Flavonoids inhibit malignant tumor invasion in vitro.
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Animals↗
Biomedical subjects
V Castronovo
Publications and source records attributed to V Castronovo.
Perfusion of human umbilical veins. A new approach to study the interactions of circulating malignant cells with vascular wall and their modulations.
Interactions of malignant or non-malignant human and rodent cells with the vascular wall were studied using perfused human umbilical cord veins. The integrity of perfused endothelium was confirmed by morphological and functional criteria. Highly malignant cells in vivo adhered to the endothelial cells, as shown by scanning electron microscopy. The specific attachment of radiolabelled malignant cells to the whole vein was already maximal within 30-60 min and remained stable for perfusion flow rates ranging between 10 and 60 ml/min. It increased proportionally to the number of cells infused and could be modulated by human platelets, human fibronectin and rabbit anti-laminin antibodies. In contrast, the binding of human or rodent non-malignant cells in vivo, of human red blood cells and of human platelets to the endothelial cells was negligible under similar experimental conditions. This perfusion system therefore represents a new model for elucidating some mechanisms involved in tumour cell arrest in vivo.
Cell Adhesion↗
[Study of the role of laminin in tumor invasion].
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Animals↗
The anti-invasive flavonoid (+)-catechin binds to laminin and abrogates the effect of laminin on cell morphology and adhesion.
To study the effect of the flavonoid (+)-catechin on cell-matrix interactions two cell types with a different morphology on and adhesion to laminin were used. MO4 virally transformed fetal mouse cells adhere and spread when cultured on top of laminin-coated coverslips or on human amnion basement membrane. M5076 mouse reticulum cell sarcoma cells poorly adhere to these substrates and remain round. Both cell types are invasive in confronting cultures with embryonic chick heart fragments. (+)-Catechin binds to laminin in a pH-dependent way. Pretreatment of laminin-coated coverslips or amnion basement membrane with 0.5 mM (+)-catechin abrogates the effect of laminin on cell morphology and adhesion. MO4 cells do not adhere to the pretreated substrates and remain round, while M5076 cells now adhere and spread. (+)-Catechin inhibits the invasion of MO4 cells but not of M5076 cells into embryonic chick heart in vitro. We speculate that the anti-invasive activity of the flavonoid to MO4 cells is the result of its interference with MO4 cell adhesion to laminin. Invasion of M5076 cells does not imply adhesion to and spreading on laminin.
Animals↗
Interactions between fibroblasts and a reconstituted basement membrane matrix.
A gel-like reconstituted basement membrane matrix containing type IV collagen, laminin, entactin, nidogen, and heparan sulfate proteoglycan was used to examine the interactions between normal calf skin fibroblasts and basement membranes. Within 6 h after seeding, fibroblasts initiated a migration that resulted in the formation of a cellular network after 1 day of culture on top of the gel. Electron microscopy revealed that fibroblasts were able to remodel the basement membrane matrix by penetrating into the gel (from day 3), depositing fibronectin and collagen fibers, and retracting this extracellular matrix. Fibroblasts cultured on the Engelbreth-Holm-Swarm reconstituted basement membrane matrix displayed ultrastructural features characterized by a poor synthetic apparatus (rough endoplasmic reticulum and Golgi vesicles), a large cytoskeleton, and intracytoplasmic vesicles containing laminin. Thus the reconstituted basement membrane matrix is remodeled by skin fibroblasts, and reciprocally their ultrastructural morphologic features are affected by this matrix.
Animals↗
Human anti-alpha-galactosyl IgG reduces the lung colonization by murine MO4 cells.
The lung colonization of MO4 cells, a highly malignant murine cell line, is strongly reduced in syngeneic C3H/He mice by a prior incubation with anti-alpha-galactosyl antibody (alpha-Gal Ab), a natural IgG antibody present in high titers in all normal human sera and specifically recognizing Gal alpha(1----3) structures (alpha-D-galactopyranosyl; alpha-D-Galp). The protective effect is due to a binding of alpha-Gal Ab to alpha-D-Galp end groups of MO4 cells, inducing both an increase in their sequestration into the liver and the spleen and a decrease in their sequestration into the lung. The F(ab')2 fragments of this antibody also exhibit a protective effect by inhibiting the homing of MO4 cells into the lung, without modifying their accumulation into the spleen and the liver. Since both the antibody and the alpha-galactosidase pretreatments of MO4 cells block their subsequent attachment to murine laminin in vitro, we suggest that, in this model, the lung colonization may be dependent on the alpha-D-Galp end groups exposed on the surface of MO4 cells.
