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

CD95 ligand (CD95L) potently induces apoptosis by activating CD95 on target cells. It has recently been reported that melanoma cells in vivo express a significant amount of CD95L, thereby being immediately able to kill CD95-bearing immunocompetent cells specific for cancer antigens, which infiltrate the lesions. In this study, we employed immunohistochemistry using an antibody directed against CD95L to investigate at which stage the melanoma CD95L expression is turned on. Skin biopsies of 49 lesions from 46 patients were assessed. These included benign and dysplastic naevi, melanoma in situ, stage I melanomas (Clark's level 2 or 3), advance-phase melanomas (Clark's level 4 or 5) and lymph node metastases. CD95L was expressed in all of the advance-phase melanomas as well as lymph node metastases of cutaneous origin, whereas neither melanoma in situ, benign naevi nor dysplastic naevi reacted positively with the antibody. To investigate a link between positivity and tumour size, the data were analysed on the basis of Breslow thickness, and indicated that expression was observed only when tumours were thicker than 0.75 mm. We next compared expression of CD95L and HMB-45. CD95L was positive only in melanomas in a more advanced phase than stage I, whereas HMB-45 was not only expressed in melanoma cells but also in benign pigmented naevi. This indicated the advantage of CD95L staining to diagnose melanoma. The present study indicates the significant correlation between tumorigenicity and expression of CD95L, and thereby raises the possibility that CD95L may be a useful diagnostic marker for malignant melanomas.
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PMID:Expression of CD95 ligand in melanocytic lesions as a diagnostic marker. 976 32

Apoptosis induced by Fas (CD95) ligation is frequently lost during tumor progression; however, there is no direct evidence to support an association of Fas loss-of-function with metastatic tumor behavior. To determine whether Fas loss-of-function is critical for acquisition of the metastatic phenotype, we have compared the ability of Fas-sensitive K1735 murine melanomas to form spontaneous lung metastases in wild-type and Fas ligand-deficient mice. Fas-sensitive melanoma clones are highly tumorigenic but rarely metastatic in wild-type syngeneic mice. However, in Fas ligand-deficient mice, both the incidence and number of metastases are increased. These findings provide the first evidence that Fas-Fas ligand interactions can suppress metastasis and that tumor Fas loss-of-function may be causally linked to metastatic progression.
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PMID:Fas and Fas ligand interactions suppress melanoma lung metastasis. 980 83

The authors examined cellular mechanisms involved in anti-tumor reactivity induced by the murine MT-9G1 mammary tumor line, which was transduced to secrete granulocyte macrophage-colony-stimulating factor (GM-CSF). Compared with the parental MT-901 tumor, MT-9G1 subcutaneous tumors elicited an influx of CD4+ cells and dendritic cells. Secondary in vitro activation of tumor-draining lymph node cells with anti-CD3 and interleukin-2 resulted in effector cells that can mediate regression of established pulmonary metastases after adoptive transfer. In vivo depletion of T-cell subsets showed that tumor regression required CD4+ tumor-draining lymph node cells rather than CD8+ cells. The activated CD4+ cells expressed CD95L and mediated lysis of CD95+ MT-901 tumor cells, which were major histocompatibility complex class II negative. The CD4+ cells also released GM-CSF in response to tumor stimulation. A Fas fusion protein inhibited tumor lysis and GM-CSF release by the CD4+ cells. These studies document an alternate pathway by which CD4+ immune cells may recognize major histocompatibility complex class II-deficient tumors in which CD95L-bearing T cells induced an anti-tumor response mediated via CD95L:CD95.
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PMID:CD95-mediated tumor recognition by CD4+ effector cells in a murine mammary model. 1074 49

Interleukin-6 (IL-6) has been shown to support either autocrine or paracrine growth in melanoma, and may prevent programmed cell death in different cell types. We have previously demonstrated that the endogenous IL-6 level is significantly correlated with tumor burden and nonresponse to biochemotherapy in metastatic malignant melanoma patients. In the present study, we investigated the relationship between endogenous IL-6 and apoptosis signal through Fas (APO-1/CD95) receptor expression in 9 responder and 15 refractory patients with metastatic disease treated by biochemotherapy. Before any treatment, double immunostaining demonstrated that 61.5% of the tumor cells were HMB45+CD95+. At day 49 in refractory patients, a significant decrease (p = 0.04) of total Fas expression was observed. Furthermore, a significant reduction (p = 0.032) in the percentage of HMB45+CD95* cells occurred. An 11-fold increase in serum IL-6 level was detected (p < 0.002). This increase was negatively correlated (r = -0.2, p = 0.008) with the decrease in total Fas expression. However, in responding patients, no detectable decrease in Fas expression was observed, while a very low increase in serum IL-6 (2-fold) was detected. These results suggest that the increased endogenous IL-6 level in refractory patients may inhibit apoptosis via modulation of Fas expression. These preliminary results must be interpreted with caution, and further study with a greater number of patients is needed to understand the mechanism by which IL-6 inhibits apoptosis in melanoma.
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PMID:Effect of endogenous interleukin-6 on Fas (APO-1/CD95) receptor expression in advanced melanoma patients. 1114 Aug 82

