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)

Effects on the liver of the antiangiogenesis agent O-(chloroacetyl-carbamoyl) fumagillol (TNP-470) on hematogenous metastasis of a human pancreatic carcinoma cell line were examined. One million PCI-43 cells, a human pancreas carcinoma cell line, were injected into the spleen of SCID beige mice, then TNP-470 at 30 mg/kg was administered subcutaneously every other day. The mice were killed 6 or 10 weeks thereafter and metastatic nodules in the liver were counted and measured microscopically. Metastases were inhibited and an approximately 10% loss of weight was evident in the TNP-470-administered mice. There was no suppression in maximal size of metastatic colonies in mice given the agent for 6 weeks, while inhibition was apparent in mice given the drug for 10 weeks. Suppression of proliferation and an increase in apoptosis were evident in metastatic nodules in the TNP-470-administered groups, following stainings for proliferative cell nuclear antigen and terminal deoxytransferase-mediated dUTP-biotin nick end-labeling, respectively. TNP-470 inhibited the proliferation of human umbilical vein endothelial cells but not PCI-43 in vitro. TNP-470 did not suppress production of vascular endothelial growth factor by PCI-43 cells. Neovascularization in vivo induced by PCI-43 cells was suppressed in the TNP-470-administered mice, using a diffusion chamber placed in subcutaneous tissues of SCID beige mice. These observations suggest that inhibition of angiogenesis is effective in suppressing establishment and subsequent growth of hematogenous micrometastases of pancreatic adenocarcinoma to the liver.
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PMID:Inhibitory effects of the antiangiogenic agent TNP-470 on establishment and growth of hematogenous metastasis of human pancreatic carcinoma in SCID beige mice in vivo. 933 88

We determined whether the IFN-beta gene can be used to suppress angiogenesis, tumor growth, and metastasis of human prostate cancer cells growing in the prostate of nude mice. Highly metastatic PC-3M human prostate cancer cells were engineered to constitutively produce murine IFN-beta subsequent to infection with a retroviral vector containing murine IFN-beta cDNA. Parental (PC-3M-P), control vector-transduced (PC-3M-Neo), and IFN-beta-transduced (PC-3M-IFN-beta) cells were injected into the prostate (orthotopic) or subcutis (ectopic) of nude mice. PC-3M-P and PC-3M-Neo cells produced rapidly growing tumors and regional lymph node metastases, whereas PC-3M-IFN-beta cells did not. PC-3M-IFN-beta cells also suppressed the tumorigenicity of bystander nontransduced prostate cancer cells. PC-3M-IFN-beta cells produced small tumors (3-5 mm in diameter) in nude mice treated with anti-asialo GM1 antibodies and in severe combined immunodeficient/Beige mice. Immunohistochemical staining revealed that PC-3M-IFN-beta tumors were homogeneously infiltrated by macrophages, whereas control tumors contained fewer macrophages at their periphery. Most tumor cells in the control tumors were stained positive by an antibody to proliferative cell nuclear antigen; very few were positively stained by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling. In sharp contrast, PC-3M-IFN-beta tumors contained fewer proliferative cell nuclear antigen-positive cells and many terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling-positive cells. Staining with antibody against CD31 showed that control tumors contained more blood vessels than PC-3M-IFN-beta tumors. PC-3M-IFN-beta cells were more sensitive to lysis mediated by natural killer cells in vitro or to cytostasis mediated by macrophages than control transduced cells. Conditioned medium from PC-3M-IFN-beta cells augmented splenic cell-mediated cytolysis to control tumor cells, which could be neutralized by antibody against IFN-beta. Collectively, the data suggest that the suppression of tumorigenicity and metastasis of PC-3M-IFN-beta cells is due to inhibition of angiogenesis and activation of host effector cells.
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PMID:Suppression of angiogenesis, tumorigenicity, and metastasis by human prostate cancer cells engineered to produce interferon-beta. 1002 78

