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)

Several lines of evidence indicate that sialosyl Le(a), tumor-associated carbohydrate antigen present on human colon carcinoma cells, is involved in formation of metastases. To study the role of this carbohydrate structure in development of metastases, we have used the clone of human colon carcinoma CX-1 cells transfected with antisense expression vector containing fragment of cDNA for alpha1,3/4-fucosyltransferase (FT III), which is involved in synthesis of sialosyl Le(a) tetrasaccharide. It has been reported previously that, in contrast to the parental cells, the antisense-transfected CX-1.1AS5 cells do not express sialosyl Le(a) and do not adhere to E-selectin-expressing CHO cells. In the present work we have studied the formation of liver metastases by CX-1.1AS5 cells after their orthotopic or intrasplenic implantation into athymic nu/nu mice. After orthotopic implantation of sialosyl Le(a)-negative colon carcinoma CX-1.1AS5 cells, the number of mice with liver metastases was markedly lower (21% of mice) in comparison with their number after implantation of the parental CX-1.1 cells (86% of mice). However, no differences in ability to form colonies in liver were observed between parental CX-1.1 cells and antisense-transfected CX-1.1AS5 cells after intrasplenic inoculation. The liver metastases were formed in 89% and 84% of mice, respectively. Our data support the thesis on the importance of sialosyl Le(a) antigen expression in the development of liver metastases by colon cancer cells, and indicate the role of transplantation route and primary tumor localization in formation of metastases.
Clin Exp Metastasis 1998 Nov
PMID:Metastatic potential of human CX-1 colon adenocarcinoma cells is dependent on the expression of sialosyl Le(a) antigen. 1021 80

We hypothesize that a major factor regulating hepatic metastasis is the ability of CEA (carcinoembryonic antigen) producing colorectal carcinomas to activate Kupffer cells. CEA and NCA (nonspecific cross-reacting antigen) bind to an 80 kDa Kupffer cell receptor by the peptide sequence PELPK and stimulate cytokine production. Cytokines induce sinusoidal endothelial cells to express intercellular adhesion molecules and increase adhesion of the tumor cells and retention in the liver. In this study human Kupffer cells were activated in vitro with CEA, NCA, and the peptide PELPK. This resulted in release of IL-1beta, TNF-alpha and IL-6. CEA non-producing MIP-101 colon carcinoma cells labeled with 51Cr were incubated on monolayers of ECV-304 human umbilical vein endothelial cells treated with these Kupffer cell derived cytokines or with comparable recombinant human (rH) cytokines. Specific antibodies to the adhesion molecules ICAM-1, VCAM-1, E-selectin and beta2integrin were used to block their functions. A significant enhancement in the adhesion of colorectal carcinoma cells occurred when endothelial cells were stimulated with a very low concentration of Kupffer-cell derived cytokines. Activated endothelium demonstrated significant up-regulation primarily of ICAM-1. The adhesion was blocked by an antibody to ICAM-1. A combination of Kupffer-cell derived cytokines was more effective than IL-1beta or TNF-alpha alone. IL-6 alone did not influence adhesion under our conditions. Our results suggest a mechanism for CEA in the modulation of colorectal carcinoma adhesion to the hepatic endothelium and its enhancement of metastatic potential.
Clin Exp Metastasis 1998 Nov
PMID:Adhesion of colorectal carcinoma cells to the endothelium is mediated by cytokines from CEA stimulated Kupffer cells. 1021 83