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

Expression of Fas (CD95, APO-1), a cell surface receptor capable of inducing ligand-mediated apoptosis, is involved in tissue homeostasis and elimination of targeted cells by natural killer and T cells. Corruption of this pathway, such as reduced Fas expression, can allow tumor cells to escape elimination and promote metastatic potential. In this study, the status of Fas expression has been examined in the parental SAOS human osteosarcoma cells that do not metastasize and in selected variants that cause lung metastases in 16 weeks (LM2) or 8 weeks (LM6) after i.v. injection into nude mice. Fas expression correlated with the metastatic potentials of the three cell lines. Northern and fluorescence-activated cell-sorting analyses indicated that LM6 cells expressed Fas at a lower level than seen in the parental cells. Infection of the LM6 cells with an adenoviral vector containing the murine interleukin (IL)-12 gene (AD:mIL-12) or treatment with recombinant murine IL-12 resulted in a dose-dependent up-regulation of FAS: The up-regulation of Fas by IL-12 was also demonstrated in human etoposide-resistant MDA-MB-231 breast cancer cells. [(3)H]Thymidine growth inhibition studies indicated that the cell surface Fas induced after IL-12 exposure was functional and able to mediate cell death on cross-linking with anti-FAS: We also demonstrate that this effect is independent of IFN-gamma. Whereas these cell lines are sensitive to IFN-gamma, incubation with IFN-gamma does not increase susceptibility to Fas-mediated cell death, nor do these cells produce IFN-gamma with or without IL-12 treatment. We hypothesize that expression of Fas may play a role in the elimination of metastatic tumor cells in the lung, an organ in which Fas ligand is expressed. The antitumor activity of IL-12 may be secondary in part to its ability to up-regulate Fas expression on tumor cells, which subsequently increases immune-mediated destruction of osteosarcoma cells.
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PMID:Interleukin (IL)-12 and IL-12 gene transfer up-regulate Fas expression in human osteosarcoma and breast cancer cells. 1135 27

Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G(0/1)-S transition block and a 'sub-G(0/1)' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.
Clin Exp Metastasis 2000
PMID:In vitro effects of cholesteryl butyrate solid lipid nanospheres as a butyric acid pro-drug on melanoma cells: evaluation of antiproliferative activity and apoptosis induction. 1182 70

Membrane-bound Fas ligand (FasL, Apo-1L, CD95L) induces rapid apoptosis of Fas (CD95)-sensitive cells on interaction with Fas, and is an important effector molecule of cytolytic T lymphocytes (CTLs). Melanomas are immunogenic and induce the production of specific CTLs, but are usually able to escape immune destruction. We investigated Fas expression and function in 53 cutaneous melanocytic lesions and 13 melanoma cell lines grown in vitro. Immunohistochemical analysis of Fas expression in cutaneous melanocytic lesions showed moderate to high levels of Fas in common benign melanocytic naevi, but low to undetectable levels in atypical naevi, primary (superficial spreading melanoma, nodular melanoma) and cutaneous melanoma metastases. Fluorescence-activated cell sorting (FACS) analysis of Fas expression in melanoma cell lines revealed undetectable or low levels of cell surface Fas expression in five of the 13 melanoma cell lines. Analysis of Fas signalling by quantification of cell death following exposure to recombinant FasL showed that a reduction in Fas expression results in resistance to FasL-mediated cell death. Furthermore, two of the 13 melanoma cell lines were found to be resistant to FasL-mediated cell death despite conserved Fas expression. Thus seven of the 13 melanoma cell lines were found to have impaired Fas signalling. Taken together, our results indicate that downregulation of Fas expression and resistance to Fas-mediated apoptosis are frequent in melanoma.
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PMID:Frequent downregulation of Fas (CD95) expression and function in melanoma. 1214 Mar 83

The purpose of this investigation was to evaluate firstly whether different protein expression patterns exist in primary squamous cell lung carcinomas of patients with and without lymph node involvement and secondly, whether or not different patterns exist in tumours with positive lymph nodes. For this reason, formalin-fixed, paraffin-embedded specimens from 130 patients with squamous cell lung carcinomas were analyzed by immunohistochemistry. In a first step, proteins were selected which showed a relationship to lymph node involvement. The expression of JUN, ERBB2, MYC, cyclin D, PCNA, bFGF, VEGF and Hsp70 proteins revealed a positive correlation to lymph node involvement. In contrast, caspase-3, Fas ligand, Fas/CD95, and PAI showed an inverse correlation to lymph node involvement. In a second step, these parameters were further analyzed by hierarchical cluster analyses. The resulting clusters were correlated to patients with or without lymph node involvement. The data show that different protein expression patterns exist between primary squamous cell lung carcinomas with and without lymph node involvement and within carcinomas with lymph node involvement. The data suggest that various metastasis profiles exist.
Clin Exp Metastasis 2002
PMID:Protein expression profile of primary human squamous cell lung carcinomas indicative of the incidence of metastases. 1219 66

Fas(APO-1/CD95) is a transmembrane protein that induces apoptosis in susceptible normal and neoplastic cells upon cross-linking by its ligand (FasL). Changes in the Fas and FasL expression were suggested to be a potential mechanism of tumor immune evasion. Thyroid cancer in children and young adults of the Republic of Belarus is the consequence of the Chernobyl accident. Papillary thyroid cancer (PTC) is the most common variant of thyroid carcinoma. This study was performed on the formalin-fixed and paraffin-embedded tissues obtained after surgery from 43 patients with PTC. The presence of Fas and FasL in thyroid tissue specimens was examined immunohistochemically. Positive staining for FasL was observed on neoplastic thyrocytes, whereas staining of normal thyroid cells was weak or absent. The pattern of staining was membranous and cytoplasmic. Staining of lymphocytes both in tumor tissue and in lymph nodes for FasL was weak or absent. Fas expression was found on normal thyroid cells, cancer cells and lymphocytes both in tumor and in lymph nodes with metastases. In lymph node metastases, in lymphocytes adjacent to FasL cancer cells morphological signs of apoptosis were observed.
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PMID:[The role of Fas/FasL system in the regulation of tumor-immune system interactions in papillary thyroid carcinoma in children and adolescents]. 1451 88


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