References of "Castronovo, Vincenzo"
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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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See detailSodium butyrate and trichostatin A induce growth arrest and apoptosis in breast cancer cells while normal breast epithelial cells are unaffected
Locigno, Roberto; Waltregny, David ULg; Verheyen, Véronique et al

Conference (2001, January)

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See detailDetection of the 67-kD laminin receptor in prostate cancer biopsies as a predictor of recurrence after radical prostatectomy.
Waltregny, David ULg; De Leval, Laurence ULg; Coppens, Luc ULg et al

in European Urology (2001), 40(5), 495-503

OBJECTIVES: Reliable prognostic indicators are needed for a better pretherapeutic assessment of the agressiveness of organ-confined prostate cancer (PC) lesions. The 67-kD laminin receptor (67LR) is a ... [more ▼]

OBJECTIVES: Reliable prognostic indicators are needed for a better pretherapeutic assessment of the agressiveness of organ-confined prostate cancer (PC) lesions. The 67-kD laminin receptor (67LR) is a cell-surface-associated protein involved in the acquisition of the invasive and metastatic phenotype of a variety of human cancer cell types. We have previously shown that 67LR detection in PC tissues from radical prostatectomy (RP) specimens is an independent predictor of biochemical (PSA) relapse in patients with clinically localized PC. In this study, we assessed 67LR detection in diagnostic PC biopsies as a predictor of biochemical relapse after RP. METHODS: Diagnostic biopsy and subsequent RP tissue specimens from 151 patients with clinically localized PC were immunohistochemically analyzed for 67LR expression. The level of 67LR expression was evaluated by both intensity and extent of the staining. Clinicopathological preoperative and postoperative parameters, including 67LR expression, were correlated with each other and tested as predictors of biochemical relapse. RESULTS: 67LR was detected in 67.5 and 68.2% of biopsies and RPs, respectively. 67LR detection in RP specimens was an independent predictor of relapse. The level of 67LR expression in the biopsy was significantly associated with the biopsy Gleason score (p<0.05) but failed to predict the pathological stage (p>0.1). Biochemical progression-free estimates for patients whose biopsy did or did not express the protein differed with only borderline statistical significance (p = 0.05). Multivariate analysis identified biopsy Gleason score as the only independent preoperative predictor of recurrence. Significant discrepancies in levels of 67LR expression were found between matched biopsy and RP specimens (p<0.05), with exact agreement rates <40%. CONCLUSIONS: 67LR detection in PC biopsies was not a significant preoperative predictor of outcome after RP. Heterogeneity of 67LR expression and biopsy sampling errors most likely represented the main reasons for discordant results between biopsy and RP specimens. [less ▲]

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See detailSodium butyrate and trichostatin-a induce apoptosis in human breast cancer cells but not in normal human mammary epithelial cells
Locigno, Roberto; Henno, Audrey ULg; Waltregny, David ULg et al

in Proceedings of the American Association for Cancer Research (2001), 42

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See detailBone Sialoprotein Mrna and Protein Expression in Human Multiple Myeloma Cell Lines and Patients
Bellahcene, Akeila ULg; Van Riet, I.; de Greef, C. et al

in British Journal of Haematology (2000), 111(4), 1118-21

Bone sialoprotein (BSP) is a glycoprotein essentially found in mineralizing connective tissues. We have recently demonstrated that BSP is ectopically expressed by carcinomas that metastasize to bone with ... [more ▼]

Bone sialoprotein (BSP) is a glycoprotein essentially found in mineralizing connective tissues. We have recently demonstrated that BSP is ectopically expressed by carcinomas that metastasize to bone with high frequency. Multiple myeloma (MM) is characterized by the localization of tumour plasma cells in the bone marrow. In this study, BSP expression was evaluated in human myeloma cell lines and in bone marrow aspirates and one ascites fluid from MM patients. BSP was detectable in conditioned media of MM cell lines. Using FACS analysis and in situ hybridization, we demonstrated that tumour cells from all MM patients and cell lines analysed express BSP at both the protein and the mRNA level. [less ▲]

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See detailAlteration of the Cytoplasmic/Nuclear Expression Pattern of Galectin-3 Correlates with Prostate Carcinoma Progression
van den Brule, Frédéric; Waltregny, David ULg; Liu, Fu Tong et al

in International Journal of Cancer = Journal International du Cancer (2000), 89(4), 361-7

Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in a variety of biological events including interactions with galactose-containing glycoconjugates, cell proliferation ... [more ▼]

Galectin-3, a member of the beta-galactoside-binding lectin family, is involved in a variety of biological events including interactions with galactose-containing glycoconjugates, cell proliferation, differentiation and apoptosis. Galectin-3 appears to intervene during tumor progression and altered expression patterns have been reported in a variety of malignancies. In our study, we have examined the expression of galectin-3 in a population of 145 prostate carcinoma samples using immunohistochemistry. We found that most of the non-tumoral prostatic glands exhibited moderate immunostaining for galectin-3 localized in both nucleus and cytoplasm. In prostatic cancer cells, galectin-3 was usually not expressed or decreased compared with the normal glands. Interestingly, when galectin-3 was detected in the cancer cells, it was consistently excluded from the nucleus and only present in the cytoplasmic compartment. The latter observation was also made for prostatic intraepithelial neoplasia (PIN) cells. Furthermore, we found that the levels of galectin-3 expression in the cancer cells were significantly associated with prostate-specific antigen (PSA) relapse in univariate analysis (p = 0.044). Cytoplasmic expression of galectin-3 in the carcinoma cells was an independent predictor of disease progression in multivariate analysis, after the pathological stage and the Gleason score. Our data demonstrate that galectin-3 is generally down-regulated in human prostate carcinoma cells, and consistently excluded from the nucleus. Interestingly, specific cytoplasmic expression of galectin-3 in a subset of lesions is associated with disease progression. These results suggest that galectin-3 might play anti-tumor activities when present in the nucleus, whereas it could favor tumor progression when expressed in the cytoplasm. Further studies should determine the exact role and mechanisms by which galectin-3 differentially affects cell behavior in the different locations where it is expressed. [less ▲]

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See detailIncreased Expression of Bone Sialoprotein in Bone Metastases Compared with Visceral Metastases in Human Breast and Prostate Cancers
Waltregny, David ULg; Bellahcene, Akeila ULg; de Leval, Xavier et al

in Journal of Bone and Mineral Research (2000), 15(5), 834-43

The recent demonstration that bone sialoprotein (BSP) is expressed in osteotropic cancers suggests that this bone matrix protein might be implicated in the preferential seed and growth of metastatic cells ... [more ▼]

The recent demonstration that bone sialoprotein (BSP) is expressed in osteotropic cancers suggests that this bone matrix protein might be implicated in the preferential seed and growth of metastatic cells in bone. High expression of BSP in breast and prostate primary carcinomas is associated with progression and bone metastases development. The exact mechanisms by which BSP may favor bone metastases formation are not clearly established yet. Although BSP expression has been detected in breast, prostate, lung, thyroid, and neuroblastoma primary tumors, no information regarding its expression in metastases is available to date. In this study, we have examined BSP expression in 15 bone and 39 visceral metastatic lesions harvested from 8 breast cancer patients and 7 prostate cancer patients who died of disseminated disease. We were able to retrieve the primary lesions from 5 of the 8 breast cancer patients as well as from all 7 prostate cancer patients. All the primary breast tumor patients and 5 of the 7 primary prostate cancer patients expressed a detectable level of BSP. Bone metastases from all 8 breast cancer patients and from 5 out of 7 prostate cancer patients exhibited detectable levels of the protein. Metastatic cells in close contact with bone trabeculae usually were highly positive for BSP. BSP also was detected in secondary lesions developed at visceral sites including liver, thyroid, lung, and adrenal glands. However, BSP expression was significantly lower in visceral metastases than in skeletal ones (Mann-Whitney test, p < 0.05). Our data represent the first demonstration of an increased expression of BSP in bone metastases compared with nonskeletal metastases in human breast and prostate cancers and add weight to the body of evidence attributing a significant role to this protein in the genesis of bone metastases. [less ▲]

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See detailBone Sialoprotein Mediates Human Endothelial Cell Attachment and Migration and Promotes Angiogenesis
Bellahcene, Akeila ULg; Bonjean, K.; Fohr, B. et al

in Circulation Research (2000), 86(8), 885-91

Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in sites of biomineralization. Recently, we demonstrated that BSP is strongly upregulated in osteotropic cancers and particularly those ... [more ▼]

