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)

Human head and neck squamous cell carcinoma (HNSCC) cell cultures were established to identify the angiogenic factors they produced and how these factors contribute to two steps of the angiogenic process: endothelial cell proliferation and migration. The HNSCC cells secreted vascular endothelial cell growth factor (VEGF), transforming growth factor-beta (TGF-beta) and prostaglandin E2 (PGE2), but only low levels of basic fibroblast growth factor. Both proliferation-stimulatory and -inhibitory cytokines were produced by the HNSCC cells, with VEGF promoting endothelial cell proliferation, prostaglandins having no effect and TGF-beta downregulating proliferation. Two methods were used to measure endothelial cell migration: migration into a wound in the endothelial cell monolayer and migration across a filter into lower compartments. HNSCC cell supernatants stimulated endothelial cell migration in both migration models. VEGF had no effect on the motility of endothelial cells. However, when TGF-beta activity in the HNSCC supernatants was neutralized with antibody or the production of prostaglandins by HNSCC cells was blocked with indomethacin, the migration-stimulatory activity in the HNSCC cell supernatants was diminished. Adding authentic PGE2 or TGF-beta 1 to endothelial cells mimicked the migration-stimulatory activity of the HNSCC supernatants. Thus, HNSCC-derived VEGF is important in stimulating endothelial cell proliferation, while the antiproliferative effect of TGF-beta and the migration-stimulatory activity of TGF-beta and PGE2 suggest their having a role in the morphogenic processes of angiogenesis.
Invasion Metastasis 1996
PMID:Regulation of the steps of angiogenesis by human head and neck squamous cell carcinomas. 937 Dec 28

Although a number of effective therapies are available for localized prostate cancer, metastatic prostate cancer is difficult to treat and impossible to cure. Identification of the gene products that enable a prostatic carcinoma cell to metastasize should facilitate an understanding of the processes leading to metastasis. To characterize the contribution of matrix metalloproteinase-9 (MMP-9, gelatinase B or the 92-kd type IV gelatinase/collagenase) to the development of metastasis in prostate cancer, we reduced MMP-9 expression in metastatic murine prostatic carcinoma cells using a ribozyme. The ribozyme transfected cells had lower basal levels of MMP-9 as well as decreased levels after stimulation by transforming growth factor-beta or phorbol 12-myristate 13-acetate when compared with the parental cells or with control transfectants. The cells with down-regulated MMP-9 were unable to form lung colonies in the experimental metastasis assay, whereas the controls and parental cells readily formed metastases. All cell types readily formed tumors after injection and down-regulation of MMP-9 did not adversely affect the rate of tumor growth. Thus, MMP-9 expression is required for hematogenous metastasis in a murine prostate model system raising the possibility that it may play an equivalent role in human prostate cancer.
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PMID:Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinoma. 946 86

Invasive growth and formation of metastases involve complex interactions between tumour cells, host cells and components of the extracellular matrix. Retinoids, a group of vitamin A derivatives, modulate cell growth and differentiation and have been found to suppress tumour cell invasion in vitro and formation of metastases in vivo. The aim of our study was to investigate changes in proliferation and invasion through membrane barriers in vitro of seven human melanoma cell lines, established from human primary melanomas or metastases, in response to treatment with retinoic acid (RA). These changes were compared with the expression regulation of molecules that have been identified as targets of RA-mediated signal pathways. Invasiveness in vitro was correlated with the origin of the cell lines and was significantly higher in the lines derived from metastases. In all the cell lines proliferation and chemotaxis were inhibited by 10(-5) M RA, but the cell lines established from metastases were significantly more sensitive with respect to inhibition of invasion by RA. The specific expression patterns of MMP-1 and TIMP-2 were detected and regulated by RA in almost all cell lines, whereas expression of MMP-2 and TIMP-1 was not influenced by RA treatment. The most striking difference between the cell lines was a strong downregulation of transforming growth factor-beta (TGF-beta) expression in cell lines derived from metastases when treated with RA in contrast to cell lines from primary melanomas. These data provide evidence that RA modulates growth, chemotaxis and invasion in a broad panel of melanoma cell lines derived both from primary non-metastasized melanomas and metastases. However, distinct molecular mechanisms are involved in mediating these effects.
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PMID:In vitro modulation of human melanoma cell invasion and proliferation by all-trans-retinoic acid. 966 42

