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)

Malignant pleural effusion (PE) is a frequent problem in lung cancer. In this study, we established a model of malignant PE of human adenocarcinoma cells, PC-14, in SCID mice. Intravenously injected PC-14 cells formed colonies in the lungs as early as week 4 after tumor inoculation, and produced bloody PE in all recipient SCID mice by week 8. Pretreatment of SCID mice with anti-mouse IL-2 receptor beta chain antibody (TM-beta 1) to deplete natural killer (NK) cells markedly promoted the production of bloody PE and metastases to multiple organs, such as the lungs, liver, kidneys, and lymph nodes 4 weeks after tumor inoculation. Histological studies indicated that PC-14 cells formed colonies in the lungs, and then invaded the pleura and spread to the pleural cavity. To establish cell lines with a high potential to produce PE, we harvested PE, expanded the tumor cells in vitro, and injected them into SCID mice again. By four in vivo selection cycles in this way we obtained PC-14-PM4 cells, which produce lung metastases and PE earlier than PC-14 cells. The survival of SCID mice inoculated with PC-14-PM4 cells was significantly shorter than that of mice inoculated with PC-14 cells. The expressions of adhesion molecules, such as CD44, CD49d, ICAM-1, and MHC class I, on PC-14-PM4 cells tended to increase compared with PC-14 cells. These changes of adhesion molecules seem to be one of possible mechanisms involved in higher metastatic potential of PC-14-PM4 cells. PE models with PC-14 and PC-14-PM4 cells should be useful for biological and preclinical studies on malignant PE produced by human lung cancer.
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PMID:Model of malignant pleural effusion of human lung adenocarcinoma in SCID mice. 956 4

Metastatic colorectal cancer is usually progressive despite infiltration of the tumours by T lymphocytes, suggesting that these tumour-infiltrating lymphocytes (TILs) are functionally deficient. Recently, TILs from other tumours have been shown to express reduced levels of the T-cell receptor signal-transducing CD3-zeta chain. We were interested to determine whether a similar abnormality existed in TILs from human colorectal hepatic metastasis (CHM) and, if so, whether correcting the abnormality in vitro would restore anti-tumour activity and provide support for the development of immunotherapy for colorectal hepatic metastases. Twelve of 19 TILs from colorectal hepatic metastases were successfully expanded in vitro in high-dose recombinant interleukin 2 (rlL-2) and their specific anti-tumour cytolytic activity was determined. CD3-positive (CD3+) TILs were HLA-Drhigh and CD69high, suggesting that they had been activated by exposure to antigen but expressed low levels of CD25, CD71 and the nuclear proliferation antigen Ki-67. Furthermore, they showed reduced expression of CD3-zeta compared with autologous peripheral blood T cells (PBTs) and failed to proliferate in the absence of high-dose rIL-2. Expansion of TILs in rIL-2 resulted in restoration of CD3-zeta expression and the ability to lyse K562 and Daudi cells but not autologous tumour cells. The absence of autologous tumour-specific cytolytic T-cell (CTL) activity may be due to the poor immunogenicity of colorectal tumour cells, which we found expressed only low levels of MHC I antigens and CD54 and failed to express MHC II antigens or the co-stimulatory molecules CD80, CD86 or CD106. The inability of rIL-2 to generate tumour-specific CTLs despite restoration of CD3-zeta expression and the presence of an intact lytic mechanism suggests that successful immunotherapy may require the development of strategies to increase the immunogenicity of this tumour.
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PMID:Interleukin 2 restores CD3-zeta chain expression but fails to generate tumour-specific lytic activity in tumour-infiltrating lymphocytes derived from human colorectal hepatic metastases. 956 42

Intercellular adhesion molecule (ICAM)-1 and mucin isotype MUC18 were originally identified as melanoma progression antigens by monoclonal antibodies (MAb) generated in a search for molecules expressed by melanomas but not detectable on benign naevi. As MAb detect single epitopes whose accessibility may be modulated, a new panel of antibodies directed against distinct epitopes and reacting with denatured nonglycosylated antigen as well as native antigen were used to examine expression of these molecules on melanocytic lesions. The antibodies were analysed in a binding inhibition assay and divided into groups defining independent epitopes. Three anti-ICAM-1 and four anti-MUC18 antibodies representing these groups were then tested on frozen sections of 10 benign naevi and 10 melanoma lymph-node metastases. The anti-ICAM-1 antibodies demonstrated concordant reactivities on both the malignant and benign lesions and reacted with all samples suggesting that antibodies that detect differences in ICAM-1 expression between these two lesions detect altered epitopes. Three of the four antibodies directed to MUC18 showed concordant reactivities and indicated that this molecule was expressed in nine melanomas and three naevi. However, one antibody (MUC18BA.3) reacted strongly with all lesions indicating either crossreactivity with another melanocyte molecule or the expression of a different form of MUC18 on naevi.
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PMID:Analysis of the expression of intercellular adhesion molecule-1 and MUC18 on benign and malignant melanocytic lesions using monoclonal antibodies directed against distinct epitopes and recognizing denatured, non-glycosylated antigen. 957 20