The expression of Fas ligand has recently been proposed as a novel tumor escape mechanism for melanoma. To establish the characteristics of Fas ligand expression during the course of melanoma progression we performed a longitudinal study analyzing primary tumors as well as subsequently evolving metastases. In primary melanoma Fas ligand was expressed in two of 20 lesions; this expression was weak and restricted to few parts of the tumors. The Fas ligand positive primary melanomas were rather thick, i.e., 8.5 and 3.8 mm, versus a median of 2.4 mm of the remaining tumors. In contrast, for metastatic melanoma Fas ligand expression was present in six of 11 cases investigated. The metastases of primary tumors displaying Fas ligand maintained its expression. As Fas ligand positive melanoma cells are capable of inducing apoptosis in susceptible cells, e.g., Fas positive tumor infiltrating lymphocytes, we tested for the presence of apoptotic cells in situ by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. This analysis revealed that apoptotic cells were present within the Fas ligand positive tumors. The number of apoptotic cells, however, never exceeded 5% of the total cells. Thus, Fas ligand mediated apoptosis does not seem to be a major immune escape mechanism for melanoma but its expression correlates with the stage of melanoma.
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PMID:Predominant expression of Fas (CD95) ligand in metastatic melanoma revealed by longitudinal analysis. 1038 36

This study was designed to determine the effect of lipid microspheres containing prostaglandin E1 (lipo PGE1) on cis-diamminedichloroplatinum (CDDP) accumulation in primary and lung metastatic lesions. Sixty mice were divided into four groups, depending on whether or not an intra-foot-pad injection of Dunn osteosarcoma cells had been administered and on whether or not an intraperitoneal injection of lipo PGE1 had been administered. CDDP was injected intraperitoneally into all the mice 6 weeks after the inoculation. Tumor colonies of spontaneous metastases in the left lung were found in 21 out of 30 tumor-inoculated mice at autopsy. Tissue platinum concentrations in the lungs with metastatic colonies and in the foot-pad tumors were significantly higher in the lipo PGE1-administered mice than in those without treatment. Terminal deoxytransferase-mediated dUTP nick end labeling (TUNEL) assay showed marked localization of dying cells in the lung metastatic lesions of the lipo PGE1-administered mice. The results of this study showed that pretreatment with lipo PGE1 may augment the antitumor effects of CDDP at the tumor site.
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PMID:Effects of lipo prostaglandin E1 on distribution of cis-diamminedichloroplatinum in lung metastasis derived from Dunn osteosarcoma cell-inoculated mouse foot-pad. 1040 54

Antimetastatic effects of 5-FU and its derivative, 1-hexylcarbamoyl-5-fluorouracil (HCFU) on human gastric cancer micrometastasis and their mode of action were evaluated, using a spontaneous lung metastasis model (HY-1) in nude mice. Metastases were first detected in the lung from 4 weeks after subcutaneous transplantation, growing intravascularly and forming micrometastases at 100% incidence by 6 weeks after implantation. Lung metastasis in mice bearing subcutaneous tumors was significantly inhibited by HCFU at doses of 100-150 mg kg(-1) day(-1) without severe toxic side-effects, when orally administered three times per week either from week 4 or week 6 to 9 weeks after implantation. Spontaneous lung metastasis was also inhibited by the administration of 5-FU, but to lesser extent than with HCFU at equimolar low doses. Apoptosis within primary tumors and lung metastatic foci, as detected by the terminal-deoxynucleotidyltransferase-mediated dUTP nick-end labeling method, was found to be significantly enhanced by HCFU as well as 5-FU administration at doses of more than 100 mg kg(-1) day(-1) and 50 mg kg(-1) day(-1) respectively. However, proliferating activity of the metastatic foci, as evaluated by MIB-1 immunostaining, was not significantly suppressed by HCFU or 5-FU treatment. Furthermore, polymerase chain reaction analysis using human specific primers for the beta-globin gene, which proved to be capable of detecting 10 tumor cells/ml mouse blood, revealed that circulating tumor cells in the peripheral blood of mice bearing primary tumors were reduced by HCFU or 5-FU administration. These results indicate that circulating tumor cells in blood and micrometastases in the lung are sensitive to these chemotherapeutic agents, and suggest that the anti-metastatic effect of these agents is mediated, at least in part, by enhanced apoptosis rather than by inhibition of cell proliferation.
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PMID:Induction of apoptosis in metastatic foci from human gastric cancer xenografts in nude mice and reduction of circulating tumor cells in blood by 5-FU and 1-hexylcarbamoyl-5-fluorouracil. 1059 98