Animals↗
Circadian CEA variability: when to sample.
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Carcinoembryonic Antigen↗
Flavonoids: tools for the study of tumor invasion in vitro.
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Animals↗
[Respiratory infections and disorders of muco-ciliary clearance].
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Cilia↗
Arrest of MCF-7 cell migration by laminin in vitro: possible mechanisms.
Laminin, a major basement membrane component, arrested the migration of MCF-7/AZ human breast adenocarcinoma cells that were not invasive in vitro. Migration of invasive MCF-7/6 cells was not affected by laminin. Both cell types expressed the 67 kD laminin receptor, at both mRNA and protein level, but did not express the alpha 6 subunit of the VLA-6 integrin-type laminin receptor. The presence of YIGSR peptides (100 micrograms/ml), reported to block the interaction between laminin and its 67 kD receptor, did not change the migratory response of MCF-7/AZ or MCF-7/6 cells when meeting laminin lanes. In addition, the migration of these cell types was not affected by the presence of 17-beta-estradiol (10(-6) M) or all-trans retinoic acid (10(-6) M), which were both reported to increase the number of 67 kD receptors. We could therefore not assign an involvement of the 67 kD receptors in migration of MCF-7 cells on laminin, nor did we find evidence that conditioned medium of MCF-7/6 cells contains factors that are able to initiate migration of MCF-7/AZ cells on laminin.
Adenocarcinoma↗
Changes in the distribution pattern of galectin-1 and galectin-3 in human placenta correlates with the differentiation pathways of trophoblasts.
Human placentation is a complex biological phenomenon that results from precisely regulated interactions between cells and the extracellular matrix. Galectin- 1 and galectin-3 belong to a newly defined family of galactose-binding lectins that can bind several glycoconjugates such as the basement membrane glycoprotein laminin, and are involved in many biological events including cell adhesion. In this study, the expression of these two galectins in first and third trimester normal human placenta was examined using single and double immunohistochemical staining and specific antibodies for galectins and cytokeratins. Galectin-3 was detected in all trophoblastic lineages including villous cytotrophoblasts and extravillous trophoblasts (trophoblastic cell columns, infiltrating trophoblasts, endovascular trophoblasts and placental bed giant cells). On the contrary, galectin-1 distribution was restricted to endometrium. A reduction of galectin-3 expression was observed from the villous trophoblasts to the trophoblastic cell columns. This pattern correlated with the switch from a proliferative to a migratory phenotype. Galectin-1 and galectin-3 were both detected in maternal decidual cells. Our data demonstrate a specific pattern of galectin-1 and galectin-3 expression in trophoblastic tissue, and suggest these lectins could contribute to cell-cell and cell matrix interactions of trophoblast during placentation.
Antigens, Differentiation↗
The potent angioinhibin AGM-1470 stimulates normal but not human tumoral lymphocytes.
BACKGROUND: AGM-1470 is a newly synthesized molecule developed as an analog of the potent anti-angiogenic fumagillin. Its efficacy in restraining tumor growth in vivo and the absence of major side effects have already led to phase I clinical trials in patients with solid cancers. However, neither the exact mechanisms of action of AGM-1470 nor its effects on the host of normal cells have been extensively studied. Recently, we showed that AGM-1470 enhanced the proliferation of B lymphocytes in the presence of T cells. Since AGM-1470 could potentially be used in patients with lymphoma, it was urgent to test the effect of the molecule on the proliferation of tumor lymphocytes. METHODS: The possible effect of AGM-1470 on the proliferation of normal or tumor lymphocytes was evaluated by thymidine-incorporated assays. Normal T and B lymphocytes were purified from human tonsils. The tumor lymphocytes used in the study were Molt 3, Molt 4 and Jurkatt cell lines for the T lineage and Daudi and Radji cell lines for the B lineage. RESULTS: As shown previously, AGM-1470 stimulates the proliferation of normal B lymphocytes through an action on normal T cells. THe angioinhibin was ineffective ont eh proliferation of both T and B transformed cells. Moreover, in the presence of the drug, tumor T cells co-cultured with normal B lymphocytes did not induce any increase in B cell proliferation, as previously observed with normal T lymphocytes. Inversely, tumor B cells co-cultured with normal T lymphocytes were insensitive to the drug. CONCLUSIONS: Our results demonstrate that AGM-1470 is ineffective on lymphoid tumor cell proliferation and could potentially be safely administered to lymphoma patients.
Antibiotics, Antineoplastic↗
[Lipids, depression and suicide].
