Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on matrix metalloproteinases (MMP) and metalloproteinase inhibitors was studied in a variety of human cell lines. Expression of the mammalian collagenase (MMP-1), 72-kD gelatinase/type IV collagenase (MMP-2), stromelysin (MMP-3), 92-kD gelatinase/type IV collagenase (MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) was assessed by zymography and Northern blot analysis. MMP-2 and TIMP-2 activities were refractory to TPA, IL-1 and TNF-alpha treatment in most of the cell lines. In contrast, MMP-3, MMP-9 and TIMP-1 activities were markedly stimulated by TPA in most of the tumor cell lines and human umbilical vein endothelial cells (HUVEC), whereas the fibroblast lines were minimally stimulated or unresponsive to TPA. The MMP-3, MMP-9 and TIMP-1 stimulation in response to IL-1 and TNF-alpha treatment was detected in some of the tumor cell lines and HUVEC. The increase in activity was less marked than in TPA. A breast carcinoma cell line, MDA-MB-231, which did not express MMP-2, had high expression of MMP-3 and MMP-9 which were unaffected by TPA and cytokine treatment. Northern blot analysis of MMP and TIMP mRNA expression reflected the zymogram findings for most of the cell lines. TPA-mediated stimulation of MMP-1 was similar to that of MMP-3 and MMP-9. Exceptions were the fibroblast cell lines which showed either a much more marked mRNA response of MMP-9 to TPA than observed at protein level, or a high constitutive MMP-9 mRNA when MMP-9 activity was not detectable by zymography. TPA-mediated stimulation of MMP-9 and TIMP-1 activity was blocked by staurosporine, an inhibitor of protein kinase C (PKC). A non-PKC-activating phorbol ester, 4 alpha-phorbol-12,13-didecanoate, did not stimulate MMP-9 and TIMP-1 activity. TPA treatment caused the increased expression of c-fos containing AP-1-specific binding activity in selected tumor cell lines. This activity was maximal at 6 h. An association was observed between AP-1 binding activity and increased expression of MMP-1, MMP-3 and MMP-9, which possess TPA-responsive elements (TRE). TPA-sensitive MMPs and TIMP-1 were variably stimulated by biologically relevant cytokines, such as IL-1 and TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
Invasion Metastasis 1992
PMID:Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. 128 26

The movement of lymphocytes through extracellular matrix (ECM) is an essential component of normal traffic and infiltration into inflammatory sites. This review surveys current knowledge of the mechanisms of lymphocyte migration through ECM, most of which was derived from work with in vitro models of basement membranes, interstitial stroma, or their constituent components. Normal lymphocyte motility is an extremely plastic property. Naive lymphocytes tend to be unresponsive to ECM components and many chemoattractants, but when exposed to antigens, artificial mitogens and certain lymphokines, they rapidly acquire locomotory capacity, which is expressed as increased polarity, adhesiveness, invasiveness and chemotactic response. Acquisition of locomotory capacity is associated with the G0/G1 transition, and activation of protein kinase C appears to be a key event. Preliminary evidence indicates that mitogenesis and differentiation to the memory phenotype trigger a long-lasting, possibly permanent elevation of locomotory response to ECM. Receptors for fibronectin, laminin and collagens I and IV have been implicated as mediators of lymphocyte motility, but these receptors have not been characterized in detail. Heparanases facilitate T cell movement through the basement membrane, but the role of proteases has not yet been defined. Major gaps remain in our understanding of the connection between in vitro models and specific stages of the infiltration process in vivo and of motility regulation at the molecular level.
Invasion Metastasis 1992
PMID:Lymphocyte migration through extracellular matrix. 139 3

Cells contracting connective tissue matrices generate tractional forces in tissues. Studies of fibroblast contraction, using collagen gels in an in vitro model, demonstrate that it involves the actin cytoskeleton, specific extracellular matrix receptors and requires stimulation by exogenous promoters. Fibroblast contraction is stimulated by factors released by platelets and potentially secreted within the contracting tissue. Endothelial cells secrete a potent promoter of fibroblast contraction which has been identified as endothelin 1. The pathway through which fibroblast contraction is stimulated appears to require activation of protein kinase C. Tumor cells can also secrete endothelin. These mechanisms may be relevant to tumor progression.
Cancer Metastasis Rev 1992 Mar
PMID:Extracellular matrix contraction by fibroblasts: peptide promoters and second messengers. 151 96

