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See detailIn Vitro and in Vivo Stimulation of the Murine Immune System by Agm-1470, a Potent Angiogenesis Inhibitor
Antoine, Nadine ULg; Daukandt, M.; Heinen, Ernst ULg et al

in American Journal of Pathology (1996), 148(2), 393-8

AGM-1470, a potent angiogenesis inhibitor, is already engaged in phase I clinical trials because of its effectiveness to restrain tumor growth and its lack of major side effects. Recently, we showed that ... [more ▼]

AGM-1470, a potent angiogenesis inhibitor, is already engaged in phase I clinical trials because of its effectiveness to restrain tumor growth and its lack of major side effects. Recently, we showed that AGM-1470 stimulates in vitro human B lymphocyte proliferation through T lymphocytes. These data prompted us to explore the in vivo effects of AGM-1470 on the immune system in a mouse model. In this study, we showed that AGM-1470, in synergy with phytohemagglutinin, stimulates the proliferation of murine lymphocytes isolated from lymph nodes. This effect was similar to the one observed with human lymphocytes. When injected subcutaneously or intraperitoneally into mice at pharmacological doses, AGM-1470 induced a significant increase of axillary and mesenteric lymph nodes, respectively. Histological and morphological analyses showed that this phenomenon is mostly due to a hyperplasia of the germinal centers. On average, the area of the germinal center of lymph nodes from AGM-1470-treated mice were three times larger than in lymph nodes from control mice. Interestingly, no effect was observed when AGM-1470 was injected subcutaneously into T-deficient nude mice. Our data demonstrate that AGM-1470 stimulates B cell proliferation in vivo as suggested by the in vitro experiments. This effect should be taken into account in the follow-up of patients treated with this molecule and calls for additional studies to determine the biological consequences of such a stimulation on the host immune system. [less ▲]

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See detailIncreased Expression of Osteonectin and Osteopontin, Two Bone Matrix Proteins, in Human Breast Cancer
Bellahcene, Akeila ULg; Castronovo, Vincenzo ULg

in American Journal of Pathology (1995), 146(1), 95-100

Microcalcifications are a common phenomenon associated with breast cancer and are often the only mammographic sign of a malignant breast disease. Although microcalcifications are not restricted to breast ... [more ▼]

Microcalcifications are a common phenomenon associated with breast cancer and are often the only mammographic sign of a malignant breast disease. Although microcalcifications are not restricted to breast cancer and can be also associated with benign lesions, it is noteworthy that they are composed exclusively of hydroxyapatite in breast carcinoma. Hydroxyapatite is the bone-associated phosphocalcic crystal the deposition of which in bone tissue requires the coordinated expression of several molecules such as osteonectin (OSN) and osteopontin (OPN), synthesized by cells of the osteoblastic lineage. In this study, we evaluated the expression of these two bone matrix proteins, using an immunoperoxidase technique and specific antibodies, in 79 breast lesions including 28 benign and 51 cancerous specimens. We found that normal mammary tissue associated with the lesions examined expressed generally undetectable or lightly detectable (0 or 1+) amounts of OSN and OPN (92 and 81%, respectively). Benign breast lesions, including fibroadenoma and fibrocystic dysplasia, were generally weakly stained (0 or 1+) with both anti-OSN and anti-OPN antibodies (96.4 and 60.7%, respectively). Interestingly, the majority of both in situ and invasive breast carcinoma lesions showed a strong expression (2+ or 3+) for OSN or OPN (74.5 and 84.3%, respectively). High expression of these two bone matrix proteins was associated with frequent microcalcification deposition in the lesion. This study is the first extensive study of OSN and OPN expression in mammary cancers. Our data suggest that OSN and OPN could play a role in the formation of ectopic microcalcifications often associated with breast cancer. It is also tempting to speculate that the expression of these two glycoproteins by breast cancer cells play a role in the preferred bone homing of breast metastases. [less ▲]

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See detailInhibition of growth of normal and human papillomavirus-transformed keratinocytes in monolayer and organotypic cultures by interferon-gamma and tumor necrosis factor-alpha.
Delvenne, Philippe ULg; al-Saleh, W.; Gilles, Christine ULg et al

in American Journal of Pathology (1995), 146(3), 589-98

The growth response of normal and human papillomavirus (HPV)-transformed cervical keratinocytes to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha was investigated in monolayer and ... [more ▼]