Bone sialoprotein (BSP) is a secreted glycoprotein primarily found in sites of biomineralization. Recently, we demonstrated that BSP is strongly upregulated in osteotropic cancers and particularly those that exhibit microcalcifications. BSP contains an Arg-Gly-Asp (RGD) motif found in other adhesive molecules that interact with cellular integrins. In bone, BSP has been shown to mediate the attachment of osteoblasts and osteoclasts via alpha(v)beta(3) integrin receptors. Ligands for alpha(v)beta(3) integrin are considered to play a central role during angiogenesis. Therefore, we used human umbilical vein endothelial cells (HUVECs) to study the potential role of BSP in angiogenesis. We found that purified eukaryotic recombinant human BSP (rhBSP) is able to promote both adhesion and chemotactic migration of HUVECs in a dose-dependent manner. These interactions involve HUVEC alpha(v)beta(3) integrin receptors and the RGD domain of BSP. Indeed, HUVECs attach to a recombinant BSP fragment containing the RGD domain, whereas this response is not observed with the same fragment in which RGD has been mutated to Lys-Ala-Glu (KAE). A cyclic RGD BSP peptide inhibits both adhesion and migration of HUVECs to rhBSP. Moreover, anti-alpha(v)beta(3) but not anti-alpha(v)beta(5) monoclonal antibodies also prevent BSP-mediated adhesion and migration of HUVECs. We observed that both rhBSP and the RGD BSP recombinant fragment stimulated ongoing angiogenesis on the chorioallantoic chick membrane assay. BSP angiogenic activity was inhibited by anti-alpha(v)beta(3) antibody, and the KAE BSP fragment was inactive. Our findings represent the first report implicating BSP in angiogenesis. BSP could play a critical role in angiogenesis associated with bone formation and with tumor growth and metastatic dissemination. [less ▲]

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See detailCombined Interferon-Gamma and Tumor Necrosis Factor-Alpha Treatment Differentially Affects Adhesion and Migration of Keratinocyte-Derived Cells to Laminin-1
van den Brule, Frédéric A; Clausse, Nathalie; Delvenne, Philippe ULg et al

in Cell Adhesion and Communication (2000), 7(4), 321-9

Interactions with the extracellular matrix constitute basic steps in cervix carcinoma cell invasion. In this study, we examined the adhesion and migration profiles of two human papillomavirus (HPV) DNA ... [more ▼]

Interactions with the extracellular matrix constitute basic steps in cervix carcinoma cell invasion. In this study, we examined the adhesion and migration profiles of two human papillomavirus (HPV) DNA-transfected keratinocyte-derived cell lines, EIL8 and 18-11S3, and of the cervix adenocarcinoma SiHa cell line, towards laminin-1, and the selective effect of a 24-72 h treatment of 1000 U/ml interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), a treatment that significantly decreases cervix carcinoma cell proliferation and progression in nude mice, on these parameters. Compared to normal cervix keratinocytes (CK) and two HPV DNA-transfected keratinocyte cell lines, in basal conditions, the SiHa cell line was characterized by increased attachment (SiHa, 48.74 +/- 4.02 vs. normal keratinocytes, 4.32 +/- 0.40, EIL8, 17.80 +/- 3.03 and 18-11S3, 17.82 +/- 1.48% of attached cells after 30 min) and marked directed chemotactic migration towards laminin-1. Interestingly, treatment of the cells with the cytokines (1000 U/ml IFN-gamma and TNF-alpha) did not modulate the adhesion properties of the cells, but chemotactic migration of SiHa cells to laminin-1 was significantly decreased, while migration towards type I collagen was increased. Similar results were obtained with the Ca Ski cervix carcinoma cell line. Our results emphasize the altered pattern of interactions of cervix carcinoma cells with extracellular matrix components such as laminin-1, compared to normal and pre-neoplastic cells, and contributes to the understanding of the effects of cytokine treatment on cervix carcinoma cells. [less ▲]

