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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) are important immunomodulators. They are capable of acting in a synergistic manner on tumor cells in vitro and in vivo. In a clinical phase I study 13 patients with malignant ascites due to abdominal spread of different primary tumors received intraperitoneally (i.p.) TNFalpha and IFNgamma once weekly over 3-8 weeks in order to evaluate the effect of locoregionally administered TNFalpha/IFNgamma on ascites formation. Therefore some peripheral and local immunological functional parameters of peripheral blood and malignant ascites were investigated. Mononuclear lymphocytes and natural killer (NK) cell activity of peripheral blood and ascites, TNF-inhibitory activity, soluble p55 and p75 TNF receptors, and prostaglandin E2 values in ascites were measured immediately before and 24 h after each TNFalpha/IFNgamma infusion. Peripheral mononuclear lymphocytes and NK activity decreased significantly 24 h after i.p. TNFalpha/IFNgamma application. However, over the entire treatment schedule, peripheral NK activity in all responders showed a continuous increase, when compared to pre TNFalpha/IFNgamma treatment levels. In contrast, NK activity in non-responders constantly decreased. In contrast to non-responders, TNF-inhibitory activity and soluble p55 TNF receptor levels, determined in ascites, decreased in responders. Taken together, our findings suggest, that successful locoregional i.p. TNFalpha/IFNgamma therapy induces systemic immunological reactions possibly after saturation of soluble p55 TNF receptors in ascites, which leads to an increase of peripheral NK activity.
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PMID:Peripheral natural killer cell activity and intraperitoneal soluble p55 tumor necrosis factor receptor in patients with malignant ascites: two possible indicators for response to intraperitoneal combined tumor necrosis factor alpha and interferon gamma treatment. 862 64

Chemotherapeutic agent-induced DNA cleavage gives rise to apoptosis in a subpopulation of SK-N-SH human neuroblastoma cells; the remaining cells undergo Schwann cell-like differentiation. Like other neural crest and primitive neurectodermal tumor-derived cell lines, SK-N-SH cultures contain cells of neural (N-type) and epithelial (substrate-adherent, or S-type) phenotypes. Using isolated N-type and S-type cells from neuroblastoma, medulloblastoma, melanoma and glioma cell lines, we demonstrate that the determinants of the response to DNA cleavage are intrinsic properties of the cell. Furthermore, using a series of analogues of enediyne deoxyribonucleic acid (DNA) cleaving agents, we show that the molecular target of these agents is likely to be the same in N- and S-type cells, implying that the difference in response characteristics is a function of different distal pathways that are triggered by DNA cleavage. We demonstrate that the concentration of the DNA damaging agent used, and not the specific characteristics of the damage it produces, is the trigger for production of the cellular response. Response type does not correlate with previously published values for expression of the apoptosis modulators Bcl-2, Bcl-XL, wildtype p53, or, in medulloblastoma lines, p75.
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PMID:Determinants of the response of neuroblastoma cells to DNA damage: the roles of pre-treatment cell morphology and chemical nature of the damage. 862 28

Increased serum levels of soluble tumor necrosis factor receptors (TNFRs) have been observed in patients with various types of malignancies. For the monitoring of ovarian cancer during treatment serum TNFRs have given information equivalent or better than that obtained by CA 125. In this study, we compared the diagnostic value of TNFRs and CA 125 in discriminating ovarian cancer from benign pelvic masses. Preoperative serum levels of p55 and p75, two distinct types of TNFRs, and that of CA 125 were determined by immunoassays in 45 patients with malignant and 27 patients with benign tumors operated consecutively. A group of 26 healthy women served as controls. For each of the three markers the group with ovarian cancer showed significantly higher values than the group with benign masses (p < 0.01). The rate of marker elevation correlated with ovarian cancer staging. Using upper cutoff levels of 2.0 ng/ml (p55), 4.3 ng/ml (p75) and 20 U/ml (CA 125), the calculated sensitivities were 58% (p55), 16% (p75) and 82% (CA 125). The specificities were 89% (p55), 96% (p75) and 85% (CA 125), respectively. Adding p55 to CA 125 did not increase the diagnostic values compared to using the CA 125 test alone. Our data confirm the superiority of serum CA 125 as a marker for discriminating ovarian cancer from benign pelvic masses. The p75 marker was found to be of no value, and for the detection of early stage ovarian cancer the sensitivity of p55 was too low to be of clinical importance.
Tumour Biol 1996
PMID:Soluble tumor necrosis factor receptors and CA 125 in serum as markers for epithelial ovarian cancer. 865 18

