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 action of IFN-alpha has been studied in patients with carcinoid tumours. More than 300 patients have been treated with IFN-alpha for long periods of time (median 2.5 years). IFN-alpha exerts many pleiotrophic effects in carcinoid tumours. Antiproliferative effects are manifest mainly by a cell cycle block in GO-G1 phase and prolongation of the S-phase. Hormone synthesis is impaired with reduced circulating hormone levels after IFN-alpha therapy and the mechanism includes reduction of mRNA expression for various hormones. Induction in vitro of the nuclear enzyme 2'-5-A synthetase in tumour cells correlates with biochemical response and might account for reduced mRNA expression. IFN-alpha induces significantly increased intratumoral fibrosis in carcinoid metastases without significant changes in tumour size. Finally IFN-alpha causes alteration of the major histocompatibility complex (MHC) with increased expression of class I antigens on the tumour cells. The net result of all these effects of IFN-alpha is an antitumour effect in 70-80% of carcinoid tumour patients with biochemical control and abrogated tumour growth for extended periods of time. However, when IFN-alpha therapy is withdrawn tumour progression occurs within 3-9 months, indicating a controlling but not curing effect.
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PMID:The action of interferon alpha on human carcinoid tumours. 135 93

Highly metastatic, weakly immunogenic Lewis lung carcinoma clones express very low levels of H-2Kb and moderate levels of H-2Db class-I major histocompatibility complex antigens. These cells metastasize spontaneously in mice with C57BL/6 genetic background possessing the H-2Db locus, and grow as local tumors across allogeneic barriers. Transfection of the H-2Db genes into the highly metastatic clone D122 did not alter the growth or metastatic capacity of these cells in syngeneic mice. However, these cells were rejected in allogeneic mice. Transfection of the H-2Kd or H-2Kk genes into D122 elicited a CTL population that cross-reacted with cells bearing native H-2Db antigens. These data suggest that overlapping allo-CTL populations are induced by a native alloantigen and by alloantigen peptides presented through self class-I molecules.
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PMID:H-2Db gene transfer into highly metastatic D122 cells results in tumor rejection in allogeneic recipients, but does not affect metastasis in syngeneic recipients. Implications for mechanisms of allorejection. 142 31

To be recognized by CD8+ T lymphocytes, target cells must process and present peptide antigens in the context of major histocompatibility complex (MHC) class I molecules. The nonimmunogenic, low class I-expressing, methylcholanthrene (MCA)-induced murine sarcoma cell line, MCA 101, is a poor presenter of endogenously generated viral antigens to specific CD8+ T lymphocytes and cannot be used to generate tumor infiltrating lymphocytes (TIL). Since interferon gamma (IFN-gamma) has been shown to upregulate three sets of molecules important for antigen processing and presentation, we retrovirally transduced wild-type MCA 101 (101.WT) tumor with the mIFN-gamma cDNA to create the 101.NAT cell line. Unlike 101.WT, some clones of retrovirally transduced 101.NAT tumor expressed high levels of class I, and could be used to generate CD8+ TIL. More importantly, these TIL were therapeutic in vivo against established pulmonary metastases from the wild-type tumor. Although not uniformly cytotoxic amongst several separate cultures, these TIL did specifically release cytokines (IFN-gamma and tumor necrosis factor-alpha) in response to 101.WT targets. 101.WT's antigen presentation deficit was also reversed by gene modification with mIFN-gamma cDNA. 101.NAT had a greatly improved capacity to present viral antigens to CD8+ cytotoxic T lymphocytes. These findings show that a nonimmunogenic tumor, incapable of generating a CD8+ T cell immune response, could be gene-modified to generate a therapeutically useful immune response against the wild-type tumor. This strategy may be useful in developing treatments for tumor histologies not thought to be susceptible to T cell-based immunotherapy.
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PMID:A nonimmunogenic sarcoma transduced with the cDNA for interferon gamma elicits CD8+ T cells against the wild-type tumor: correlation with antigen presentation capability. 158 73

In vivo experiments performed with NIH (nu/nu, bg/bg, xid/xid) triple immunodeficient (TD) mice revealed the striking ability of i.v. injected B16-F1 and B16-F10 murine melanoma cells to colonize not only the lungs but also the liver of TD mice. Subsequently, B16 melanoma cell cultures, which express very low levels of H-2Kb antigen, were cotransfected with plasmids pRSVneo, containing the neomycin resistance gene, and 6-2B1pMT, expressing the H-2Kb complentary DNA under the control of the metallothionein enhancer-promoter. Several neomycin-resistant clones were analyzed for H-2Kb and H-2Db expression by RNase protection and flow cytometry assays. All parental lines and transfected clones expressed normal levels of H-2Db mRNA, while only some of the transfected clones expressed easily detectable levels of H-2Kb mRNA. Moreover, in these clones H-2Kb expression could be enhanced in the presence of Zn2+, indicating that the metallothionein enhancer was functioning properly. Parental cells and transfected clones were injected i.v. in TD mice to assess the possible involvement of H-2Kb antigen in regulating the metastatic potential of B16 melanoma cells. We observed a remarkable correlation between expression of H-2Kb antigen and suppression of liver-specific metastases in TD mice. Identical results were obtained when we gave TD mice injections of mixed populations of transfectants expressing H-2Kb antigen, obtained by fluorescence-activated cell sorting. These experiments allowed us to rule out the possibility that the observed changes in metastatic potential were due to clonal variability among individual transfected clones. Taken together, the results of our in vivo studies with immunodeficient mice support the notion that specific major histocompatibility complex Class I molecules modulate the metastatic potential of malignant cells also by mechanisms which are independent of their well-established role in antigen presentation.
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PMID:Expression of a transfected H-2Kb gene in B16 cells correlates with suppression of liver metastases in triple immunodeficient mice. 161 80