During postnatal development, the formation of new blood vessels is possible only through angiogenesis. The initial growth of solid neoplasms, including childhood brain tumors, during the genetically determined stages of carcinogenesis, even at clinically undetectable sizes (a few mm3), depends upon the continuous formation of new blood capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a malignant, invasive cellular immunophenotype (CIP) and distant metastases are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during brain tumor related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded (3-5 microns thick), as well as frozen tissue sections (6 microns thick) of 62 childhood brain tumors [34 medulloblastomas (MEDs) and 28 astrocytomas (ASTRs)], were employed for the assessment of EDG expression. Both an indirect, four-step, alkaline phosphatase (AP) conjugated, biotin-streptavidin based (or a diamino-benzidine [DAB]) conjugated immunoperoxidase antigen detection technique were employed, utilizing the SN6h anti-EDG monoclonal antibody (DAKO Corp.). Another antigen detection method, based on the Histogold (Zymed) reaction was also employed using the same antibody on formalin fixed, paraffin-wax embedded tissues. Strong expression (A; +3 to +4) of EDG on endothelial cells and demonstrated in all 62 childhood brain tumor cases. The most striking feature of the newly formed tumor-related capillaries was the presence of a markedly enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. A close apposition between the capillaries and the adjacent parenchyma was also observed. Brain tumors, especially glioblastoma, are among the most vascularized human neoplasms, and thus are candidates for antiangiogenic therapy. VEGF/PF-R1 (flt-1) and VEGF/PF-R2 (flk-1) are formed de novo in a glioma progression-dependent manner. Further studies should substantiate the importance of EDG in the earliest possible detection, diagnosis and NRA inhibition-based treatment of mammalian solid neoplasms, especially childhood brain tumors.
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PMID:Upregulation of endoglin (CD105) expression during childhood brain tumor-related angiogenesis. Anti-angiogenic therapy. 967 60

The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including malignant melanomas, depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a dedifferentiated, malignant, highly invasive cellular immunophenotype (CIP) and distant metastases, as aspects of constant neoplastic progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during malignant melanoma (MM) related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PAA) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 25 MMs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; +3 to +4) of EDG on endothelial cells was demonstrated in all MM cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. MMs, like most mammalian neoplasms, are characterized by extensive neovascularization, and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including MMs. The importance of TGF-beta in all of the various aspects of neoplastic transformation, as well as malignant disease progression should also be studied more extensively in the future.
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PMID:Immunocytochemical detection of endoglin is indicative of angiogenesis in malignant melanoma. 970 32

The commencement of the complex process of carcinogenesis, and subsequent, rapid tumor growth and progression of mammalian neoplasms, including breast carcinomas (BCs), depends upon the continuous de novo formation of capillaries [i.e. neovascularization (NV)/neoplasm-related angiogenesis (NRA)]. The generation of a malignant, invasive cellular immunophenotype (CIP) and distant metastases, as aspects of tumor progression, are also NRA-dependent processes. Endothelial cells undergo rapid proliferation during mammary carcinoma-related angiogenesis. Human endoglin (CD105/EDG), is a homodimeric cell surface component of the transforming growth factor-beta (TGF-beta) type I receptor complex and is also a proliferation-associated antigen (PM) expressed at high density on endothelial cells. Formalin fixed, paraffin-wax embedded, tissue sections (3-5 microns thick) of 15 BCs were employed for the assessment of EDG expression. An indirect, four-step, alkaline phosphatase (AP) (or diamino-benzidine [DAB]) conjugated, biotin-streptavidin based, antigen detection technique, employing the SN6h anti-EDG monoclonal antibody was conducted. Zymed's Histogold System was also utilized for immunocytological antigen detection. Strong expression (A; ++ + to ++ ++) of EDG on endothelial cells was demonstrated in all 15 BC cases. The most striking feature of the newly formed neoplasm-related capillaries was the presence of an enlarged perivascular space. Blood vessels in several normal human tissues (cortex, cerebellum, thymus, tonsil, spleen, lymph node, skin) used as control tissues contained significantly lower levels of EDG (B and mostly C; +/- to +), in accordance with the extremely slow turnover rate of normal endothelial cells. Furthermore, a close apposition between the capillaries and the adjacent parenchyma was observed in these normal controls. BCs, as most mammalian neoplasms, are characterized by extensive neovascularization and thus are candidates for anti-angiogenic therapy. Further studies should substantiate the importance of EDG expression in the earliest possible detection, diagnosis and NRA inhibition-based treatment of solid tumors, including BCs.
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PMID:Over-expression of endoglin (CD105): a marker of breast carcinoma-induced neo-vascularization. 985 49

Malignancy is a common and dreaded complication following organ transplantation. The high incidence of neoplasm and its aggressive progression, which are associated with immunosuppressive therapy, are thought to be due to the resulting impairment of the organ recipient's immune-surveillance system. Here we report a mechanism for the heightened malignancy that is independent of host immunity. We show that cyclosporine (cyclosporin A), an immunosuppressant that has had a major impact on improving patient outcome following organ transplantation, induces phenotypic changes, including invasiveness of non-transformed cells, by a cell-autonomous mechanism. Our studies show that cyclosporine treatment of adenocarcinoma cells results in striking morphological alterations, including membrane ruffling and numerous pseudopodial protrusions, increased cell motility, and anchorage-independent (invasive) growth. These changes are prevented by treatment with monoclonal antibodies directed at transforming growth factor-beta (TGF-beta). In vivo, cyclosporine enhances tumour growth in immunodeficient SCID-beige mice; anti-TGF-beta monoclonal antibodies but not control antibodies prevent the cyclosporine-induced increase in the number of metastases. Our findings suggest that immunosuppressants like cyclosporine can promote cancer progression by a direct cellular effect that is independent of its effect on the host's immune cells, and that cyclosporine-induced TGF-beta production is involved in this.
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PMID:Cyclosporine induces cancer progression by a cell-autonomous mechanism. 1002 62