Since no effective therapeutic approach is known so far for metastatic renal cell carcinoma (RCC), we analyzed the anti-proliferative effects of TNF-alpha and retinoic acid (RA), applied either alone or in combination on 7 different RCC cell lines in vitro. In 5 out of 7 cell lines, a significant (p < 0.05) dose-dependent inhibition of tumor cell proliferation became evident after exposure to TNF-alpha, the response being of modest magnitude in 5 cell lines. In 2 cell lines the effects were more pronounced with a reduction of cell viability to 55 +/- 11% of the control. Northern blot analysis revealed no expression of TNF-alpha and p75 TNF-receptor in any cell line. All the cell lines showed p55 TNF-receptor mRNA. Scatchard analysis revealed no correlation between TNF-alpha receptor status and growth inhibitory response to TNF-alpha, the number of TNF-receptors per cell ranging from 0 to 3,976, and the affinity values from Kd = 0.621 nmol/l to Kd = 4.28 nmol/l. Exposure to RA alone resulted in significant (p < 0.05), but modest growth inhibition in 2 out of 7 cell lines with a reduction of cell viability to 83 +/- 1% of the control. In 2 out of 7 cell lines, combination of RA and TNF-alpha was significantly (p < 0.05) more effective than the single application of each compound. Northern blot analysis revealed no transcripts of CRABP I and retinoic acid receptor (RAR)-beta. All the cell lines expressed RAR-alpha mRNA and one cell line additionally expressed RAR-gamma mRNA. A correlation between RAR status and RA response was not seen.
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PMID:Effects of TNF-alpha and retinoic acid on the proliferation of the clear cell and chromophilic types of human renal cell carcinoma in vitro. 871 81

Members of the TNF receptor superfamily are type I membrane glycoproteins with limited homology (overall homologies: 25%-30%) in the extracellular domain containing variable numbers of cysteine-rich repeats. In contrast, the TNF ligand superfamily members (with the exception of LT-alpha) are type II membrane glycoproteins with limited homology to TNF (overall homologies: 20%) in the extracellular region. TNF and LT-alpha are trimeric proteins and are composed of beta-strands forming a beta-jellyroll, the homology of the beta-strand regions for the TNF ligand superfamily members suggests a similar trimeric or multimeric complex formation for the other members. A genetic linkage, as evidence for evolutionary relatedness, is also found by chromosomal cluster for CD30, CD120b, 4-1BB and OX40 to 1p36; CD27, CD120a and TNFR-RP to 12p13; TNF, LT-alpha and LT-beta to 6p21; CD27L and 4-1BBL to 19p13; CD95L and OX40L to 1q25. TNF, LT-alpha and LT-beta and their receptors (CD120a, CD120b, TNFR-RP) interact in a complex fashion. Other family members, however, show a one ligand/one receptor binding principle. Signals can also be transduced through at least some of the ligands. TNF superfamily ligands are involved in induction of cytokine secretion, upregulation of adhesion molecules, activation antigens and costimulatory proteins, all known to amplify stimulatory and regulatory signals that occur during immune responses. On the other hand, differences in the distribution, kinetics of induction and requirements for induction support the view of a defined role for each of the ligands for T-cell-mediated immune activities. The shedding of members of the TNF receptor superfamily could limit the signals mediated by the corresponding ligands, as a functional regulatory mechanism. Induction of cytotoxic cell death is another common functional feature of this cytokine family (TNF, LT-alpha, CD30L, CD95L and 4-1BBL). Further studies have to identify unique versus redundant biological and physiological functions for each of the TNF superfamily ligands. In addition to other cytokines primary H-RS cell frequently express at least TNF, LT-alpha, CD27L and CD30L, but not CD40L. Furthermore, H-RS cells express several TNF receptors, such as CD30, CD40, CD95, CD120a, CD120b and 4-1BB. The TNF-like ligands might support growth and activation of HD-associated tumor cells and/or interact with surrounding reactive bystander cells, particularly T-cells. The different interactions between H-RS cells and surrounding reactive bystander cells are part of the pathobiology of HD. Detailed functional analysis have to confirm the predicted biological activities of TNF, LT-alpha, CD27L, CD30L, CD40L, CD95L, 4-1BBL and gp34/OX40L for the H-RS cell/T-cell interactions with impact on tumor growth and pathogenesis of HD. TNF and LT-alpha/CD120a and CD120b, CD30/CD30L, and CD40/CD40L are clearly critical elements in the deregulated network of interactive signals between H-RS cells and surrounding bystander cells with membrane-associated and cytokine-mediated events. Several TNFR superfamily members are also candidates for novel treatment protocols, including CD30 and CD40.
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PMID:Structural and biological features of the TNF receptor and TNF ligand superfamilies: interactive signals in the pathobiology of Hodgkin's disease. 883 4