E-Selectin is an inducible adhesion molecule, which is expressed on cytokine-activated endothelial cells and is thought to interact with cancer cells to initiate metastases. The relationship between serum E-selectin levels and prognoses in 101 patients with resected non-small cell lung cancers (NSCLCs) was studied, and survival curves were compared in relation to E-selectin levels and expression of two carbohydrate antigens, Sialyl Lewisx (SLX) and Sialyl Lewisa (CA19-9), which were immunohistochemically detected in resected specimens in 65 of the 101 cases. The serum E-selectin level on admission was 48.9+/-25.7 ng/ml (mean+/-SD, n=101), and the E-selectin-positive rate was 22.7%, being correlated with the progression of T-factor. The high E-selectin group showed a significantly worse survival rate than the normal E-selectin group. Multivariate analysis confirmed the significant prognostic value of E-selectin. The mean postoperative E-selectin level in 52 cases (36.93 ng/ml) was significantly lower than the preoperative E-selectin level (43.57 ng/ml), indicating that certain NSCLCs might induce the expression of E-selectin. In cases expressing carbohydrate antigens (SLX, CA19-9), the high E-selectin group showed a significantly worse survival curve than the normal E-selectin group. On the other hand, there was no significant difference in the survival curve between the high and normal E-selectin groups when carbohydrate antigens were negative. These results suggest that patients who have high serum E-selectin levels, especially with carbohydrate antigen-positive NSCLC, might be expected to have poor prognoses.
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PMID:Relation between the serum E-selectin level and the survival rate of patients with resected non-small cell lung cancers. 1035 45

Although the loss of sulfomucins was known as an indicator of carcinogenesis and malignant progression of colonic epithelia, it was not known whether the loss was directly related to the malignant behavior of colon carcinoma cells. We have studied the biological properties of LS174T human colon carcinoma cells before and after suppression of sulfomucin production. Incorporation of [35S]-sulfate into high molecular weight mucins decreased after carcinoma cell treatment with 1.5% dimethylsulfoxide (DMSO) for 8 days. The amounts of sulfomucin determined using a sulfomucin-specific monoclonal antibody (mAb 91.9H), in Western blot and flowcytometric analyses, also decreased. In addition, the levels of MUC2 and MUC5B mucin gene expression measured by RT-PCR were reduced after DMSO-treatment, whereas the levels of MUC1, MUC5AC, and MUC6 mucin gene expression were not. The DMSO-treated cells were tested in vitro and in vivo for their properties. Differences were not detected in their anchorage-independent growth, anchorage-dependent growth, E-selectin-dependent cell adhesion or sensitivity to interleukin (IL)-2-activated lymphocyte cytolysis. When untreated or DMSO-treated LS174T cells were injected intrasplenically into nude mice, the treated cells lacking certain cell surface sulfomucins formed fewer metastatic colonies in the liver. These results suggest that the loss of sulfomucins by colonic epithelial cells during progression is not directly related to the enhanced malignant behavior.
Clin Exp Metastasis 1999 Mar
PMID:Malignant and other properties of human colon carcinoma cells after suppression of sulfomucin production in vitro. 1041 Nov

The structural and functional heterogeneity of hepatocytes and non-parenchymal cells across the liver lobule or acinus has been well documented. The geographic distribution and potential for induced expression of adhesion molecules on murine hepatic microvascular cells has not been reported, although these molecules are able to influence the metastatic outcome of intravascular cancer cells. We have postulated that the expression of adhesion molecules on these cells is susceptible to regulation by environmental factors and that these molecules have a zonal distribution across the acinus. To test this hypothesis, we injected C57BL/6 mice with bacterial lipopolysaccharide, 1 microg/g body weight, i.p. At various time points (0-48 h) after stimulation, liver tissue sections were prepared for immunohistochemistry. Confocal microscopy was used to detect the expression of vascular cell adhesion molecule-1 (VCAM-1), E-selectin, intercellular adhesion molecule-1 (ICAM-1) and alpha v integrin. The expression patterns were quantitatively measured by histomorphometry. Under basal conditions, ICAM-1 was weakly expressed in terminal portal veins while minimal VCAM-1 and no E-selectin were detected. Following stimulation with lipopolysaccharide, VCAM-1 and E-selectin were expressed on the endothelium of terminal portal veins and on sinusoidal lining cells with significantly stronger expression in the periportal zone than midzone. VCAM-1 expression peaked at 4 h and decreased gradually by 48 h. E-selectin peaked at 2 h and disappeared by 12 h after stimulation. ICAM-1 expression showed a much stronger and more uniform expression across the acinus with the peak reached by 4 h and sustained for longer than 48 h after lipopolysaccharide administration. The alpha v integrin was not detected under basal conditions or after lipopolysaccharide stimulation. Expression of all these adhesion molecules (ICAM-1, VCAM-1, E-selectin and alpha v integrin) was induced by growth of B16F1 melanoma cells in the peritoneal cavity of the mouse. These results support the hypotheses that expression of microvascular adhesion molecules in the mouse liver is susceptible to regulation by environmental stimuli and has a zonal heterogeneity across the acinus.
Clin Exp Metastasis 1999 Mar
PMID:Murine hepatic microvascular adhesion molecule expression is inducible and has a zonal distribution. 1041 Nov 7