The liver is the most common site of metastasis in pancreatic cancer, and there are no promising strategies to treat it. Angiostatin, a kringle-containing fragment of plasminogen, is a potent inhibitor of angiogenesis. The effect of angiostatin on liver metastasis in pancreatic cancer was investigated by using our established hamster model of liver metastasis. Pancreatic cancer cells (PGHAM-1, 1 x 10(6)) derived from N-nitrosobis(2-oxopropyl)amine (BOP)-induced pancreatic tumor in Syrian golden hamsters were transplanted into the spleen of female hamsters, and the animals were subcutaneously injected with angiostatin and saline. Subsequently, the macroscopic appearance of liver surface metastases was evaluated. In addition, histological sections of the liver metastases were analyzed for neovascularization, proliferation, and apoptosis on the basis of von Willebrand factor, argyrophilic nucleolar organizer region (Ag-NOR), and TdT-mediated dUTP-biotin nick end labeling (TUNEL) staining, respectively. The results showed significant tumor growth retardation and inhibition of angiogenesis in metastatic liver tumors in response to treatment with angiostatin. Moreover, the metastases remained in a nearly dormant state due to a balance between apoptosis and proliferation of the tumor, with no detectable side effects. This is the first experimental trial of angiostatin on pancreatic cancer and liver metastasis. The results suggest that angiostatin therapy could be effective against liver metastases of pancreatic cancer.
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PMID:Effect of angiostatin on liver metastasis of pancreatic cancer in hamsters. 1092 Feb 80

The role of endogenous NO on cell survival was investigated in human melanoma cells and melanocytes. Inducible NO synthase (iNOS) was always expressed in a panel of melanoma cell lines from metastatic lesions and in normal adult melanocytes. iNOS was also detected by immunohistochemistry in melanoma cells from metastases. Release of NO by tumor cells and melanocytes was inhibited by a specific iNOS inhibitor, aminoguanidine (AMG). Inhibition of endogenous NO synthesis did not affect cell cycle progression of melanoma cells but led to cell death by apoptosis, as indicated by Annexin V/propidium iodide and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assays. By contrast, iNOS inhibition by AMG did not promote apoptosis in normal adult melanocytes. A mitochondrial pathway was involved in melanoma apop tosis, as indicated by altered mitochondrial membrane potential (delta psi(m)) and down-regulation of Bcl-2 protein level after iNOS inhibition. AMG treatment triggered release of caspase-1, enzymatic activation of caspase-3, and degradation of poly(ADP-ribose) polymerase, one of the main caspase-3 substrates. Melanoma cell apoptosis induced by iNOS inhibition was completely blocked by peptide inhibitors of caspase-1 and caspase-3 (Ac-DEVD-CHO and AC-YVAD-CHO) or by an exogenous NO donor, sodium nitroprusside, or by addition of serum. Finally, comparison of control and AMG-treated melanoma cells by pathway-specific gene array analysis indicated that inhibition of NO synthesis led, before induction of apoptosis, to up-regulation of mRNA levels of genes involved in the apoptosis pathway such as Bax, caspase-1, caspase-3, caspase-6, gadd45beta, mdm2, and TRAIL. Taken together, these results indicate that melanoma cell survival is regulated by endogenous NO resulting from iNOS activity.
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PMID:Antiapoptotic role of endogenous nitric oxide in human melanoma cells. 1119 80