Neurotrophins act through their cognate receptors to promote the differentiation and/or survival of neuronal progenitor cells, immature neurons, and other cells. Here, we examined the effects of nerve growth factor (NGF) and its cognate receptor (Trk or TrkA) on the survival of a common childhood brain tumor, i.e., medulloblastoma, a tumor that resembles CNS neuroepithelial progenitor cells. To do this, we engineered two human medulloblastoma cell lines (i.e., D283MED and DAOY cells) to express human TrkA using a retroviral expression vector. Surprisingly, NGF-treated medulloblastoma cells expressing the TrkA receptor (D283trk and DAOYtrk cells) grown in the presence or absence of serum underwent massive apoptosis, but similar treatment did not induce apoptosis in wild-type uninfected cells, cells expressing an empty vector, or cells expressing the TrkC receptor. Furthermore, D283MED cells engineered to express the human p75 NGF receptor (D283p75) also did not undergo apoptosis. Significantly, NGF-induced apoptosis in D283trk and DAOYtrk cells can be inhibited by anti-NGF antibodies and by K-252a, an inhibitor of TrkA tyrosine phosphorylation and mimicked by high concentrations of NT3. Because NGF treatment primarily eliminated D283trk cells from the S phase of the cell cycle, this form of NGF-mediated apoptosis is cell cycle-dependent. These findings suggest that a NGF/TrkA signal transduction pathway could activate apoptotic cell death programs in CNS neuroepithelial progenitor cells and in childhood brain tumors.
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PMID:Nerve growth factor induces apoptosis in human medulloblastoma cell lines that express TrkA receptors. 898 76

The neurotrophins signal cell survival, differentiation, growth cessation, and apoptosis through two cell surface receptors, the Trks and p75NTR (p75 neurotrophin receptor). Recent advances indicate that the particular events that are mediated by neurotrophins are dependent upon the cell type and the expression pattern of each neurotrophin receptor. For example, TrkA activation induces cell death of neural tumor cells, and survival and differentiation of neurons. Likewise, p75NTR, when activated in the absence of a strong Trk signal, induces apoptosis of neurons, while in the presence of Trk it enhances responses to neurotrophin. These differing responses point to a complex interplay between neurotrophin-stimulated survival, differentiation, and apoptosis pathways.
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PMID:Signal transduction by the neurotrophin receptors. 906 67

Autocrine and paracrine influences of growth factors play a critical role in the regulation of the growth, survival, differentiation, and invasion potential of tumor cells. These influences on the neoplastic phenotype are particularly important in those cancers in which tumor-stroma interactions constitute important components of tumor development, as exemplified by prostatic, breast, and pancreatic carcinomas. The neurotrophins and their corresponding Trk and p75(NGFR) receptor subtypes are families of growth factors and receptors that have received relatively little attention with respect to neoplasia. This review attempts to summarize their biochemical properties, their role in neuronal and non-neuronal systems, and their involvement in the development of a variety of cancers, particularly those in which perineural invasion and/or metastasis to the CNS are a part of the pathophysiological presentation. In this regard, we have focused on our studies of neurotrophin-Trk/p75(NGFR) expression and interactions in pancreatic ductal carcinoma (PDAC) and their potential role in the perineural invasive phenotype characteristic of this cancer.
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PMID:Neurotrophin-Trk receptor interactions in neoplasia: a possible role in interstitial and perineural invasion in ductal pancreatic cancer. 910 99

