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)

The formation of brain metastases is an important clinical end point in patients with cancer. The brain provides a unique microenvironment enclosed by the skull, lacking lymphatic drainage and maintaining a highly regulated vascular transport barrier. In the brain microcirculation, brain-metastatic tumor cells must attach to endothelial cells, respond to brain-derived invasion factors, and invade the blood-brain barrier. Neurotrophins are important brain invasion-stimulating factors in this process, and in responsive tumor cells neurotrophins can promote invasion by enhancing the production of basement-membrane-degradative enzymes (gelatinase and heparanase) capable of locally destroying the blood-brain barrier. We examined human melanoma variant lines that express low-affinity p75 neurotrophin receptor in relation to their brain-metastatic potentials. Expression of p75 in these variants occurs in the absence of expression of trkA, the gene encoding the high-affinity nerve growth factor (NGF) tyrosine kinase receptor. Brain-metastatic tumor cells can also produce factors and inhibitors that influence their growth, invasion and survival in the brain. We found that brain-metastatic melanoma cells synthesize transcripts for tumor growth factor-beta, basic fibroblast growth factor, tumor growth factor-alpha, and interleukin-1 beta. Synthesis of these factors may influence the production of neurotrophins by adjacent brain tissues. In support of this, we found increased amounts of NGF in tumor-adjacent tissues at the invasion front of human melanoma tumors in the brain. These and other factors may determine whether metastatic cells can successfully invade, colonize, and grow in the central nervous system.
Invasion Metastasis
PMID:Involvement of neurotrophins and growth factors in brain metastasis formation. 765 30

The aim of the investigation was to study directly the IL-2 receptor (IL-2R) and its subunits, p55 and p75 chains, either membrane-bound or soluble, on PBMC of patients with solid malignancies and, indirectly, the same patients' PBMC ability to produce IL-2. Fifty-eight cancer patients, 29 men and 29 women, were studied: their mean age was 57.3 yr, range 35-79. Twenty-two healthy age-sex-matched subjects served as controls. The tumors were the most common and the most representative among human cancers, i.e., breast, lung, head and neck, digestive tract and liver, prostate and gynecologic cancers: they were generally in advanced stages and in 23 cases metastatic. The PBMC proliferative response to PHA, PHA plus IL-2, and IL-2 was evaluated along with the response to PHA in the presence of anti-p55, anti-p75 monoclonal antibodies, or both. Moreover, membrane-bound IL-2R (p55 and p75 chains) on PHA-stimulated PBMC was detected, along with soluble IL-2R in the serum and in the culture supernatants. The conclusions suggest that in solid malignancies: the membrane-bound IL-2Rs, both p55 and p75 chains, are expressed normally, there is an high serum level of soluble IL-2R, there is a normal release of soluble IL-2R in culture, and there is an indirect evidence of a lack of IL-2 production. Therefore, no primary impairment of IL-2R was found in solid tumors. Moreover, in our study we have found no difference in any parameter studied between patients with and patients without metastases.
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PMID:Membrane-bound and soluble IL-2 receptors (p55 and p75 chains) on peripheral blood mononuclear cells from patients with solid malignancies. 788 44

Treatment of metastatic melanoma patients with an autologous vaccine modified by the hapten, dinitrophenyl (DNP), produces a striking immunological effect: the induction of clinically evident inflammatory responses in metastatic tumors. Histological examination shows these tumors to be infiltrated with T lymphocytes. We studied the expression of activation markers on those cells and compared them with matched peripheral blood lymphocytes (PBL) and with lymphocytes extracted from metastases before treatment with DNP-conjugated vaccine. The median fraction of cells that were T cells in post-vaccine tumors was 41%, as compared with 9% in pre-treatment tumors, and those T cells were predominantly CD8+ (mean CD8/CD4 ratio = 5.0). A high proportion of both pre- and post-treatment infiltrating T cells expressed HLA-DR (mean +/- SE = 48% +/- 4%), CD69 (56% +/- 7%), and ganglioside GD3 (68% +/- 5%). This distinguished them from matched PBL in which expression of those markers was significantly lower (HLA-DR = 10% +/- 2%; CD69 = 2% +/- 0.4%; GD3 = 49% +/- 4%). These changes were not accompanied by increased cell-surface expression of interleukin-2 (IL-2) receptors, either CD25 or p75, which were expressed by 1%-2% and 12% of tumor-infiltrating lymphocytes (TIL), respectively. The pattern of activation marker expression that we identified appears to be characteristic of tissue T cells with the memory phenotype. The low expression of IL-2 receptors could indicate functional impairment of TIL in situ, perhaps because of inhibitory molecules produced by melanoma cells.
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PMID:Activation markers on T cells infiltrating melanoma metastases after therapy with dinitrophenyl-conjugated vaccine. 792 43