To search for host genes for resistance/susceptibility to cancer metastasis, mutation analysis was employed. Ten putative mutants of resistance to lymphoma EL4 and four putative mutants of resistance to sarcoma MCA/77-23 of C57BL/6J (B6) mice were produced. These mutants were designated S (for "survivor") mutants; they do not reject parental strain B6 skin grafts. S-mutants resist moderate tumor cell doses: TD50 values in them were increased by a factor of 12 to 600. Genetic linkage tests showed that five S-mutants were linked to mouse major histocompatibility complex (H-2) and five other S-mutants were not linked to this locus. A group of H-2-linked S-mutants resisting EL4 and a mutant, S-87/2, resisting MCA/77-23 were tested for resistance to spontaneous metastases of the same two tumors, EL4 and MCA/77-23. Two of the mutants, S-31 (lymphoma-resisting) and S-87/2 (sarcoma-resisting), were shown to carry mutations of mouse gene(s) for resistance to tumor metastases. In both of these mutants resistance to the original tumor transplant coexisted with highly increased susceptibility to metastasis. These mutants are a new tool to study genes for resistance to cancer metastasis and of mechanism of resistance controlled by each individual gene.
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PMID:Screening mouse mutations for resistance to cancer metastasis. 163 40

Previous laboratory studies have suggested that natural immunity is a primordial defense mechanism against blood-borne metastatic cancer, its function being most effective against dedifferentiated, low-major-histocompatibility-complex-class-I-antigen-expressing tumors. In this clinical study, 263 previously untreated patients with squamous cell carcinoma of the upper aerodigestive tract were evaluated for natural killer (NK) cell cytotoxicity mediated by peripheral blood lymphocytes against K562 target cells. All patients were evaluated before treatment, underwent subsequent attempts at curative therapy in which they were initially rendered disease-free, and then followed longitudinally for clinical outcome. Using a Cox proportional hazards model, quantitated NK cell cytotoxicity was inversely related to subsequent death with disease (p = 0.05), regional metastases (p = 0.008) and distant metastases (p = 0.03). No relationship between NK cell function and local recurrence could be identified (p = 0.81). Patients were further stratified by degree of differentiation of their respective primary cancer. The prognostic implication provided as to risk of death with disease and progressive metastatic growth was confined to the population with moderate-to-poorly differentiated cancers. Conversely, its function was nonpredictive in patients with well-differentiated cancers; the latter cancers were observed to express higher levels of major histocompatibility complex-class I framework antigens. Results of this clinical study are consistent with previous laboratory investigations and suggest that, within humans, the NK cell functions in metastatic sites against more primitive cancers. Such findings may have implications in designing therapeutic strategies.
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PMID:Quantitation of natural killer cell function and risk of metastatic poorly differentiated head and neck cancer. 175 68

An astoundingly high frequency of micrometastatic cells have been found in bone marrow aspirates of patients with colon carcinomas (G. Schlimok et al., J. Clin. Oncol., 8:831-837, 1990), although these tumors very rarely metastasize to the skeleton. This observation has raised questions about the malignant potential of such cells. In a first attempt to characterize this potential, we have assessed the expression of major histocompatibility complex (MHC) class I antigens on bone marrow micrometastases, inasmuch as down-regulation of these molecules is a potential mechanism to escape from MHC class I-restricted lysis by cytotoxic T-cells. The two groups of cancer patients compared were those with tumors known to rarely (stomach and colon cancer) or frequently (breast cancer) manifest skeleton metastases. Bone marrow aspirates taken from these patients were probed for individual disseminated tumor cells using the immunoalkaline phosphatase technique with monoclonal antibody CK2 to the epithelial differentiation antigen cytokeratin 18 (CK-18), as described previously (G. Schlimok et al., Proc. Natl. Acad. Sci. USA, 84:8672-8676, 1987). Specimens containing CK18-positive cells were colabeled with monoclonal antibody W6/32 directed to a framework (or nonpolymorphic) antigenic determinant of MHC class I heavy chains associated with beta 2-microglobulin. W6/32-positive CK-18-positive cells could be detected in 25 of 54 patients (46.3%) with significantly higher incidences in 26 breast cancer patients (61.9%) as compared to 28 patients with carcinomas of the stomach and colon (27.3 and 29.4%). Independent from the origin of the primary carcinoma, the incidence of W6/32-negative CK18-positive cells was positively correlated to both the differentiation grade of the primary tumor (P less than 0.05) and appeared to be linked to the occurrence of regional lymph node metastases (statistically not significant) determined by conventional histological examination. The present results demonstrate for the first time that down-regulation of MHC expression on individual micrometastatic cells correlates to the differential pattern of metastasis obtained by comparing breast and gastrointestinal carcinomas. This finding together with the suggestive link to clinical risk factors supports the significance of reduced MHC class I expression for the survival of residual metastatic cells which is a major determinant of prognosis for patients with solid tumors.
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PMID:Frequent down-regulation of major histocompatibility class I antigen expression on individual micrometastatic carcinoma cells. 187 15