The growth response of normal and human papillomavirus (HPV)-transformed cervical keratinocytes to interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha was investigated in monolayer and organotypic raft cultures. The proliferation rates of monolayer cultures were assessed by [3H]TdR incorporation and fluorimetric DNA titration. The growth of keratinocytes in organotypic cultures was estimated by their ability to stratify on collagen rafts and by immunohistochemistry for Ki67 antigen expression. IFN-gamma reduced the DNA synthesis of normal and HPV-transformed keratinocytes in monolayer cultures and exerted a marked growth inhibitory effect in organotypic raft cultures. In control raft cultures, normal keratinocytes produced an epithelial sheet of approximately 10 cells in thickness that closely resembled normal cervical epithelium and was characterized by sparse Ki67 antigen-positive cells whereas HPV-transformed keratinocytes produced up to 15 poorly differentiated epithelial layers that were reminiscent of high grade cervical lesions seen in vivo and exhibited a full thickness Ki67 antigen expression. When normal and HPV-transformed keratinocytes were maintained in the presence of IFN-gamma, the epithelial sheet was reduced to a few cells in thickness and the density of Ki67 antigen-positive cells was decreased. A more pronounced growth inhibitory effect in monolayer and organotypic cultures was observed when IFN-gamma was associated with tumor necrosis factor-alpha Tumor necrosis factor-alpha alone reduced the DNA synthesis of normal keratinocytes but was significantly less effective than IFN-gamma to inhibit the growth of HPV-transformed keratinocytes. These results suggest that similar responses in vivo to regulatory molecules may play a role in the development of HPV-related lesions. [less ▲]

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See detailDetection of laminin receptor mRNA in human cancer cell lines and colorectal tissues by in situ hybridization.
Campo, E.; Monteagudo, C.; Castronovo, Vincenzo ULg et al

in American Journal of Pathology (1992), 141(5), 1073-83

The 67-kd high-affinity laminin receptor (67 LR) is a gene product whose expression appears to be associated with the invasive and metastatic phenotype of a variety of human cancer cells. Northern blot ... [more ▼]

The 67-kd high-affinity laminin receptor (67 LR) is a gene product whose expression appears to be associated with the invasive and metastatic phenotype of a variety of human cancer cells. Northern blot hybridization has been routinely used to quantify the level of 67 LR mRNA from total cellular RNA extracts of homogenized tissue specimens or in vitro grown cell populations. This technique is useful to assess the average expression of the 67 LR mRNA of a particular sample but does not provide information about expression in specific cell types nor about heterogeneity of expression from cell to cell. In this study, we analyzed the expression of 67 LR mRNA in four human cancer cell lines with varying degrees of expression of 67 LR protein (renal cancer A-704, breast carcinoma MCF-7/4 and MCF-7/7, and pancreatic cancer Panc-1) using in situ hybridization performed with 67 LR riboprobes. Total cellular RNA was simultaneously extracted from the cell lines and hybridized on Northern blots with a 67 LR cDNA probe to assess the validity of the mRNA detection by in situ hybridization. Sixty-seven LR mRNA expression was higher in Panc-1 and MCF-7/4 cells than in MCF-7/7 and renal carcinoma A-704. There was a direct correlation (R2 = 0.88) between the in situ hybridization analysis and the mRNA levels detected by Northern blot analysis. The in situ hybridization method showed a heterogeneous expression of the 67 LR mRNA in the four cell lines with different subpopulations of cells showing a range from negative to high levels of the message. Sixteen freshly frozen human colorectal tissues (seven adenocarcinomas, five matched normal mucosae, and four adenomas) were also analyzed by in situ hybridization. The 67 LR mRNA was localized in normal and neoplastic epithelial cells. Adenocarcinoma cells showed a 1.6- to 5-fold higher expression (P < 0.02 according to the Wilcoxon-Mann-Whitney test) than did epithelial colonic cells from normal mucosae or adenomas. The signal tended to be stronger in poorly differentiated carcinomas and carcinomas with metastases than in moderately differentiated and nonmetastatic tumors. We conclude that the high expression of 67 LR mRNA in colorectal tumors is due to an increased production by tumor cells. Furthermore, in situ hybridization is an effective method to detect the expression of LR mRNA in cultured cell lines as well as in frozen tissue sections. [less ▲]