Adoptive immunotherapy in humans may be limited by the lack of autologous tumor cells to activate and expand tumor-specific T cells. Pharmacologic manipulation of protein kinase C (PKC) and intracellular calcium may substitute for tumor antigen and stimulate T cells for adoptive immunotherapy. In the present study, we evaluated the ability of the PKC activator Bryostatin 1 (B) plus the calcium ionophore ionomycin (I) to activate lymphocytes obtained from popliteal lymph nodes (DLN) draining an MCA-105 footpad tumor. The adoptive transfer of B/I-stimulated DLN cells eradicated MCA-105 pulmonary metastases. These lymphocytes do not require concomitant IL-2 administration to mediate regression of lung metastases. Three days after intrasplenic injection of tumor cells and splenectomy, mice were given iv injections of B/I-stimulated DLN cells. Adoptive immunotherapy with these cells induced regression of established liver metastases. In an intradermal tumor model, the adoptive transfer of B/I-stimulated MCA-105 DLN cells cured mice of MCA-105 intradermal (id) tumors, but did not induce regression of MCA-206 tumors. Mice cured of MCA-105 id tumors were protected against MCA-105, but not MCA-203, tumor challenge in the footpad 7 weeks after adoptive immunotherapy.
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PMID:Bryostatin 1-activated T cells can traffic and mediate tumor regression. 152 28

We examined the ability of bryostatin 1 (Bryo), a novel protein kinase C activator, plus ionomycin (Io), a calcium ionophore, to activate T-cells with specific antitumor activity. Lymphocytes from the draining lymph nodes (DLN) of MCA-105 tumor-bearing host mice were stimulated with Bryo/Io, either fresh or after in vitro stimulation with autologous tumor, and then were incubated in interleukin-2 at 20 units/ml. Lymphocytes sensitized with tumor cells in vitro and then stimulated with Bryo/Io exhibited significant expansion (12-fold) after a total of 3 weeks in culture and moderate cytolytic activity (40% at an effector:tumor cell ratio of (80:1) and were exclusively CD8+ T-cells. DLN cells activated immediately with Bryo/Io, without tumor antigen sensitization in vitro, displayed marked growth (130-fold expansion) over 3 weeks in culture, had weak cytolytic activity (8% at an effector:tumor ratio of 80:1), and were a mixed population of CD8+ and CD4+ cells. Despite the differences in phenotypes and in cytotoxicity, both groups of DLN cells were highly effective in vivo against MCA-105 pulmonary metastases. Bryo/Io-activated DLN cells from MCA-105 tumor-bearing hosts had no therapeutic efficacy against B16 melanoma or MCA-203 sarcoma metastases. Lymph node cells from normal mice and non-draining lymph node cells from tumor-bearing hosts could be expanded with Bryo/Io to a degree similar to that of DLN cells but had no antitumor activity. Phenotypic analyses and in vitro and in vivo depletion studies demonstrate that CD8+ cells mediated tumor regression.
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PMID:Activation and growth of murine tumor-specific T-cells which have in vivo activity with bryostatin 1. 173 41

Essentially all tumors express aberrantly glycosylated glycosphingolipids and glycoproteins, more commonly known as "tumor-associated carbohydrate antigens." In this article I propose two new forms of cancer therapy, anti-adhesion therapy and ortho-signaling therapy, which exploit these tumor-associated carbohydrates in distinct ways. The aim of anti-adhesion therapy is to disrupt the requisite carbohydrate-initiated interactions that occur between tumor cells and other cell types (e.g., endothelial cells, platelets) as tumors progress and metastasize. Candidate anti-adhesion agents include purified carbohydrates or glycosphingolipids representing H, Ley, sialosyl-Lex (or -Lea) GM3, or LacCer antigens, and monoclonal antibodies directed to these structures. The aim of ortho-signaling therapy is to disrupt mitogenic signaling pathways in tumor cells that are regulated by glycosphingolipids and/or their derivatives, including pathways involving receptor protein-kinases and protein kinase C. Candidate ortho-signaling agents are the glycosphingolipid regulator PDMP (1-phenyl-2-[decanoylamino]-3-morpholino-1-propanol) and the protein kinase C inhibitor DMS (N,N-dimethylsphingosine), both of which show antitumor activity in vitro and in animal studies.
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PMID:New directions in cancer therapy based on aberrant expression of glycosphingolipids: anti-adhesion and ortho-signaling therapy. 182 92

Bryostatins are a novel class of protein kinase C activators which were isolated from the marine bryozoan Bugula neritina and found to possess both antineoplastic and immunoenhancing properties. In this report, we examined the relationship between the in vivo and in vitro antineoplastic effects of bryostatin 1. The in vivo antitumor activity of bryostatin 1 was demonstrated in a B16 melanoma pulmonary metastases model, in which treatment of tumor-bearing C57BL/6 mice with 5 days of bryostatin 1 resulted in a significant reduction in of the number of lung nodules (control, 87; bryostatin, 7). There was a clear dose-response effect, with the optimal antimelanoma dose being 100 micrograms/kg/day, but even low doses of bryostatin 1 of 1 micrograms/kg/day resulted in a 53% reduction in the number of metastases. Although bryostatin 1 shares many biological properties with the phorbol esters, parallel treatment with 12-O-tetradecanoyl 13-phorbol acetate was ineffective against B16 melanoma in vivo. Using a clonogenic assay, bryostatin 1 was found to have a direct antiproliferative effect against B16 melanoma. This inhibition occurred at relatively high bryostatin 1 concentrations (10(-6) M), in comparison with a sensitive cell line REH (10(-10) M). Treatment of mice with bryostatin 1 or preincubation of normal spleen cells with bryostatin 1 failed to enhance nonspecific cell-mediated cytotoxicity against B16 melanoma in vitro. Moreover, bryostatin 1 was found to inhibit both natural killer cell activity and interleukin 2 generation of lymphokine-activated killer cells. Thus, a role for an in vivo immune enhancement mechanism as the basis for the antimelanoma activity observed with bryostatin 1 cannot be invoked from these experiments. These findings indicate that bryostatin 1 may act directly on the B16 melanoma pulmonary metastases. The precise mechanism whereby bryostatin exerts its antimelanoma effects remains unclear.
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PMID:Successful treatment of murine melanoma with bryostatin 1. 198 85