Preincubation of murine colon 26 colon adenocarcinoma cells with gamma-interferon (IFN-gamma), but not alpha-interferon, produced a significant increase in experimental pulmonary metastases in syngeneic BALB/c and T-cell-deficient BALB/c nude mice. The enhancement was seen after as little as 1 h of exposure to 1 unit/ml of IFN-gamma and persisted for at least 72 h following removal of the cytokine. IFN-gamma exerted its effects by increasing the pulmonary retention of cells during the first 6 h following tumor cell injection. During this period all cells visualized in the lung were trapped in pulmonary capillaries. The enhancement was not due to modulations in class I major histocompatibility complex surface antigen expression; nor was it due to alterations in cell size, adhesion to components of the extracellular matrix in vitro, heterotypic or homotypic adhesion, sensitivity to lysis by activated peritoneal macrophages, osmotic fragility, enhancement of surface class II major histocompatibility complex antigen expression, or enhancement of intercellular adhesion molecule-1 (ICAM-1). Colon 26 was completely resistant to natural killer cell-mediated lysis in vitro, and IFN-gamma did not modulate the ability of colon 26 to form conjugates with isolated splenocytes. In vivo elimination of anti-asialo GM1 + cells increased pulmonary metastasis, and in such mice, there was no longer a difference in metastatic potential between control and IFN-gamma-treated cells. We conclude that low doses of IFN-gamma generated at the site of the tumor by host-infiltrating cells or during cytokine therapy could enhance the survival of tumor cells in the circulation and enhance their metastatic potential.
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PMID:Enhancement of metastatic potential by gamma-interferon. 190 80

Tumor-draining lymph node cells from mice bearing the methylcholanthrene-induced MCA 106 tumors can be sensitized in vitro to acquire antitumor reactivity. We examined the effect of interferon alfa on the function of cells that underwent in vitro sensitization in adoptive immunotherapy. Interferon alfa increased the antitumor reactivity of in vitro sensitized cells in the treatment of MCA 106 pulmonary metastases. This effect was evident in irradiated mice, indicating that a host response to the interferon alfa was not required. Interferon alfa treatment increased class I major histocompatibility complex antigen expression on tumor cells and increased their susceptibility to lysis by in vitro sensitized cells. These results suggest that interferon alfa enhancement of adoptive immunotherapy was mediated by its effect on tumor cells. Interferon alfa may be a useful adjunct to the adoptive immunotherapy of human cancer.
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PMID:Enhanced antitumor reactivity of tumor-sensitized T cells by interferon alfa. 199 72

Cell lines derived from squamous cell carcinoma of the upper aerodigestive tract (head and neck cancer) were phenotypically characterized with regard to differential sensitivity to nonmajor histocompatibility restricted (non-MHCr) killer cell activity. Requirements for detectable lysis of the cell lines in a standard chromium release assay included either isolation of fresh enriched Leu 19+ large granular lymphocytes (both Leu 19+CD3+ and Leu 19+CD3- populations) or interleukin-2 (IL-2) stimulation of peripheral blood lymphocytes (PBL). In neither circumstance could lytic activity be identified among Leu 19- populations. With PBL IL-2 stimulation significant differential sensitivity to lysis expressed by the head and neck cancer cell lines (P less than 0.001 by analysis of variance) was identified and maintained regardless of PBL source, i.e., PBL from healthy controls and three differing populations of head and neck cancer patients categorized by disease status and treatment. One factor associated with a cell line's increased sensitivity was degree of tumor differentiation, poorly differentiated tumors (as defined by intermediate filament cytochemical staining [decreased keratin and increased vimentin]) being more sensitive. Furthermore, as tumor cell lytic sensitivity increased, major histocompatibility complex (MHC)-class I antigen expression diminished concurrently. In 1 of 4 cell lines tested, however, pretreatment of tumor cells with interferon-gamma induced diminished lytic sensitivity independent of changes in MHC-class I expression, indicating factors not related to MHC-class I expression are likewise relevant. In previous studies we defined the in vivo prognostic significance of non-MHCr killer cell cytotoxicity activity against K562 targets, diminished activity being principally predictive of metastatic disease development in persons with poorly differentiated head and neck cancers. This report extends these observations by demonstrating in vitro that poorly differentiated head and neck cancer target cells are highly sensitive to changes in lytic function expressed by Leu 19+ non-MHCr effector cells.
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PMID:Differential sensitivity of head and neck cancers to non-major histocompatibility-restricted killer cell activity. 210 56


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