The actual mechanisms responsible for lymph node metastasis in gastric cancer are still unclear. To investigate the mechanisms of lymph node metastasis in gastric cancer, we established a lymph node metastatic model for human scirrhous gastric carcinoma. Lymph node metastasis had frequently developed after orthotopic implantation of OCUM-2M LN derived from a scirrhous gastric cancer cell line, OCUM-2M, which had low capacity for lymph node metastasis. We elucidated the different characteristics including binding ability, migratory capacity and immunoresponses induced by the cell surface molecules of these two cell lines. The binding ability to Matrigel and migratory capacity of OCUM-2M LN cells were significantly greater than those of OCUM-2M cells. On flow cytometric analysis, both OCUM-2M and OCUM-2M LN cells strongly expressed HLA-I (99.5 and 97.1%) and LFA-3 (76.6 and 99.2%) in level of expression between the two cell lines, but neither cell line expressed HLA-II (0.0 and 0.0%), B7-1 (0.0 and 0.0%) or B7-2 (0.4 and 0.3%). ICAM-1 expression in OCUM-2M LN cells was weaker (0.7%) than that in OCUM-2M cells (36.8%). Strong adhesiveness and cytotoxicity of mononuclear lymphocytes for OCUM-2M cells were observed in adhesion and cytotoxic assays, both of which were significantly decreased by the addition of anti-ICAM-1 antibodies. On the other hand, the adhesiveness and cytotoxicity of OCUM-2M LN cells were significantly less than those of OCUM-2M cells, and were not affected by the addition of anti-ICAM-1 antibodies. These findings suggest that decreased ICAM-1 expression in a new gastric cancer cell line with a high rate of lymph node metastasis may in turn decrease immune responses mediated through LFA-1-dependent effector cell adhesion, and that this escape from the immunosurveillance system may be one of the factors inducing lymph node metastasis. In conclusion, we established a gastric cancer cell line, OCUM-2M LN, with a high rate of lymph node metastasis. An in vivo lymph node-metastatic model with this cell line should be useful for analysing the mechanism and therapeutic approach of lymph node metastasis.
Clin Exp Metastasis 1998 May
PMID:Establishment of lymph node metastatic model for human gastric cancer in nude mice and analysis of factors associated with metastasis. 962 18

To investigate the cellular mechanism of lymph node metastasis by tumor cells through the lymphatic vessels in the uterine corpus, we selected an active metastatic subline (PL3) from rat Walker 256 tumor cells and used it to develop a novel experimental model of lymph node metastasis induced by intrauterine inoculation of the tumor cells. Light- and electron-microscopic examinations revealed that the inoculated PL3 cells could actively infiltrate the endometrium from the uterine cavity and form a primary lesion in the uterine corpus. A few PL3 cells in the myometrium were found in the lumen of the peripheral lymphatic vessels on day 7 after inoculation. The regional lymph nodes around the uterus were then invaded by the migrated PL3 cells, and finally (after 3 weeks), most of the parenchyma of the nodes was replaced by metastasized tumor cells. By flow-cytometric analysis, the metastatic PL3 cells expressed CD44, like Walker 256 cells, but lacked integrin alphaL- and alpha4-chains. However, expression of ICAM-1 was considerably down-regulated in the PL3 cells compared to the parent cells. More aggressive invasion was shown by the PL3 cells compared to the parent cells in the in vitro invasion assay. These findings suggest that this experimental model and the separated PL3 cells are suitable for thorough investigations of the unidentified metastatic process and the related cellular behavior involved in the onset of lymphatic invasion by the primary lesion. Furthermore, our model more closely reproduces the clinical conditions related to lymph node metastasis of malignant carcinomas through the lymphatic vessels than does any previously reported animal model.
Invasion Metastasis 1997
PMID:Novel animal model of lymph node metastasis by intrauterine inoculation of the actively metastatic subline PL3 separated from rat Walker 256 tumor cells. 970 41

Cultures of endothelial (En) cells derived from human brain microvessels were established in order to characterize adhesion molecule expression and to assay the adhesion properties of neoplastic cell lines to monolayers of En cells. Low constitutive expression of beta1 integrin (CD29), and ICAM-2 (CD102) was detected on human brain microvessel En cells. The beta1 chain of the VLA integrin family, ICAM-1, E-selectin (CD62E) and VCAM-1 (CD106) but not ICAM-2 and PECAM-1 (CD31) expression was upregulated by IL1-alpha, and TNF-alpha proinflammatory cytokines. High expression of PECAM-1 was found on non-activated human brain EN cells. In order to study the potential role of adhesion molecules in neoplastic cell adhesion two tumor cell lines were chosen. Adhesion of a cell line (DU145) derived from a cerebral metastasis of prostate carcinoma to human brain microvessel En cell monolayers was less pronounced compared to adhesion of a primary prostate carcinoma cell line (ND1). Adhesion of cerebral metastatic neoplastic cell line (DU145) was not significantly influenced by incubation of endothelial cells with different proinflammatory cytokines. The adhesion capability of primary prostate carcinoma line (NDI) was significantly upregulated by TNF-alpha proinflammatory cytokine. Furthermore, the adhesion of ND1 was partly inhibited using anti-E-selectin and VCAM-1 monoclonal antibodies. There was no significant effect of anti-adhesion antibodies on the adhesion characteristics of the cerebral metastatic (DU145) cell line. Our data demonstrate that different mechanisms are involved in the adhesion of neoplastic cells to cerebral En cells and turn our attention to the importance of adhesion molecule expression in the formation of metastases.
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PMID:Influence of adhesion molecule expression by human brain microvessel endothelium on cancer cell adhesion. 972 32

