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  • 1
    ISSN: 1573-7276
    Keywords: cancer ; collagenase IV ; invasiveness ; metastasis ; phosphatidic acid ; signal transduction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Metastatic spread depends critically upon the invasiveness of tumor cells, i.e. their ability to breach basement membranes by elaborating and secreting specific proteolytic enzymes such as gelatinase A (MMP-2). Laminin is a major constituent of the extracellular matrix that can trigger production of MMP-2 in metastatic cells, but not in non-metastatic cells. The present study was designed to examine the role of phospholipase D (PLD) and its product, phosphatidic acid, in the intracellular signal transduction mechanisms that mediate induction of MMP-2 by laminin. Here we show that stimulation of tumor cells with laminin results in a time- and dose-dependent activation of PLD. Laminin-induced production of MMP-2 is attenuated by 1-butanol, a competitive substrate of PLD that reduces PLD-catalyzed production of PA. Moreover, phosphatidic acid itself can induce production of MMP-2 in metastatic tumor cells. MMP-2 can also be induced by exposing the cells to exogenous bacterial PLD. Elevated cellular phosphatidic acid induces MMP-2 in metastatic ras-transformed 3T3 fibroblasts but, like laminin, fails to do so in normal cells. These data indicate that laminin-induced activation of PLD and consequent generation of phosphatidic acid are involved in a signal propagation pathway leading to induction of MMP-2 and enhanced invasiveness of metastatic tumor cells.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-7276
    Keywords: cancer ; Lewis lung carcinoma ; matrix metalloproteinases ; metastasis ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Matrix metalloproteinases are a family of zinc-containing proteases that degrade extracellular matrix and basement membranes. These enzymes are thought to play a role in processes essential for tumor growth, invasion, and metastasis. Here we report pharmacokinetic and anti-tumor efficacy studies with a series of structurally related inhibitors of these enzymes that were synthesized at Agouron Pharmaceuticals using protein structure based drug design. The compounds studied were AG3287, AG3293, AG3294, AG3296, AG3319, and AG3340. Rat oral bioavailability ranged from 15 to 68%. Despite similar profiles of enzyme inhibition across the family of enzymes, and similar pharmacokinetics following i.p. administration to mice, efficacy against the Lewis lung carcinoma murine model varied from tumor growth enhancement, to significant reductions in the size of primary tumors and the number of lung metastases. AG3340 was the most efficacious compound against the Lewis lung carcinoma model, resulting in the complete cessation of primary tumor growth throughout the experiment in 4/6 mice treated with daily i.p. injections at a dose of 50 mg/kg. This treatment inhibited the formation of lung metastases greater than 5 mm in diameter by 90%.
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  • 3
    ISSN: 1573-7276
    Keywords: Aequorea victoria ; cancer ; green fluorescent protein (GFP) gene ; metastasis ; video microscopy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Video microscopy allows dynamic observation of cancer-cell activity in the microcirculation of live animals. However, observation of cancer invasion and metastasis in situ has never been successful because of the lack of a technique for labeling cancer cells. We report here our success with video microscopy of cancer-cell activity, detection of remote metastases and cancer cells endogenously generated using the green fluorescent protein (GFP) gene as a cell-labeling system in live animals. As a cell-labeling system, GFP is stable, efficient, and nontoxic, and it is passed on to subsequent generations of cells. This pilot experiment has demonstrated the feasibility of direct observation and documentation of tumor growth and tumor invasion as well as the metastatic activities of cancer cells in live animals.
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  • 4
    ISSN: 1573-7276
    Keywords: cancer ; colorectal ; αE-catenin ; invasion ; hMSH6
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Transition from an epithelioid (E) to a round (R) morphotype, in the human colon cancer cell line HCT-8, is associated with loss or truncation of αE-catenin and acquisition of invasiveness in organ culture. In E clones, like in parental HCT-8 cells, one allele of the αE-catenin gene (CTNNA1) is mutated. HCT-8 cells have also a “Microsatelite Instability-High” (MSI-H) phenotype presumably due to a mutated hMSH6 gene. Fusion of E type cells doubles the wild type CTNNA1 alleles and prevents the loss of αE-catenin. Introduction of an extra chromosome 2, carrying a wild type hMSH6 gene, restores post-replicative mismatch repair and also prevents the frequent inactivation of the remaining wild type CTNNA1 allele.