This study was undertaken to investigate the pathways involved in the interleukin 2 (IL-2)-driven growth of tumour-infiltrating lymphocytes (TILs). For this purpose, TIL lines and freshly isolated TILs obtained from 16 patients with solid cancer (three melanoma, seven primary colorectal carcinoma, four hepatic metastases from colorectal cancer and two lung cancer) were evaluated for (a) expression of IL-2 receptor (IL-2R) both at the RNA level and on the cell surface by flow cytometric analysis and (b) their proliferative activity in response to IL-2 and the role of IL-2R subunits in the IL-2-driven TIL growth. Northern blot analysis showed that TILs express a strong message for both the p55 and the p75 IL-2R. Accordingly, flow cytometric analysis demonstrated that TILs bear both IL-2R chains. TILs cultured in vitro in the presence of rIL-2 were able to proliferate in response to different concentrations of this cytokine. Monoclonal antibodies (MAbs) specifically recognising the p55 and p75 IL-2R chains (anti-Tac and TU27 respectively) exhibited a marked inhibitory effect on IL-2-driven growth when added individually or in appropriate combinations. Our results demonstrated that TILs are equipped with a fully functional IL-2 receptor system, thus suggesting the involvement of this structure in the activation and expansion of TILs following immunotherapy with IL-2.
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PMID:Functional role of IL-2 receptors on tumour-infiltrating lymphocytes. 819 69

Eleven metastatic cancer patients were studied during three different regimens of immunotherapy with interleukin-2 (IL-2) and/or interferon alpha (IFN alpha): group A received 4 days of IL-2 i.a. infusion (n = 3), group B IFN alpha s.c. during 5 days (n = 4), followed on day 3 by 5 days of a continuous IL-2 i.v. infusion, and group C had 4 days of IL-2 i.v. infusion together with s.c. IFN alpha on days 1 and 4 (n = 4). Soluble tumor necrosis factor receptors (sTNFR) p55 and p75 and TNF alpha concentrations in serum were analyzed before therapy and daily during 8 days of the first therapy cycle. sTNFR was measured by radioimmunoassay. sTNFR p55 increased in all patient groups from a baseline value of 5.2 +/- 0.9 ng/ml to a maximum of 13.6 +/- 1.2 ng/ml by days 3-4 (P = 0.003). sTNFR p75 increased from 7.6 +/- 1.1 ng/ml to peak values of 30.1 +/- 2.6 ng/ml in groups A and B (P = 0.02). In group C the sTNFR p75 response was weak (NS). In group B, the increase of both p55 and p75 occurred only after addition of IL-2 to IFN alpha. TNF alpha increased weakly during treatment with IFN alpha alone (group B); it rose strongly during IL-2 and the combined treatment (groups A-C) from 8 +/- 2 pg/ml to 115 +/- 13 pg/ml (P = 0.003). In group B, it reached the maximum 24 h after addition of IL-2 to IFN alpha and decreased thereafter. There was a significant relationship between TNF alpha and sTNFR p55 or sTNFR p75 in groups A and C, (P = 0.001), but not in group B. Group C was also investigated during the third therapy cycle. The increase of sTNFR p75 was stronger (P = 0.01) and that of TNF alpha weaker than in the first cycle; the sTNFR p55 response was similar in both cycles. In conclusion sTNFR p55 and p75 are rapidly induced during IL-2 and IL-2+ IFN alpha treatment, the increase of sTNF receptors parallels or exceeds that of TNF alpha and may influence the immunomodulatory effects of TNF alpha during cytokine therapy.
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PMID:Relationship between soluble tumor necrosis factor (TNF) receptors and TNF alpha during immunotherapy with interleukin-2 and/or interferon alpha. 830 66