Tumors may escape a host's immune response by means of various mechanisms. The Fas (CD95/APO-1)/Fas ligand (FasL) system is one of the major apoptotic pathways. Recently, it has been reported that tumor cells can express FasL, induce apoptosis in tumor infiltrating lymphocytes, and thus can escape host immune surveillance. In gastric carcinoma, tumor progression by way of the lymphatics is often seen, and lymph node metastasis is a critical factor influencing the recurrence of cancer and its prognosis. We, therefore, investigated the relationship between the expression of FasL and the lymphatic spread of gastric carcinoma. FasL-expression was examined by an immunohistochemical method using 100 surgically resected gastric carcinomas and 55 metastatic lymph nodes. Apoptotic cells among tumor infiltrating T lymphocytes were detected by T lymphocyte staining and the terminal deoxynucleotidyl transferase (TdT) mediated dUTP nick end labeling (TUNEL) method in a series of sections of metastatic lymph nodes. FasL-expression was detected in 86% of primary lesions and 71% of metastatic lymph nodes. In cases with high levels of FasL-expression, the observed expression of lymph node metastases was significant (p=0.047). Moreover, FasL-positive cases with both primary lesions and metastatic lymph nodes showed also distant lymph node metastasis beyond the regional lymph nodes (p=0.030). Apoptosis among tumor infiltrating T lymphocytes was more frequently seen in FasL-positive lesions (p=0.057). Furthermore, patients with FasL-negative primary lesions tended to exhibit longer survival times than patients with FasL-positive primary lesions. The results suggest tumor escape through the lymphatic pathway via FasL-expression in gastric carcinomas.
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PMID:Expression of Fas ligand in gastric carcinoma relates to lymph node metastasis. 1135 Dec 45

Our objective was to investigate the prognostic significance of cell turnover (apoptosis and proliferation) in breast cancer patients. Apoptosis was microscopically quantitated on histological sections from 791 breast cancer patients with long-term follow-up (median, 16.3 years). Apoptotic counts were also compared with proliferation data (mitotic counts and MIB-1 labeling); apoptosis data derived from terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay; and pathobiological variables, including p53, erbB-2, and estrogen receptor (ER). High apoptotic counts were associated with increased cellular proliferation, ER negativity, immunopositivity of erbB-2 and p53 (P < 0.0001), and shortened disease-specific survival (DSS; P = 0.0009) and disease-free survival (DFS; P = 0.0006). Other factors associated with shortened DFS and DSS by univariate analysis were high tumor grade, nodal metastases, and large tumor size (P < 0.0001 for each). Multivariate analysis of data for all of the patients demonstrated that tumor size, nodal status, ER, histological grade, and erbB-2 showed independent prognostic value. In node-negative patients, tumor size and mitotic rate per 1000 cells independently predicted DFS (P = 0.0055). Tumor grade was the only independent predictor of DSS. For node-positive patients, tumor size, nodal status, ER, and erbB-2 were independent prognostic factors. The number of mitoses per 1000 was independently associated with DFS (P = 0.043) but not with DSS. Apoptosis data did not provide independent prognostic value in any, node-positive or node-negative, breast cancer patients.
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PMID:Measures of cell turnover (proliferation and apoptosis) and their association with survival in breast cancer. 1141 May 11

Prognosis of patients with renal cell carcinoma (RCC) is mainly determined by metastases. The understanding of the metastatic process will give the basis for a differential diagnosis leading to an individual prognosis and to new therapeutical strategies. In order to define specific genetic alterations which are common in renal cancer metastases of the lung, we performed comparative genomic hybridization (CGH) on metastases and in some cases on their related primary renal tumors. For CGH, DNA was isolated from 2 or 5 paraffin sections (5 micro m). Tumor and normal (control) DNAs were amplified by DOP-PCR and labeled with biotin-dUTP and digoxigenin-dUTP, respectively. Hybridization and detection were carried out according to standard protocols. In 33 out of 40 metastases, genetic alterations were detected, most frequently these were losses of chromosomes 3p (74%), 8p (31%), 9 or 9q (34%), 14 [26%, 18q (40%) and gains of chromosome 5/5q 34%], 7 (31%) and 12 (26%). Combination of loss of 8p and gain of 8q occurred frequently. The mean number of aberrations per tumor was 8.1 (1-11). The comparison of alterations in related primary and metastatic tumors showed identical alterations in 5 out of 8 cases. This study demonstrates, that lung metastases from renal cell carcinoma are characterized by an accumulation of specific genetic alterations which show a clonal relationship to the related primary tumors.
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PMID:Genetic characterization of lung metastases in renal cell carcinoma. 1279 66


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