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in cell to cell interactions. In malignant melanoma, ICAM-1 expression correlates with malignant behavior. We used monoclonal antibodies, anti-ICAM-1, anti-CD4+, anti-CD8+, and anti-CD11c+ to study the effect of interferon-alpha (IFN-alpha) on the expression of ICAM-1 by melanoma cells in regional metastases and its correlation to the occurrence of CD4+, CD8+, and CD11c+ cells close to tumor cells and in the tumor stroma. We also estimated the expression of ICAM-1 and regressive changes in malignant melanoma metastases, correlating the duration of treatment to these effects of IFN-alpha. Twenty-three IFN-alpha-treated and 10 untreated patients with regional metastatic malignant melanoma were studied. The duration of IFN-alpha treatment influenced the expression of ICAM-1. In metastases from patients treated for 1 week only, 1 of 5 showed high expression of ICAM-1 compared with 6 of 11 of those treated for 3 weeks (p = 0.01, chi-square test for trend comparing untreated patients and patients with various durations of IFN-alpha treatment). In IFN-alpha-treated patients with low expression of ICAM-1, none of 7 metastases showed CD4+ cells infiltrating close to tumor cells, in contrast to 6 of 10 metastases expressing high amounts of ICAM-1 (p = 0.03). Similarly, the expression of ICAM-1 was found to correlate with the occurrence of CD8+ cells close to the tumor cells (p = 0.04). We also showed a correlation between ICAM-1 expression and histologic evidence of tumor regression (p = 0.02).
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PMID:Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumor-infiltrating mononuclear cells and regressive tumor changes. 1009 Apr 2

We hypothesized that adoptively increasing the density of antigen-presenting cells (APCs) at a tumor site would improve tumor-infiltrating lymphocyte (TIL) in vivo antitumor efficacy. Irradiated splenocytes were used as crude APCs. Alone, they did not have in vitro antitumor activity nor did they augment TIL efficacy in vitro. Pulmonary metastases were established by intravenous (i.v.) injection of 5 x 10(5) MC-38 tumor into irradiated C57B1/6 mice (500 cGy). After 3 days, MC-38 TIL (0.1, 0.5, and 1 x 10(6) cells) +/- irradiated splenocytes (5,000 cGy) as APCs were administered intravenously (0.25, 0.5, and 1 x 10(6) cells) to each group (n = 5/group). Interleukin-2 (60,000 IU) was injected intraperitoneally three times daily for 3 days. Mice were sacrificed 9 days later and metastases elaborated in blinded fashion. A titer of 1 x 10(6) TIL, completely eradicated pulmonary metastases. In two consecutive experiments, when increasing titers of irradiated splenocytes were coinfused with a constant titer of TIL that did not completely eradicate pulmonary metastases, a moderate reduction in pulmonary metastases was observed. The contribution of splenocytes to an improvement in TIL antitumor efficacy was not altered when irradiated splenocytes derived from mice bearing 10-day subcutaneous MC-38 tumors were used. The coinfusion of nonirradiated splenocytes did not improve TIL antitumor in vivo activity. Activated B cells (expressing ICAM-1, B7.1, and B7.2) had no effect on in vitro tumor lysis and did not augment in vivo TIL efficacy. The results show a modest but statistically significant improvement in adoptive immunotherapy antitumor efficacy with fewer TIL by coinfusion of irradiated splenocytes. Further studies to characterize the active potential APC cell subpopulation and to clarify the mechanism(s) responsible for in vivo augmentation of TIL antitumor efficacy are in progress.
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PMID:Coinfusion of irradiated splenocytes with low titer tumor-infiltrating lymphocytes augments antitumor efficacy in adoptive immunotherapy. 1009 37

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

Outgrowth of solid tumors and metastases is dependent on the process of angiogenesis. Tumors escape from the formation of an effective infiltrate by downregulation of endothelial adhesion molecules. This downregulation of adhesion receptors is governed by the exposure to angiogenic factors. In recent years proof for this has been provided by demonstrating that freshly isolated tumor endothelial cells exhibit a decreased expression of ICAM-1 and -2 as compared to endothelial cells in normal tissue. In addition, adhesion molecules are downregulated on normal tissue endothelial cells when cultured with angiogenesis stimulators such as basic fibroblast growth factor and vascular endothelial cell growth factor, while under these conditions endothelial cells become less responsive to cytokines such as tumor necrosis factor-alpha with respect to the upregulation of endothelial adhesion molecules. Very recently it has been demonstrated that this harmful endothelial cell anergy can be counteracted by inhibitors of angiogenesis.
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PMID:Angiogenesis modulates the tumour immune response. 1031 18


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