The effect of dose and schedule of continuous i.v. rIL-2 infusions on leucocyte subset counts, activation status of CD56+CD3- natural killer (NK) and CD3+ T lymphocytes, and cytolytic activities of peripheral blood mononuclear cells (PBMC) was studied. A single 4-day course of rIL-2 in escalating doses (0.9-11.5 x 10(6) U/m2 per day) was given to 18 patients with various types of metastatic cancer. The serum IL-2 concentration during rIL-2 therapy ranged between 23 and 64 U/ml and was proportional to the administered rIL-2 dose, as was the rebound lymphocytosis following therapy. Before therapy, the CD56+CD3- NK cells expressed low levels of the p75 chain of the IL-2 receptor (IL-2R) and virtually no IL-2R(p55). Most CD3+ T cells were IL-2R(p55-,p75-). Between 2 and 4 days following therapy, i.e. at the time of lymphocytosis, the percentage of CD56+,CD3- NK cells among the lymphocytes had increased proportional to the administered rIL-2 dose. The levels of IL-2R(p75) expression by the CD56+,CD3- NK cells had increased. The percentages of CD3+ T cells expressing IL-2R(p55), HLA-DR and CD45RO had increased proportional to the administered rIL-2 dose. The level of lymphokine- activated killer (LAK) activity against Daudi cells was also positively correlated with rIL-2 dose. Subsequently, seven patients received 4-weekly cycles of rIL-2 (2.9-4.4 x 10(6) U/m2 per day) during 4 consecutive weeks. This schedule led to marked increments in lymphocyte and eosinophil counts, and to increased cytolytic activities compared with pretreatment. We conclude that CD56+,CD3- NK and CD3+ T cells are activated differentially by continuous i.v. rIL-2 proportional to dose and duration of treatment.
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PMID:Activation of the immune system of cancer patients by continuous i.v. recombinant IL-2 (rIL-2) therapy is dependent on dose and schedule of rIL-2. 848 6

An important clinical endpoint in patients with cancer is formation of metastases in the brain. Understanding this phenomenon is important in several types of malignancies, including melanoma, lung and breast cancers. Metastatic tumor cells use specific adhesion molecules to home to brain, and there they must attach to microvessel endothelial cells and respond to brain endothelial cell-derived motility factors and brain invasion factors to invade the CNS. Neurotrophins are important invasion factors in this process, and the ability to invade into the brain may well depend on metastatic cell responses to neurotrophins and production of basement membrane-degradative enzymes capable of locally destroying the blood-brain barrier. Brain-metastatic human melanoma cells express low-affinity p75 receptor for neurotrophins such as nerve growth factor, but they do not express the high-affinity-type receptors for nerve growth factor encoded by the protooncogene trkA. Tumor cells can proliferate in the CNS in response to local paracrine growth factors and inhibitors, but their growth also depends on their producing and responding to autocrine growth factors. A major organ-derived (paracrine) growth factor has been isolated that differentially stimulates the growth of cells metastatic to the brain. Characterization of this mitogen demonstrated that it is a transferrin-like glycoprotein; cells that are metastatic to brain express greater numbers of transferrin receptors on their surfaces than cells that are poorly metastatic or metastatic to other sites. Transferrin-like factors are expressed in fetal brain and could represent the transferrin-like factors that stimulate growth of brain-metastatic melanoma and breast cancer cells. These and other factors are probably important in determining whether metastatic cells can successfully invade, colonize, and grow in the CNS.
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PMID:Tumor metastasis to brain: role of endothelial cells, neurotrophins, and paracrine growth factors. 851 8

The neurotrophins (NTs) are a group of growth factors involved in the development of the nervous system and presumed to play a role in neural crest-derived tumours. The expression of three NTs (NGF, BDNF, and NT-3) and their receptors (NTRs; i.e. low-affinity pan-NT receptor p75, Trk-B, and Trk-C) was studied in frozen sections of benign and malignant cutaneous pigment cell lesions, using immunohistochemistry. In order to understand the possible role of these growth factors and their receptors in the progression of primary cutaneous malignant melanomas (PCMMs), their distribution in the radial (RGP) and vertical (VGP) growth phases was particularly studied. While most of the common acquired naevi were unreactive, Spitz and blue naevi showed scattered immunoreactive cells, especially for the p75 NTR. Dysplastic naevi, but not common naevi, expressed NT-3 in their junctional component. PCMM and melanoma metastases often showed a diffuse pattern of immunostaining. NT-3 was significantly more frequently expressed in the RGP of PCMMs than in the junctional component of benign naevi, whereas more extensive immunoreactivity for NGF was found in the VGP of PCMMs, compared with the RGP; metastases more frequently expressed NGF, BDNF, and Trk-B than PCMMs. Interestingly, neurotropic melanoma expressed all NTs/NTRs except Trk-B. These immuunohistochemical data confirm suggestions from previous in vitro studies that autocrine loops of certain NTs and their respective receptors may be involved in melanoma progression; in addition, NT-3 may be involved in the junctional growth of dysplastic naevi. The precise role of these growth factors in melanoma, however, will await further functional studies.
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PMID:Expression of neurotrophins and their receptors in pigment cell lesions of the skin. 1132 47