The involvement of protein kinase C (PKC) in regulation of cellular properties related to tumor cell invasiveness was tested in a murine methylcholanthrene-induced fibrosarcoma tumor cell model. A metastatic clone (IE7) derived from the T10 fibrosarcoma was found to possess 30 and 90% more cytosolic and membrane-bound PKC, respectively, compared with the IC9 metastatic clone. Intravenous injection of IE7 but not IC9 cells resulted in lung tumor formation. Long-term (3 months) treatment of IE7 cells with 500 ng/ml phorbol 12,13-dibutyrate (PDB) resulted in a 4-fold reduction in total PKC activity and increase in the tumor cell metastatic ability. Short-term (2h) PDB treatment induced cytosol-to-membrane PKC translocation and decreased the IE7 cells' ability to form hematogenous metastases. Treatment of IC9 cells with PDB did not render them metastatic. To test the possible involvement of distinct PKC isoenzymes in the determination of metastatic properties, we stained the cells with appropriate anti-PKC antibodies followed by FACS analysis. IC9 and IE7 cells exhibited similar levels of fluorescent intensity when stained with either anti-PKC alpha or anti-PKC beta antibodies. The relative proportion of PKC alpha and PKC beta was not changed following short-term PDB treatment of cells, but the intensity of staining was reduced 1.5- to 2-fold following long-term PDB treatment of both cell types. The results indicate that phorbol ester-induced alterations in PKC levels and subcellular distribution affect the metastatic ability of tumor cells and suggest that tumor promoting agents that promote induction of primary tumors may also affect tumor spread by regulating hematogenous metastases formation.
Invasion Metastasis 1991
PMID:Effect of protein kinase C activating tumor promoters on metastases formation by fibrosarcoma cells. 206 Oct

The nature of the relationship between agonist-stimulated cyclic AMP production and metastatic potential was examined in detail for four B16 melanoma cell lines of varying metastatic potential. Highly metastatic cells (B16 F10C1) appeared to differ from cells of low metastatic potential (B16 F1C29) in the degree to which cyclic AMP production in intact cells was stimulated by protein kinase C activation. No significant difference was found in the adenylate-cyclase enzyme activities of the broken cells, irrespective of the agonist used, or in the distribution of cyclic AMP between the intracellular and extracellular compartment. Although B16F1, F10 and F10C1 cells all produced equally pigmented tumors in vivo, the cells differed in their melanogenic response to cyclic AMP elevating agents in vitro: the least metastatic cells produced least agonist-induced cyclic AMP but this induced greatest tyrosinase activation and melanin production in vitro; conversely, the more metastatic cells produced more cyclic AMP but less tyrosinase activation and melanin production in response to agonist stimulation. Thus, agonist-stimulated cyclic AMP production does not appear to be coupled to the differentiated function of melanogenesis for highly metastatic B16 melanoma cells.
Clin Exp Metastasis
PMID:The regulation of cyclic AMP production and the role of cyclic AMP in B16 melanoma cells of differing metastatic potential. 216 82

Evidence is provided to show that two secondary cell-signaling pathways, Ca2+ mobilization and the activation of protein kinase C (PKC), are involved in the induction of spontaneous metastasis in mouse adenocarcinoma cell line SP1. Unlike the parental cells, which were found to be tumorigenic but unable to metastasize from a s.c. site, SP1 cells treated with ionophore A23187 (to mobilize Ca2+) or phorbol 12-myristate 13-acetate (to activate PKC) were able to metastasize spontaneously. Analysis of SP1 cells treated with either agent separately or with both agents simultaneously revealed that both pathways contributed to the final response in a separate and nonsynergistic way. The induced metastatic phenotype in most cases appeared to be heritable. Examination of Ca2+ sources during cell activation by ionophore A23187 suggested that internal Ca2+ was sufficient for the process of induction. Examination of PKC activity and its intracellular distribution during and after treatment of SP1 cells with ionophore A23187 and phorbol 12-myristate 13-acetate were also evaluated. The results suggested that the basal levels of PKC and the activation of the enzyme appear to be involved in the induction of spontaneous metastasis. Taken together, these observations are consistent with the hypothesis that cell-signaling pathways exist which can induce the metastatic phenotype and that this may be related to phosphatidylinositol turnover.
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PMID:Possible involvement of Ca2+ mobilization and protein kinase C activation in the induction of spontaneous metastasis by mouse mammary adenocarcinoma cells. 249 16


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