The selectins are a family of intercellular adhesion molecules that mediate the attachment of leukocytes to the endothelial lining of blood vessels. Another biological process that may involve selectins is the adhesion of circulating tumour cells to endothelium in cancer metastasis. This review discusses the evidence for the involvement of E-, P- and L-selectin in the metastasis of different tumour types. It is concluded that, with certain reservations and qualifications, selectins can play a role in metastasis. For example, the evidence for the involvement of E-selectin in breast and colon cancer metastasis is very strong. For the other selectins and tumour types the evidence is less convincing and further investigations are required to clarify the situation. Certainly, selectins are not the only mechanism available for tumours to metastasise. In the future, measurement of selectins could be useful prognostically and manipulation of their levels could lead to new cancer therapies.
Clin Exp Metastasis 1999 May
PMID:Are selectins involved in metastasis? 1043 3

The carbohydrate antigen sialyl-Lewis(a) is important to pancreatic tumour biology because the circulating antigen is used in serological tests for malignancy and because cell surface antigen is involved in tumour cell binding to the endothelial adhesion molecule, E-selectin, in extravasation. In this study, we examined the effects of the adenylyl cyclase activator, forskolin, and the diacylglycerol analogue, phorbol 12-myristate 13-acetate (PMA), on the expression and release of sialyl-Lewis(a) in human pancreatic cancer cells. Increases in the release of sialyl-Lewis(a) from SW1990 cells produced by forskolin and PMA were associated with increases in the activities of protein kinases A and C, respectively, and could be blocked by inhibitors specific for these enzymes. Immunoprecipitation experiments showed that sialyl-Lewis(a) was associated with MUC1 mucin. Forskolin also increased the cellular content of antigen and MUC1 mRNA. Actinomycin D and a protein kinase A inhibitor, H8, blocked these effects. In contrast, PMA reduced cellular antigen and MUC1 mRNA levels, although it produced a temporary increase in release of the antigen. The effects of PMA were blocked by the protein kinase C inhibitor, H7. PMA also reduced cell binding to the adhesion molecule E-selectin. In summary, PKA and PKC alter cell MUC1-associated sialyl-Lewis(a) in opposite directions. These changes may have clinical utility in the diagnosis of pancreatic cancer and the prevention of metastases.
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PMID:Forskolin and phorbol ester have opposite effects on the expression of mucin-associated sialyl-Lewis(a) in pancreatic cancer cells. 1074 4

In our previous studies we have found that human uroepithelial cell lines differ in their expression of sialosyl LewisA antigen. We have also shown that among the studied cell lines, only Hu 1703He cells with the highest expression of this tetrasaccharide bind to E-selectin-expressing cells. In the present study we put forward the question, of whether sialosyl LewisA-mediated adhesion of uroepithelial cells to E-selectin is important in the formation of metastases. The HCV 29T and Hu 1703He cells, representing two uroepithelial cell lines, were transplanted into NCr nu/nu mice. Hu 1703He cells express on their surface a high level of sialosyl LeA antigen, while HCV 29T cells are sialosyl LewisA-negative. We have shown that human uroepithelial cancer cells, in addition to their tumorigenic and invasive properties, are highly metastatic when inoculated into athymic nu/nu mice. The ability to form secondary tumour foci in lung and liver seems to be independent of the expression of sialosyl LewisA antigen.
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PMID:Metastatic potential of human uroepithelial cancer cells is not dependent on their adhesion to E-selectin. 1081 Mar 76