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) differentiates polyunsatured omega 3 fatty acids (for example: alpha-linolenic acid or alpha-LNA) and polyunsatured omega 6 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 omega 3 are present in linseed oil, nuts, soya beans, wheat and cold water fish whereas omega 6 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 functioning, 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 3 fatty acids contained in fish, game and vegetables have been largely replaced by polyunsatured omega 6 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 may be associated with a significant increase of total cholesterol. CHOLESTEROL AND SUICIDAL BEHAVIOR: 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 with 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 ACID AND DEPRESSION: In major depression, all studies revealed a significant decrease of the polyunsaturated omega 3 fatty acids and/or an increase of the omega 6/omega 3 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 3 fatty acids or the ratio omega 3/omega 6 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-1b, IL-6 and interferon g) 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 3 or omega 6 precursor. Arachidonic acid (omega 6) is, among others, precursor of pro-inflammatory prostaglandin E2 (PGE2), whereas polyunsaturated omega 3 fatty acids inhibit the formation of PGE2. It has been shown that a dietary increase of polyunsaturated omega 3 fatty acids reduced strongly the production of IL-1 beta, IL-2, IL-6 and TNF-alpha (tumor necrosis factor-alpha). In contrast, diets with a higher supply of linoleic acid (omega 6) increased significantly the production of pro-inflammatory cytokines, like TNF-alpha. Therefore, polyunsaturated omega 3 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 omega 3 are limited. In a double blind placebo-controlled study on 30 patients with bipolar disorder, the addition of polyunsaturated omega 3 fatty acids was associated with a longer period of remission. Moreover, nearly all the other prognosis measures were better in the omega 3 group. Very recently, a controlled trial showed the benefits of adding an omega 3 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.
Adolescent↗
Screening of histone deacetylases (HDAC) expression in human prostate cancer reveals distinct class I HDAC profiles between epithelial and stromal cells.
Histone deacetylases (HDACs) represent a large family of enzymes identified as key regulators of nucleosomal histone acetylation, a major epigenetic event that controls eukaryotic gene transcription. Inappropriate deacetylation mediated by HDACs has been associated with profound alterations in cellular biology. We have thus hypothesized that an altered HDAC expression may favor cancer development/progression. To test this possibility, we have sought to screen the expression profiles of several class I and class II HDACs (HDAC1-8) in DU-145, PC-3 and LNCaP human prostate cancer cell lines as well as in matched malignant and non-malignant prostate tissues by use of real time RT-PCR, immunoblot and immunohistochemistry. All HDAC transcripts tested were detected at various levels in all prostate cancer cell lines and tissue samples analyzed. In prostate tissues, the abundance of HDAC1 protein, which was exclusively expressed in the cell nucleus, was similar in normal and malignant epithelial cells, but was usually lower in stromal cells. Unexpectedly, HDAC8, another class I HDAC, was not detected in epithelial cells but was uniquely expressed in the cytoplasm of stromal cells. HDAC5, a class II HDAC involved in myogenesis, was not detected in the tissues. Altogether, our findings indicate that epithelial and stromal cells exhibit distinct class I HDAC expression profiles, and the abundance of HDAC1 is not altered in human prostate cancer. In addition, our observations are the first to demonstrate the prominently cytosolic distribution of a class I HDAC, HDAC8.
Cell Line, Tumor↗
Recent advances in prostate cancer metastasis.
Prostate cancer in men has now surpassed lung cancer as the most frequent non-cutaneous cancer. From a biological perspective, prostate carcinoma is unique among human malignancies in the wide discrepancy that exists between the prevalence of 'latent' cancer, recognizable only histologically, and that of the clinical disease. Histologically detected localized prostate cancers are heterogeneous, with only a small subset having undergone all of the malignant changes required to produce clinically aggressive tumors. Most of these 'latent' carcinoma never become fully malignant and do not threaten the life or well-being of the host. At present, it is not possible to predict which localized cancers will progress to clinically overt disease. Likewise, many patients have underevaluated and unpredictable extent of their prostate carcinoma, thus resulting in inadequate therapeutic strategies. It is clear that we need to identify molecular and/or cellular markers that are able to define the invasive and metastatic potential of prostate cancer on an individual patient basis. Acquisition of metastatic ability is a definitive criterion by which substage localized prostate cancers. Under the light of recent studies designed to identify some of the features associated with the metastatic phenotype of prostate cancer, the authors review recent advances aimed at gaining insight into those factors that may be involved in prostate cancer metastasis.
Cadherins↗