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  • 5
    ISSN: 1573-7276
    Keywords: cancer ; model ; murine ; orthotopic ; osteosarcoma ; spontaneous pulmonary metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To provide an investigative tool for the study of osteosarcoma (OSA) biology we have developed a syngeneic (balb/c) murine model of OSA, using cell lines derived from a spontaneously occurring murine OSA (Schmidt et al. Differentiation 1988; 39: 151-60). This model is characterized by orthotopic primary tumor growth, a period of minimal residual disease, spontaneous pulmonary metastasis, and clonally related variants (K7M2 and K12) that differ in pulmonary metastatic potential. Primary tumor and pulmonary metastasis histology was consistent with OSA in human patients. Expression of bone sialoprotein, biglyan, decorrin, and osteopontin was suggestive of bone lineage cells. The development and use of a more aggressive OSA cell line (K7M2) resulted in spontaneous metastasis to the lungs in over 90% of mice, whereas metastases were seen in only 33% of mice when a less aggressive OSA cell line (K12; Schmidt et al. Differentiation 1988; 39: 151-60) was used. Death from metastasis occurred at a median of 76 days using K7M2 whereas no median was achieved after 140 days using K12. Angiogenic potential, characterized by CD31 and factor VIII staining of primary tumors and pulmonary metastases, was greater in the K7M2 model compared to the K12 model. No significant differences in the in vitro or in vivo expression of angiogenesis associated genes (flt1, flt4, TIE1, TIE2, and VEGF) was found between K7M2 and K12. This well characterized and relevant model of OSA will be a valuable resource to improve our understanding of the biology and treatment of metastasis in OSA.
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  • 6
    ISSN: 1573-7276
    Keywords: cadherins ; cancer ; Copenhagen rat ; fibronectin ; integrins ; prostate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We compared the levels of mRNA transcripts encoding E-cadherin, N-cadherin,Β 1 integrin subunit,α 5 integrin subunit and fibronectin in the normal rat prostate gland, as well as in tumors derived from three invasive sublines (G, MatLyLu, AT-2) of the Dunning R-3227 rat prostatic adenocarcinoma. E-cadherin mRNA transcripts were only detectable in total RNA extracts prepared from normal rat prostates, whereas N-cadherin mRNA transcripts were only found in normal rat brains. In contrast, the mRNA transcripts encoding theΒ 1 integrin subunit,α 5 integrin subunit and fibronectin were all elevated in the tumors, as compared to the levels of these transcripts in normal tissues. Our results suggest that there is an inverse correlation between cadherin and integrin mRNA levels in rat prostatic tumors.
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  • 7
    ISSN: 1573-7276
    Keywords: cancer ; endothelium ; invasion ; melanoma cells ; metastasis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Adhesion of circulating tumor cells to microvascular endothelium plays an important role in tumor metastasis to distant organs. The purpose of this study was to determine whether nitric oxide (NO) would attenuate tumor cell adhesion (TCA) to naive or lipopolysaccharide (LPS)-treated postcapillary venules. A melanoma cell line, RPMI 1846, was shown to be much more adhesive to postcapillary venules isolated from rat mesentery than to corresponding precapillary arterioles. Although venules exposed to LPS for 4 h demonstrated an increased adhesivity for the melanoma cells, TCA to LPS-treated arterioles was not altered. Isolated venules exposed to DETA/NO (1 mm), an NO donor, for 30 min prior to tumor cell perfusion prevented the increment in adhesion induced by LPS and attenuated TCA to naive postcapillary venules. While L-arginine (100 μm), an NO precursor, failed to decrease TCA to naive postcapillary venules, this treatment abolished LPS-stimulated TCA to postcapillary venules. The effect of l-arginine was reversed by administration of N ω-nitro-l-arginine methyl ester (l-NAME, 100 μm), an NO synthase (NOS) inhibitor. These observations indicate that both exogenous and endogenous NO modulate TCA to postcapillary venules. To assess the role of NO-induced activation of cGMP in the reduction in TCA produced by DETA/NO, two additional series of experiments were conducted. In the first series, LY-83583 (10 μm), a guanylyl cyclase inhibitor, was shown to completely reverse the effect of DETA/NO on TCA to both naive and LPS-activated postcapillary venules. On the other hand, administration of 8-bromoguanosine 3′,5′-cyclic monophosphate (8-B-cGMP) (1 mm), a cell permeant cGMP analog, mimicked the effect of DETA/NO and reduced TCA to LPS-stimulated postcapillary venules. These data suggest that (a) tumor cells are more likely to adhere to postcapillary venules than to corresponding precapillary arterioles, (b) LPS enhances TCA to postcapillary venules, (c) both exogenously applied (DETAINO) and endogenously generated (l-arginine) NO attenuate the enhanced adhesion induced by LPS, but only DETA/NO reduced TCA to naive postcapillary venules, and (d) the NO-induced reduction in TCA to LPS-activated postcapillary venules occurs by a cGMP-dependent mechanism.[/p]
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  • 8
    ISSN: 1573-7276
    Keywords: cancer ; metastasis ; tumor progression ; urokinase plasminogen activator