The C6-2B is a well-characterized glioma cell line used extensively in the study of malignant glial biology. While the C6-2B cell line has traditionally been thought of as a homogenous cell line, the in vitro phenotype of the C6-2B cell line can vary considerably depending on the culture technique used and the stratum on which the cells are grown. Thus, we asked whether the in vitro phenotype of the C6-2B cell line was significantly different than the in vivo phenotype of the cell line once it was engrafted into the striatum of nude rats. Under culture conditions used in our laboratory, 100% of the C6 cells were found to express p75, the low-affinity nerve growth factor (NGF) receptor, and Major Histocompatability Class I (MHC Class I), while only 10-15% demonstrated vimentin reactivity. Immunohistochemistry was consistently negative for GFAP, trkA (the high-affinity receptor for NGF), CD4, CD8, and a macrophage specific marker (Ox-41). Once engrafted into the striatum of nude rats, the cells remained 100% p75 and MHC Class I positive, and again, only 15% of the cells demonstrated vimentin reactivity. The grafted cells retained this characteristic for 28 days in vivo. Although an immunoincompetent host was selected to minimize the effects an inflammatory response would have on the graft, a transient inflammatory response was detected. During the first week of engraftment, numerous MHC class II cells, some of which were macrophages, were seen infiltrating the graft. However, by 4 weeks postengraftment, no inflammatory cells were appreciated in the graft and surprisingly little reactive gliosis was seen in the penumbra of the tumor mass. Thus, the limited number of in vitro phenotypic characteristics we examined in the C6-2B cell line remained constant once the cells were engrafted into the striatum of athymic nude rats.
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PMID:Engraftment of C6-2B cells into the striatum of ACI nude rats as a tool for comparison of the in vitro and in vivo phenotype of a glioma cell line. 917 Nov 64

Several costimulatory molecules play a key role in the differentiation of B lymphocytes and in T-B-cell interactions. In this study, we addressed the question of whether different receptors and counter-receptors may be expressed on malignant B lymphocytes from chronic B-cell malignancies. Using flow cytometry and reverse transcription PCR analyses, the expression of molecules belonging to the tumor necrosis factor receptor (TNFR) and tumor necrosis factor ligand (TNFL) families, as well as the expression of CD80 and CD86 molecules, was analyzed in normal B cells and in different chronic lymphoproliferative disorders of B-cell type, including B-cell chronic lymphocytic leukemia (CLL), mantle cell lymphoma, hairy cell leukemia (HCL), and HCL variant. Different patterns of expression of TNFR and TNFL superfamily molecules were demonstrated among B-cell malignancies. In particular, CD40 was commonly observed on all B cells (both tumor and normal), whereas its ligand (CD40L), which is usually undetectable on resting normal B lymphocytes, was expressed in CLL and HCL but not in other chronic lymphoproliferative disorders. CD27 was not shown in normal B cells, although it was present in all malignancies and with particularly high density in mantle cell lymphoma. CD70 was widely distributed on tumor B lymphocytes, but not on the CD5+ normal counterpart. CD30 was strongly expressed in HCL variant and weakly in B-cell CLL, whereas its ligand showed a wide pattern of expression, including all neoplastic and normal B cells. TNFR II (CD120b) and CD80 were distributed on neoplastic B cells from all groups, usually at an intermediate to high degree of intensity, whereas the CD86 molecule was present at lower intensity than CD80. Finally, reverse transcription PCR analysis confirmed the presence of CD40L, CD30, and CD30L mRNAs in those B cells expressing the corresponding membrane-bound proteins at low density. Our data indicate that TNFR and TNFL molecules are of use clinically both in differentiating B-cell malignancies from the normal counterpart (i.e., CD27, CD70, CD40L, CD30, and CD80) and in defining different chronic B-cell disorders (i.e., CD40L, CD27, and CD30). Interestingly, the observation that several receptors and their ligands (i.e., CD40/CD40L, CD30/CD30L, and CD27/CD70) can be expressed on the same cell suggests that these molecules play a role in initiating and maintaining the neoplastic process by mediating B-T and B-B interactions.
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PMID:B lymphocytes from patients with chronic lymphoproliferative disorders are equipped with different costimulatory molecules. 935 61


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