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See detailTnp-470, a Potent Angiogenesis Inhibitor, Amplifies Human T Lymphocyte Activation through an Induction of Nuclear Factor-Kappab, Nuclear Factor-at, and Activation Protein-1 Transcription Factors
Locigno, Roberto; Antoine, Nadine ULg; Bours, Vincent ULg et al

in Laboratory Investigation : Journal of Technical Methods & Pathology (2000), 80(1), 13-21

TNP-470, an angiogenesis inhibitor derived from fumagillin, is foreseen as a promising anti-cancer drug. Its effectiveness to restrain tumor growth and its lack of major side effects have been ... [more ▼]

TNP-470, an angiogenesis inhibitor derived from fumagillin, is foreseen as a promising anti-cancer drug. Its effectiveness to restrain tumor growth and its lack of major side effects have been demonstrated in several animal models and have led the drug to reach phase III clinical trials. Beside its antiangiogenesis activities, TNP-470 exhibits several effects on the immune system. We had shown previously that TNP-470 stimulated B lymphocyte proliferation through an action on T cells. In this study, we examined the cellular and molecular modifications induced by TNP-470 in normal human T lymphocytes. Transmission electron microscopic examination of PHA/TNP-470-treated T cells revealed significant morphologic modifications when compared with PHA-treated control T cells. TNP-470 induced indeed an important and significant increase of the nuclear size as well as major nuclear chromatin decondensation. This observation indicated that TNP-470 amplified T-cell activation and led us to investigate its effects on the activation of transcription factors involved in T-cell activation. Using electrophoretic mobility shift assays, we have demonstrated that TNP-470 amplifies and extends the DNA-binding activity of nuclear factor-AT, nuclear factor-KB, and activation protein-1 in T cells. Furthermore, the angioinhibin significantly increased the secretion of IL-2 and IL-4. Our data demonstrate that TNP-470 amplifies the activation of T cells. This effect, whose molecular mechanisms remain to be elucidated, has to be taken into account in the assessment of the antitumor effect of the drug. [less ▲]

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See detailDetection of the 67-kD laminin receptor in prostate cancer biopsies as a predictor of recurrence after radical prostatectomy
Waltregny, David ULg; de Leval, Laurence ULg; Coppens, Luc ULg et al

Conference (2000)

INTRODUCTION & OBJECTIVES: The identification of reliable prognostic indicators for prostate cancer (PC) is a major challenge of today cancer research. The 67-KD laminin receptor (67LR) is a cell surface ... [more ▼]

INTRODUCTION & OBJECTIVES: The identification of reliable prognostic indicators for prostate cancer (PC) is a major challenge of today cancer research. The 67-KD laminin receptor (67LR) is a cell surface associated molecule whose increased expression is associated with the aggressiveness of a variety of human cancers. We recently showed that 67LR detection in PC tissues from radical prostatectomy (RP) specimens was an independent predictor of biochemical relapse in patients with clinically localized PC (JNCI, 89:1224-1227, 1997). In this study, we assessed 67LR detection in diagnostic biopsies as a predictor of biochemical relapse after RP. MATERIAL & METHODS: A total of 151 patients with clinically confined PC underwent RP. PC tissue sections from both biopsy and RP specimens were immunohistochemically analyzed for 67LR expression. The importance of 67LR expression was evaluated according to the intensity and extent of the staining. Preoperative and postoperative clinicopathological parameters, including 67LR expression, were correlated with each other and tested as predictors of biochemical relapse. RESULTS: 67LR was detected in 67.5% and 68.2% of biopsies and RPs, respectively. 67LR detection in RP specimens was an independent predictor of relapse. The level of 67LR expression in the biopsy was significantly associated with the biopsy Gleason score (p<0.05) but failed to predict the pathological stage (p>0.1). Biochemical progression-free estimates for patients whose biopsy did or did not express the protein differed with only borderline statistical significance (p=0.05). Multivariate analysis identified biopsy Gleason score as the only independent preoperative predictor of recurrence. Significant discrepancies in levels of 67LR expression were found between matched biopsy and RP specimens, with exact agreement rates <40% (p<0.05). CONCLUSIONS: 67LR detection in PC biopsies was not a significant preoperative predictor of outcome after RP. Heterogeneity of 67LR expression and biopsy sampling errors most likely represented the main raisons for discordant prognostic results depending on whether 67LR expression was evaluated either in biopsies or in RPs. [less ▲]

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