Systemic effects on T-cell-mediated antitumor immunity, on expression of T-cell adhesion/homing receptors, and on the promotion of T-cell infiltration of neoplastic tissue may represent key steps for the efficacy of immunological therapies of cancer. In this study, we investigated whether these processes can be promoted by s.c. administration of low-dose (0.5 microg/kg) recombinant human interleukin-12 (rHuIL-12) to metastatic melanoma patients. A striking burst of HLA-restricted CTL precursors (CTLp) directed to autologous tumor was documented in peripheral blood by a high-efficiency limiting dilution analysis technique within a few days after rHuIL-12 injection. A similar burst in peripheral CTLp frequency was observed even when looking at response to a single tumor-derived peptide, as documented by an increase in Melan-A/Mart-1(27-35)-specific CTLp in two HLA-A*0201+ patients by limiting dilution analysis and by staining peripheral blood lymphocytes (PBLs) with HLA-A*0201-melanoma antigen-A/melanoma antigen recognized by T cells (Melan-A/Mart)-1 tetrameric complexes. The CTLp burst was associated, in PBLs, with enhanced expression of T-cell adhesion/homing receptors CD11a/CD18, CD49d, CD44, and with increased proportion of cutaneous lymphocyte antigen (CLA)-positive T cells. This was matched by a marked increase, in serum, of soluble forms of the endothelial cell adhesion molecules E-selectin, vascular cell adhesion molecules (VCAM)-1 and intercellular adhesion molecules (ICAM)-1. Infiltration of neoplastic tissue by CDS+ T cells with a memory and cytolytic phenotype was found by immunohistochemistry in eight of eight posttreatment metastatic lesions but not in five of five pretreatment metastatic lesions from three patients. Increased tumor necrosis and/or fibrosis were also found in several posttherapy lesions of two of three patients in comparison with pretherapy metastases. These results provide the first evidence that rHuIL-12 can boost the frequency of circulating antitumor CTLp in tumor patients, enhances expression of ligand receptor pairs contributing to the lymphocyte function-associated antigen-1/ICAM-1, very late antigen-4/VCAM-1, and CLA/E-selectin adhesion pathways, and promotes infiltration of neoplastic lesions by CD8+ memory T cells in a clinical setting.
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PMID:Peripheral burst of tumor-specific cytotoxic T lymphocytes and infiltration of metastatic lesions by memory CD8+ T cells in melanoma patients receiving interleukin 12. 1091 69

We recently developed a method for the isolation and purification of tumour-derived endothelium. In this study the phenotypic and functional properties of human tumour-derived microvascular endothelial cells (TdMEC) were examined. Endothelium obtained from human adrenal gland specimens (HAMEC) was used as a reference microvascular endothelial cell population. TdMEC formed a confluent monolayer with the typical morphological appearance of endothelium and were positive for endothelial markers such as Ulex-1 lectin, CD31 antigen, von Willebrand Factor and VE-cadherin. The addition of acidic Fibroblast Growth Factor (aFGF), basic FGF (bFGF) or Vascular Endothelial Growth Factor (VEGF) substantially improved proliferation of TdMEC; and kidney carcinoma derived endothelial cells were more responsive to FGFs, whereas glioblastoma derived endothelial cells greatly responded to VEGF TdMEC expressed high levels of the VEGF receptors, KDR/flk-1 and Flt-1, as shown by northern blot analysis. TdMEC expressed the adhesion molecules ICAM-1, VCAM-1 and E-selectin that could be further increased by exposing TdMEC culture to interleukin-1. All the TdMEC expressed interleukin-8 mRNA. These findings show that TdMEC in vitro maintain several of the features described for microvasculature. Thus, TdMEC represent a useful tool to study markers for tumor vasculature.
Clin Exp Metastasis 1999
PMID:Phenotypic and functional characteristics of tumour-derived microvascular endothelial cells. 1091 10


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