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)

HLA class I antigens are composed of a major histocompatibility complex (MHC) encoded heavy chain that is associated non-covalently with a light chain beta-2 microglobulin (beta-2m). When the HLA complex is metabolized, beta-2m is shed into the serum. A large variety of human and experimental tumours have altered MHC class I expression. In a previous study we observed elevated mean beta-2m serum levels in breast cancer patients, as compared to controls. To study the relationship between tumour expression and serum levels, we examined 54 patients with breast cancer. Tumour beta-2m was determined by immunohistochemistry and serum levels by the ELISA technique. Of the 54 patients, 38 had low and 16 had high beta-2m expression on the tumour. There was a significant correlation between tumour beta-2m and serum beta-2m levels (P = 0.02), with patients whose tumours expressed high beta-2m having high serum beta-2m levels. There was an inverse correlation between tumour grade and tumour beta-2m expression which approached statistical significance (P = 0.06). These findings suggest that in a substantial number of patients the high serum levels derive from shedding of beta-2m from tumour cells. These levels may have implications for tumour growth and metastases due to influences on immunological responses.
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PMID:Correlation between tumour and serum beta 2m expression in patients with breast cancer. 897 39

This study was undertaken to investigate the effectiveness of interleukin-2 (IL-2) and gamma interferon (gammaIFN)-modified B16 melanoma cells in the immunotherapy of established melanoma pulmonary metastases. The genes for IL-2 and gammaIFN were introduced retrovirally into B16 melanoma cells. Transduction with the gammaIFN, but not the IL-2, gene caused significant increases in the expression of major histocompatibility complex (MHC) antigens on B16-gammaIFN cells. The in vivo tumor-forming capacity of both IL-2- and gammaIFN-transduced B16 cells was drastically reduced when the cells were inoculated subcutaneously (SC) in syngeneic C57BL/6 mice. After intravenous (IV) inoculation, most of the B16-gammaIFN cells were rejected, but B16-IL-2 cells were relatively tumorigenic and formed pulmonary metastases. C57BL/6 mice bearing 4-day established parental B16 lung metastases were treated with B16 parental (B16P) unmodified cells, IL-2- or gammaIFN-modified B16 cells, or a combination of both transduced cells. Treatment consisted of a weekly intraperitoneal (IP) injection of one million irradiated (10,000 rad) tumor cells alone or in combination with exogenous IL-2 for a total of three to four injections. Immunotherapy with B16 parental or B16-IL-2 secreting cells caused a moderate reduction in the number of lung metastases. However, mice treated with gammaIFN-secreting B16 cells showed a significant reduction or complete elimination of lung metastases. There was no additive effect for combining both IL-2- and gammaIFN-modified tumor cells in the immunotherapy. Exogenous IL-2 (50,000-100,000 U/day for 3 days) caused a significant enhancement of the immunotherapeutic benefit of the vaccines. Moreover, mice treated with gammaIFN-modified B16 cells survived longer than the other groups. Twenty-five percent of these mice were tumor free and remained alive for an observation period of 4 months. The in vitro cytolytic activity of splenocytes in chromium release assays did not correlate in every case with the in vivo antitumor effect of the treatment. Our findings have implications for the use of cytokine-modified cells for immunotherapy and for evaluating the therapeutic benefit of this novel treatment.
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PMID:Eradication of melanoma pulmonary metastases by immunotherapy with tumor cells engineered to secrete interleukin-2 or gamma interferon. 901 49

Constitutive expression of major histocompatibility complex (MHC) class II molecules is normally restricted to professional antigen-presenting cells (APCs) of the immune system, although it also occurs frequently in melanoma. Clinical evidence suggesting that MHC class II expression by melanoma is associated with tumor progression led us to postulate a role for MHC class II-mediated antigen presentation in this disease. First, we investigated whether melanoma cells derived from metastases can process antigen and/or present peptide vi MHC class II molecules to a peptide-specific CD4+ T-cell clone. In all cell lines tested, melanoma cells were able to process antigen and present peptide efficiently to CD4+ T cells, resulting in T-cell proliferation increased 5-26-fold over controls. Next, we found that CD28-mediated costimulation was not required, because blocking with CTLA-4Ig had no effect on the T-cell response to either melanoma or B cells as APCs. In contrast, blocking CD54 (ICAM-1) resulted in a decrease in proliferation in response to peptide presentation by melanoma but not B cells. These data demonstrate that MHC class II molecules on melanoma cells are functional and that antigen-processing pathways are intact. In addition, CD54 seems to play a significant role in peptide presentation by melanoma.
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PMID:MHC class II-mediated antigen presentation by melanoma cells. 904 57