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See detailA histologic study of the extracellular matrix during the development of glomerulosclerosis in murine chronic graft-versus-host disease.
Bergijk, E. C.; Munaut, Carine ULg; Baelde, J. J. et al

in American Journal of Pathology (1992), 140(5), 1147-56

The development of glomerulosclerosis was studied in murine chronic graft-versus-host disease (GvHD), which is a model for human systemic lupus erythematosus. The authors investigated the distribution ... [more ▼]

The development of glomerulosclerosis was studied in murine chronic graft-versus-host disease (GvHD), which is a model for human systemic lupus erythematosus. The authors investigated the distribution patterns of six components of the extracellular matrix (ECM), i.e., laminin, fibronectin, collagen types I, III, IV, and VI during the course of the disease. All of these ECM components except collagen type I were found in the glomeruli of normal mice, where all of them were intrinsic constituents of the mesangium. Laminin, fibronectin, and collagen type IV were also found in the glomerular capillary walls. Starting 6 weeks after the induction of GvHD and continuing at week 8, the onset of an expansion of the mesangial matrix was observed. At the same time, the amounts of laminin, fibronectin, and collagen types IV and VI increased. Ten weeks after the onset of the disease, glomerulosclerosis developed. Traces of the interstitial collagen type I were found in sclerotic glomeruli. The levels of four ECM components, i.e., collagens III, IV, VI, and laminin were markedly decreased in the sclerotic glomeruli as compared with week 8. In contrast, the amount of fibronectin in the sclerotic glomeruli increased dramatically. Immunoelectron microscopic examination showed fibronectin in the sclerotic lesions, in contrast to laminin, collagen type I, and collagen type IV. It is concluded that the sclerotic lesions in murine chronic GvHD contain fibronectin. The small amounts of the ECM components laminin, as well as collagens III, IV, and VI in the sclerotic glomeruli in GvHD, might represent remnants of mesangial material and collapsed capillary walls. These components are probably replaced by increased production and/or accumulation of collagen type I and fibronectin. [less ▲]

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See detailImmunodetection of the metastasis-associated laminin receptor in human breast cancer cells obtained by fine-needle aspiration biopsy.
Castronovo, Vincenzo ULg; Colin, Claude; Claysmith, A. P. et al

in American Journal of Pathology (1990), 137(6), 1373-81

Fine-needle aspiration biopsy of the breast is a very useful technique for the evaluation of a suspect lesion before surgical removal. Increased expression of the 67-kd laminin receptor has been ... [more ▼]

Fine-needle aspiration biopsy of the breast is a very useful technique for the evaluation of a suspect lesion before surgical removal. Increased expression of the 67-kd laminin receptor has been associated with the metastatic phenotype of cancer cells, particularly in colon and breast cancers. In this study, the expression of laminin receptor was evaluated using the immunoperoxidase technique in 81 breast aspirates (26 benign and 55 neoplastic lesions). Cells obtained from benign samples exhibited a low level of laminin receptor antigen detected by affinity-purified antibody raised against a cDNA-derived laminin receptor peptide. In contrast, 71% of smears obtained from malignant breast lesions contained cells that were strongly stained by the antibody. Heterogeneous expression of the laminin receptor was noted in both breast aspirates and fixed tissue specimens. These data suggest that the immunodetection of laminin receptor in cells obtained by fine-needle aspiration of breast lesions could be a valuable adjunct in the prognostic evaluation of breast lesions. [less ▲]

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See detailRelationship between interphasic nucleolar organizer regions and growth rate in two neuroblastoma cell lines.
Derenzini, M.; Pession, A.; Farabegoli, F. et al

in American Journal of Pathology (1989), 134(4), 925-32

The relationship between the quantity of silver-stained interphasic nucleolar organizer regions (NORs) and nuclear synthetic activity, caryotype, and growth rate was studied in two established ... [more ▼]