The aim of this study was to characterize phenotypic alterations along the progression of breast carcinoma from primary tumor to pleural effusion through analysis of the expression of nerve growth factor (NGF) and its receptors phospho-TrkA (p-TrkA activated receptor) and p75. Sections from 42 malignant pleural effusions from breast cancer patients and 65 corresponding solid tumors (34 primary, 31 metastatic) were evaluated for protein expression of the activated p-TrkA receptor. The majority of lesions were additionally studied for NGF and p75 expression. Six effusions and four breast carcinoma cell lines were studied for expression of p-TrkA using immunoblotting (IB). Membrane expression of p-TrkA was high in carcinoma cells in effusions (39/42, 93%) and locoregional recurrences (12/13, 92%), with significantly lower expression in both primary tumors (14/34, 41%) and lymph node metastases (8/18, 44%), respectively (p < 0.001 for effusions vs. primary tumors; p = 0.001 for effusions vs. lymph nodes). In contrast, p75 expression was less frequent in effusions compared to both primary tumors and lymph node metastases, significantly so for the latter (p = 0.019). NGF expression was comparable at all sites, but its expression in tumor cells in effusions (7/21 cases) was limited to cases in which time to progression (TTP) to effusion occurred within 5 years or less from primary operation. In univariate analysis of survival, mean and median TTP were 6.3 and 6 years for NGF-negative effusions, compared to 3 and 4 years for NGF-positive cases (p = 0.013). IB confirmed expression of p-TrkA in five of six effusions, while all four breast cancer cell lines were p-TrkA-negative. Our data provide the first documented evidence of molecular events that occur along tumor progression of breast carcinoma from primary tumors to effusion. The almost universal expression of p-TrkA in cancer cells in effusions and late recurrences is in full agreement with our recent report linking this factor with poor prognosis in ovarian cancer. Furthermore, the rapid progression to effusion in cases showing NGF expression in tumor cells underscores the aggressive clinical behavior of tumors that are able to utilize this pathway in an autocrine manner.
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PMID:Altered expression and activation of the nerve growth factor receptors TrkA and p75 provide the first evidence of tumor progression to effusion in breast carcinoma. 1499 42

The p75 neurotrophin receptor (p75(NTR)) has been characterized as a metastasis and tumor suppressor in prostate cancer. In order to investigate the mechanism(s) by which the p75(NTR) functions as a metastasis suppressor in prostate cancer cells, we characterized the ectopic expression of p75(NTR) on the urokinase plasminogen activator (uPA) and the type IV collagen matrix metalloproteinases (MMP-2 and MMP-9) in PC-3 human prostate cancer cells. Rank-order expression of p75(NTR) greatly reduced protein levels and enzymatic activities of uPA, MMP-2, and MMP-9 as shown by immunoblot and zymography analyses. Conversely, expression of the MMP-9 antagonist, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) exhibited an increase in protein levels with an increase in p75(NTR) levels, whereas TIMP-2 was not detected. Transient transfection with an inducible dominant negative antagonist Deltap75(NTR) rescued uPA, MMP-2, and MMP-9 protein levels and protease activities, and conversely suppressed TIMP-1 levels. Since p75(NTR) signal transduction occurs via the NFkappaB and JNK pathways, antagonism of signaling intermediates in these pathways, using dominant negative IKKbeta or dominant negative MKK-4, respectively, was shown to further decrease expression of uPA, MMP-2, and MMP-9 protein and enzymatic activity levels, and conversely up-regulate levels of TIMP-1. These results indicate that expression of uPA, MMP-2, MMP-9, and TIMP-1 are directly regulated by expression of p75(NTR) and its downstream signal transduction cascade. These results suggest that the metastasis suppressor activity of p75(NTR) is mediated, in part, by down-regulation of specific proteases (uPA, type IV collagenases) implicated in cell migration and metastasis.
Clin Exp Metastasis 2006
PMID:The p75(NTR) metastasis suppressor inhibits urokinase plasminogen activator, matrix metalloproteinase-2 and matrix metalloproteinase-9 in PC-3 prostate cancer cells. 1691 16


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