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Tumor establishment and metastasis are dependent on extracellular matrix proteolysis, tumor cell migration, and angiogenesis. Urokinase plasminogen activator (uPA) and its receptor are essential mediators of these processes. The purpose of this study was to investigate the effect of a recombinant human uPAR antagonist on growth, establishment, and metastasis of tumors derived from human cancer cell lines. A noncatalytic recombinant protein, consisting of amino acids 1-137 of human uPA and the CH2 and CH3 regions of mouse IgG1 (uPA-IgG), was expressed, purified, and shown to bind specifically to human uPAR and to saturate the surface of human tumor cells which express uPAR. Daily i.p. administration of uPA-IgG to nude mice extended latencies of unstaged tumors derived from Lox melanoma and SW48 colon carcinoma cells by 7.7 and 5.5 days, respectively. uPA-IgG treatment did not affect the growth of Lox or KB tumors staged to 200 mg before antagonist treatment commenced. The effect of uPA-IgG on the establishment of micrometastases was assessed in SCID mice. KB head/neck tumor cells were injected in the tail vein and allowed to seed for 48 h before initiation of daily i.p. injections of uPA-IgG for 24 days. The number of lung colonies ranged between 5 and 30% of vehicle-treated mice in two separate experiments. Furthermore, a single 800 μg dose of uPA-IgG administered 1 h prior to tail vein injection of KB cells reduced lung colony formation to just 3.5% of vehicle-treated SCID mice. These data demonstrate that antagonism of uPAR arrested metastasis and inhibited the establishment of primary tumors and micrometastases. Thus, small molecule uPAR antagonists may serve as useful adjuvant agents in combination with existing cancer chemotherapy. © Rapid Science 1998
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  • 9
    ISSN: 1573-7276
    Keywords: cancer ; extracellular matrix ; Laminin-5 ; metastasis ; MMP-2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The occurrence of metastases is the hallmark of cancer. Development of metastasis severely affects prognosis and survival. It limits or discourages therapeutic interventions since no therapies are available to block or prevent cancer invasion. In order to invade, epithelial cancer cells need to penetrate through the basement membrane (BM) and remove extra-cellular matrix (ECM) tissue boundaries. In this context, proteases play a key role since they can either degrade or process the ECM components and thereby support cancer cell invasion. Laminin-5 (Ln-5) is an ECM protein, expressed predominantly in the BM structure, that promotes static adhesion and hemidesmosome formation. However, it also stimulates cell migration and/or invasion after having been cleaved by matrix metalloproteinases (MMPs) such as MMP-2 and MT1-MMP. Based on its dual functions, it would be intriguing to elucidate the role that Ln-5 plays in cancer cell motility and metastasis. One possibility is that MMPs, secreted by cancer cells or by neighbouring stromal cells, can cleave the γ2 chain of Ln-5 deposited along the advancing edge of tumors. Ln-5, and in particular its γ2 chain, has been found to be preferentially expressed in the cytoplasm of epithelial human cancer cells located at the advancing edge of the tumor. Such a distribution, which is restricted only to malignancies, suggests that the γ2 chain may be implicated in epithelial cancer growth and invasion. Although the clinical significance of this finding is not yet clear, it seems often to be associated with a more aggressive and invasive cancer phenotype. This article will review the current body of evidence implicating the Ln-5 molecule, and in particular its γ2 chain, as an important player in the tumor cascade and progression to metastatic disease. This will then be followed by a discussion of the presented data and its limitations. Finally, suggestions will be provided to improve the current state of knowledge in the field and future implications will be briefly discussed.
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  • 10
    ISSN: 1573-7276
    Keywords: antimetastatic ; cancer ; CBA mice ; histology ; host toxicity ; ruthenium complex ; survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ruthenium-dimethylsulfoxide complex Na(trans-RuCl4(DMSO)Im] was given i.v. to mice bearing MCa mammary carcinoma and its effects on tumor growth and on healthy host tissues were studied by macroscopic examination of primary tumor growth, by survival time, and by histological analysis using light microscopy and SEM. Either by means ofvivo-vivo bioassays or by microscopic examination it appeared that the growth of lung tumors was markedly reduced, whereas the growth of the i.m. primary tumor was much less affected. These effects account for the prolongation of survival time and for the cure rate observed. The favourable effect on survival time was also influenced by the lack of significant cytotoxicity for normal tissues such as lung and kidney epithelia, muscle and liver cells, splenocytes and bone marrow. It thus appears that the selective interaction with tumor cells in the lungs cannot simply be attributed to a selectively higher localization of the compound at this site, nor to a modification of the histological structure of primary tumor. These results highlight the pharmacologic properties of this compound for the control of solid tumor metastases, an effect that was shown to be similarly exerted on advanced tumor metastases.
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