Ex vivo genetically engineered cytokine-secreting tumor cell vaccines have been shown to prevent metastatic disease in animal models of lung and breast cancer. Because of the inefficiency of existing modes of gene delivery in transducing primary human tumor cells, it has been difficult to clinically apply this strategy. In this study, liposome-mediated delivery of an adeno-associated virus (AAV)-based plasmid containing the sequence for murine gamma-interferon (gamma-IFN) (pMP6A-mIFN-gamma) was used to generate cytokine-secreting murine tumor cell vaccines. High levels of gamma-IFN and elevated class I major histocompatibility complex expression after transfer of pMP6A-mIFN-gamma into the murine lung cancer cell line, D122, was demonstrated. The efficiency of gene transfer was determined by two different methods and was estimated to be 10-15%. Irradiated gamma-IFN D122 cells generated by this novel gene delivery system (D122/pMP6A-mIFN-gamma) and also by standard retroviral methods (DIF2) were administered as weekly vaccinations by intraperitoneal injection to animals bearing 7-day-old intrafootpad D122 tumors. Hindlimb amputation was performed when footpad diameters reached 7 mm, and lungs were harvested 28 days later. Animals vaccinated with gamma-IFN-secreting D122 cells produced by AAV-based plasmids delivery demonstrated a significant delay in footpad tumor growth when compared with controls and DIF2 cells. Fifty-seven percent of animals vaccinated with D122/pMP6A-mIFN-gamma were free of pulmonary metastases 28 days after amputation, significantly improved from the 0, 7, and 15% observed in animals vaccinated with irradiated parental D122 cells, irradiated D122 cells lipofected with an empty-cassette vector (pMP6A), or DIF2 cells, respectively. These results and the ability to transfer genes with this delivery system to a broad range of tumor types support its use in the generation of cytokine-secreting tumor cell vaccinations for use in clinical trials.
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PMID:Active immunization with tumor cells transduced by a novel AAV plasmid-based gene delivery system. 910 11

Extracts produced from Viscum album L. (mistletoe) as well as certain isolated components are able to stimulate different functions of the immune system. The natural killer cells have been suggested as one of the candidates for direct tumour cell destruction. These cells are defined by their ability to mediate non-major histocompatibility complex (MHC) restricted cytotoxicity without prior sensitization against a specific antigen. However, their effectiveness in tumor defence in vivo is unclear. In general, natural killer cells are unable to lyse fresh autologous tumour cells in vitro unless activated by interleukin-2-preincubation. The results of clinical studies are contradictory, but there is evidence that they may contribute to the prevention of the development of recidives and metastases. In this regard it is interesting that mistletoe extracts are able to stimulate natural killer cell-mediated cytotoxicity in vitro directly as well as indirectly in a cytokine-like manner, with the active components being carbohydrates rather than lectins. Clinical application of mistletoe extracts or isolated lectins is reported to induce augmentation of both number and activity of natural killer cells in peripheral blood in a dose-dependent manner; however, non-responders also have been described. In future work it has to be clarified whether a mistletoe-derived modulation of the natural killer system is of benefit in the tumour defence of cancer patients.
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PMID:Mistletoe therapy for human cancer: the role of the natural killer cells. 917 68

We have developed an immunotherapy in which tumor cells transfected with syngeneic major histocompatibility complex (MHC) class II genes are cell-based vaccines for the treatment of established tumor and metastatic disease. If this strategy is to be used clinically, convenient methods for generating class II+ tumor cells are necessary. Interferon-gamma treatment or transduction of the class II transactivator (CIITA) gene induces class II expression but also up-regulates the class II-associated accessory molecules, invariant chain (Ii) and DM. To determine if interferon-gamma treatment and CIITA transduction are potential immunotherapies, we assessed the tumorigenicity of sarcoma cells expressing combinations of class II, Ii, and DM. Since we hypothesized that class II-transfected tumor cells not coexpressing Ii and DM present endogenously encoded tumor peptides, we have assessed the transfectants for antigen presentation activity to MHC class II-restricted antigen-specific CD4(+) T cells. Tumor challenge studies demonstrate that tumor cells expressing class II without coexpression of Ii or Ii plus DM are highly immunogenic and preferentially present endogenous antigens, while tumors coexpressing class II with Ii or Ii plus DM are not effective immunogens. Because tumor rejection correlates with expression of class II without coexpression of Ii and DM, the most efficacious vaccines will express MHC class II without coexpression of Ii and DM and will preferentially present endogenous antigen.
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PMID:Major histocompatibility complex class II-transfected tumor cells present endogenous antigen and are potent inducers of tumor-specific immunity. 919 61

Renal cell carcinomas belong to the small group of tumors that are able to induce antitumor responses. Here we describe two general types of cytotoxic effector lymphocytes that can eliminate autologous tumor cells and discuss the role that major histocompatibility complex encoded molecules play in governing their specificities. Improved understanding of the cellular and molecular basis of renal cell carcinoma recognition opens new avenues of research with the potential to develop better immunotherapies for patients with metastatic disease.
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PMID:Cellular and molecular analyses of major histocompatibility complex (MHC) restricted and non-MHC-restricted effector cells recognizing renal cell carcinomas: problems and perspectives for immunotherapy. 923 80