The relationship between the quantity of silver-stained interphasic nucleolar organizer regions (NORs) and nuclear synthetic activity, caryotype, and growth rate was studied in two established neuroblastoma cell lines (CHP 212 and HTB 10). Statistical analysis of silver-stained NORs revealed four times as many in CHP 212 cells compared with HTB 10 cells. No difference was observed in the ribosomal RNA synthesis between the two cell lines. The caryotype index was 1.2 for CHP 212 and 1.0 for HTB 10 cells. The number of chromosomes carrying NORs and the quantity of ribosomal genes was found to be the same for the two cell lines. Doubling time of CHP 212 cells was 20 hours compared with 54 hours for HTB 10 cells. In CHP 212 cells bindering of cell duplication by serum deprivation induced a progressive lowering (calculated at 48, 72, and 96 hours) of the quantity of silver-stained interphasic NORs. Recovery of duplication by new serum addition induced, after 24 hours, an increase of the quantity of silver-stained interphasic NORs up to control levels. In the light of available data, these results indicate that the quantity of interphasic NORs is strictly correlated only to the growth rate of the cell. [less ▲]

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See detailMultiple peroxysomal deficiency syndromes: a comparative and multidisciplinary study in Zellweger and Neonatal Adrenoleukodystrophy patients
Vamecq, Joseph; Draye, J. P.; Van Hoof, François et al

in American Journal of Pathology (1986), 125

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See detailMultiple peroxysomal deficiency syndromes: a comparative and multidisciplinary study in Zellweger and Neonatal Adrenoleukodystrophy patients
Vamecq, Joseph; Draye, J. P.; Van Hoof, François et al

in American Journal of Pathology (1986), 125

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See detailDistribution of basement membrane antigens in glomeruli of mice with autoimmune glomerulonephritis.
Matsuo, S.; Brentjens, J. R.; Andres, G. et al

in American Journal of Pathology (1986), 122(1), 36-49

Glomerulonephritis was induced in mice by the repeated injection of human glomeruli or purified glomerular basement membrane. The glomerular basement membranes of nephritic animals were observed to ... [more ▼]

Glomerulonephritis was induced in mice by the repeated injection of human glomeruli or purified glomerular basement membrane. The glomerular basement membranes of nephritic animals were observed to develop subepithelial extensions, "spikes." Although normally Type IV collagen is found throughout the full thickness of basement membranes, the "spikes" reacted with antibodies to laminin but not with antibodies to Type IV collagen. It is proposed that in murine autoimmune glomerulonephritis, the visceral epithelial cells produce an excess of laminin. [less ▲]

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See detailAbortion in mice induced by intravenous injections of antibodies to type IV collagen or laminin.
Foidart, Jean-Michel ULg; Yaar, M.; Figueroa, A. et al

in American Journal of Pathology (1983), 110(3), 346-57

Purified antibodies to laminin or Type IV collagen administered intravenously to pregnant mice were found to localize in the basement membranes of all maternal tissues as well as the parietal and visceral ... [more ▼]

Purified antibodies to laminin or Type IV collagen administered intravenously to pregnant mice were found to localize in the basement membranes of all maternal tissues as well as the parietal and visceral yolk sacs and trophoblast basement membranes but not in embryonic tissues. Antibodies to Type IV collagen induced a higher incidence of abortions, retroplacental hematomas and fetal deaths. When administered intraamniotically, both antiserums were embryotoxic. The functional consequences of the attachment of antibodies to these specific basement membrane antigens appear to be hemorrhage within the parietal and visceral yolk sacs and separation of fetal from maternal tissues. Complement activation appears to play an important role in the interruptions of pregnancy, because this was not observed in strains of mice lacking C5, the fifth component of complement, in mice depleted of C3 by administration of cobra venom factor, or in mice injected with the F(ab) fragments of antibody to Type IV collagen or laminin. [less ▲]

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See detailIron Kinetics with emphasis on Iron overload
Cook, J. D.; Barry, W. E.; Hershko, C. et al

in American Journal of Pathology (1973), 72

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