

in Journal of Pathology (The) (2001), 193(1), 80-7

Galectin-1, a member of the beta-galactoside-binding galectin family, is a pleiotropic dimeric protein participating in a variety of normal and pathological processes, including cancer progression ... [more ▼]

Galectin-1, a member of the beta-galactoside-binding galectin family, is a pleiotropic dimeric protein participating in a variety of normal and pathological processes, including cancer progression. Modulation of the interactions with the basement membrane glycoprotein laminin and induction of apoptosis in activated T lymphocytes are well-known functions of this galectin. In this study, the expression of galectin-1 was examined in 148 human primary prostate carcinoma samples. Immunohistochemical staining of paraffin sections of prostate tissues revealed that galectin-1 was not detected in normal, PIN (prostatic intraepithelial neoplasia) or carcinoma cells, but accumulated in the stroma and associated fibroblasts. Galectin-1 expression was significantly increased in the tumour-associated stroma compared with the non-neoplastic gland-associated stroma in 21.3% of the cases (Mantel-Haenszel test, p=0.001; Wilcoxon signed rank test, p<0.0001). Increased galectin-1 expression in the cancer-associated stroma compared to the normal gland-associated stroma (p=0.03) was identified by multivariate analysis as a strong independent predictor of prostate-specific antigen (PSA) recurrence, just after the pathological stage (p<0.0001). The association between accumulation of galectin-1 in the stroma of the malignant tissue and aggressiveness of the tumour adds weight to the body of evidence that identifies a role for galectin-1 in the acquisition of the invasive phenotype. In addition to modulating cancer cell interactions with laminin, galectin-1 accumulated around the cancer cells may act as an immunological shield by inducing activated T-cell apoptosis. This exciting hypothesis warrants further investigation. [less ▲]

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