HLA class I antigens of the human major histocompatibility complex (MHC) play an important role in immune response. Consistent with their role in immune surveillance, these antigens are expressed on most cell types. However, a marked deficiency or lack of expression of these antigens has been observed in a variety of human neoplasms. We have shown that a number of class I-deficient human tumor cell lines, including small-cell lung carcinoma, lacked products of MHC-encoded TAP1 and LMP2 genes. Since a direct evidence for the role of these genes in class I expression in tumor cells is not available, in the present study we transfected class I-deficient human small-cell lung carcinoma cells with cDNAs corresponding to TAP1 gene and to LMP2 gene. Following transfection, tumor cells expressed products of the respective transfected gene. Cell-surface expression of class I molecules was, however, observed in cells transfected with TAP1, but not in tumor cells transfected with LMP2 gene. Our results provide conclusive evidence for a role of TAP1 gene in class I expression and suggest that transfection of TAP genes may be useful to upregulate class I expression in tumor cells. This strategy for restoration of class I expression by transfection of TAP genes is relevant for tumor rejection and/or abrogation of metastases formation.
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PMID:Transfection of TAP 1 gene restores HLA class I expression in human small-cell lung carcinoma. 942 98

A major goal of tumor immunotherapy is the effective eradication of established metastases associated with the induction of a T cell-mediated protective immunity. We achieved this in a poorly immunogenic murine neuroblastoma model by gene therapy with a single chain interleukin 12 (scIL-12) fusion protein that assures equal expression of its p35 and p40 subunits. Thus, NXS2 hybrid neuroblastoma cells (C1300 x dorsal root ganglion cells), which form experimental bone marrow and liver metastases in syngeneic A/J mice, were transduced with a gene encoding murine interleukin 12, monomerized by introduction of a protein linker between the p35 and p40 protein chains of this heterodimeric cytokine. We demonstrate for the first time that subcutaneous vaccination with these transduced cells induces a protective immunity, as indicated by the complete absence of liver and bone marrow metastasis after challenge with NXS2 wild-type tumor cells. Furthermore, vaccination of animals with established liver and bone marrow metastases completely eradicated liver metastases and suppressed bone marrow metastases. The local and systemic immune response against scIL-12-transduced NXS2 cells is largely dependent on CD8(+) T cells. This was demonstrated in vivo by depletion of immunocompetent A/J mice with monoclonal anti-CD4 and anti-CD8 antibodies and in vitro by specific major histocompatibility complex, class I-restricted CD8(+) T cell-mediated killing of NXS2 and their parental C1300 neuroblastoma cells. In conclusion, we demonstrate successful anti-tumor immunotherapy with an scIL-12 fusion protein that could facilitate clinical application of interleukin 12 gene therapy.
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PMID:Gene therapy with a single chain interleukin 12 fusion protein induces T cell-dependent protective immunity in a syngeneic model of murine neuroblastoma. 948 10

We have developed a novel approach to adoptive therapy of cancer based on the use of a human T cell line (TALL-104) which is endowed with major histocompatibility complex non-restricted cytotoxic activity against a broad range of tumors and across several species, while sparing cells from normal tissues. The present study investigates the efficacy of TALL-104 cell therapy in severe combined immunodeficient (SCID) mice implanted with human solid tumors. The human cell lines DU-145 (prostate cancer), A549 (lung carcinoma) and WM451 (melanoma) were implanted subcutaneously (s.c.) in the flank region of the mice. Multiple intraperitoneal (i.p.) transfers of lethally irradiated TALL-104 cells into animals bearing small tumor masses (150 mg) resulted in 50-75% reduction of local tumor growth and complete prevention of pulmonary metastasis. In mice implanted s.c. with A549 cells, dramatic antitumor effects against both local and metastatic disease were observed when cell therapy was initiated after surgical excision of the primary tumor mass. In another set of experiments, the DU-145 and WM451 cells were injected intravenously (i.v.); cells disseminated aggressively in various organs and all animals died within 6-10 weeks from engraftment. However, experimental mice that received TALL-104 cell therapy i.p. daily, starting 1 week after tumor inoculation, showed longer survival and a slower tumor growth (as measured monthly by plasmatic levels of the sICAM-1 tumor marker). At necropsy 1/6 of these animals were disease free. Taken together, these data indicate the effectiveness of this novel antitumor agent in prolonging disease-free survival and controlling tumor growth and invasion.
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PMID:TALL-104 cell therapy of human solid tumors implanted in immunodeficient (SCID) mice. 970 68


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