Melanoma cells in culture express a variety of growth factors and cytokines and some of their autocrine and paracrine roles have been investigated. However, less information is available on the potential dynamic changes in expression of these molecules on cells during melanoma development and progression in situ. Using immunohistochemistry, we tested 40 nevi and primary and metastatic melanoma lesions for the expression of 10 growth factors and cytokines and the respective receptors representing 10 cell surface molecules. Nevi and thin (< 1 mm) primary melanomas showed little expression of ligands except weak reactivity of tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta (TGF-beta), interleukin-8 (IL-8) and reactivity of TGF-betaR and c-kit. Marked up-regulation of growth factors, cytokines and receptor expression was observed in thick (> 1 mm) primary melanomas, which were stained with polyclonal or monoclonal antibodies (MAbs) for IL-1alpha, IL-1beta, IL-6, IL-8, TNF-alpha, TGF-beta, granulocyte-macrophage colony-stimulating factor (GMCSF) and stem cell factor (SCF), but not IL-2. Metastases showed similar expression patterns except that SCF was absent. Co-expression of ligand and receptor was observed for TGF-beta, GM-CSF and IL-6, suggesting an autocrine role for these ligands. TNF-alpha appears to be a marker of benign lesions; IL-6 and IL-8 expression is associated with biologically early malignancy; TGF-beta, GM-CSF and IL-1alpha are highly expressed in biologically late lesions; and TNF-beta is an apparent marker of metastatic dissemination. Our results indicate that melanoma cells utilize cascades of growth factors and cytokines for their progression.
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PMID:Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. 1009 49

Nasopharyngeal carcinoma (NPC) is an epithelial cancer that is causally associated with Epstein-Barr virus (EBV) infection. NPC tumor biopsies are characterized histopathologically by an abundant infiltration of nonmalignant lymphocytes. We analyzed the expression of various cytokines in NPC tissues to investigate the interaction of the infiltrating lymphocytes and tumor cells. Analysis using reverse transcriptase-PCR revealed the expression of a panel of cytokines in the NPC biopsies: interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IFN-gamma, tumor necrosis factor-alpha, transforming growth factor-beta, and IL-1 receptor types I and II. Elevated expression of IL-1alpha and IL-1beta was observed in primary tumors and NPC metastases compared to control tissues. Interestingly, this increased expression correlated with the EBV-encoded viral IL-10 transcript. To determine which cells were responsible for producing IL-1, we determined the cellular constituents of NPC biopsies by immunoflow cytometric analysis. On the basis of data from these analyses, the three major specific cell populations, epithelial cells, CD4+ T cells, and CD8+ T cells, were selected from five NPC tumors using specific, antibody-coated paramagnetic beads. Reverse transcriptase-PCR of RNA from these fractionated cells showed that transcripts of IL-1alpha and IL-1beta were present not only in the malignant epithelial cells but also in CD4+ T cells infiltrating the tumor, a finding confirmed by immunohistochemical staining. We hypothesize that the unusual synthesis of IL-1alpha and IL-1beta by EBV-positive epithelial cells as well as by CD4+ T cells might contribute to lymphocyte infiltration and/or tumor growth during NPC development.
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PMID:Profile of cytokine expression in nasopharyngeal carcinomas: a distinct expression of interleukin 1 in tumor and CD4+ T cells. 1019 35

Bone marrow stroma produces positive and negative growth regulators which constitute the hematopoietic microenvironment. As many tumors metastasize to the bones, these regulators may also influence tumor growth. Hematopoietic cytokines may indeed exert both positive and negative effect on tumor growth. We report that, when mixed with tumor cells. adherent bone marrow cells inhibit primary tumor growth and metastases formation in mice transplanted with Lewis lung carcinoma or B16 melanoma. Peritoneal macrophages or lymph node cells did not exert any influence. The tumor inhibition was apparently due to soluble factor(s) released by marrow stromal cells. In cocultures with B16 melanoma cells, adherent bone marrow cells exerted a significant antiproliferative effect which was increased by previous culture of the bone marrow cells with granulocyte-macrophage colony-stimulating factor but not with macrophage colony-stimulating factor. Neither neutralizing antibodies against tumor necrosis factor-alpha, transforming growth factor-beta or interferon alpha/beta nor addition of Escherichia coli lipopolysaccharide to generate inflammatory cytokines could affect the antiproliferative effect of bone marrow stromal cells. The bone marrow stroma factor(s) which inhibit tumor growth might, therefore, be a novel growth regulator.
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PMID:Factor(s) from nonmacrophage bone marrow stromal cells inhibit Lewis lung carcinoma and B16 melanoma growth in mice. 1035 34


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