Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major histocompatibility complex (MHC) class II genes encode surface molecules that are required for presentation of antigenic peptides to helper T-cells. The concentration of these proteins on the surface of effector cells (antigen-presenting cells such as B-cells and macrophage) is one of the parameters affecting the intensity of the immune response. Many studies have thus focused their attention on the mechanisms that control the expression of class II genes, particularly in B-cells. The anatomy of MHC class II promoters has been dissected in detail, and many trans-acting factors and their cognate DNA regulatory elements have been identified and characterized, thus helping to elucidate the molecular circuitry which determines tissue-specific, coordinate expression of these genes. In most cases, regulation has been investigated at the level of mRNA transcription. MHC class II gene expression has been observed as well, under physiological conditions, in many other tissues and organs such as brain, thyroid, thymus, and intestine, thus implying that class II molecules may be involved, whether directly or indirectly, in the modulation of other important biological responses in addition to the control of the immune reaction against soluble antigens. Spurious MHC class II activity is also detected in tumor cells and in other pathological conditions such as those found in autoimmune, inflammatory, and infectious diseases. In autoimmunity, cells that express class II molecules may present tissue-specific antigens, thus triggering a mechanism of self-destruction. In tumors, instead, unscheduled MHC class II expression may be part of a mechanism that prevents tumor progression. Comprehension of the regulatory functions operating in pathological conditions as compared to those active in B-cells and in macrophages is still rudimentary. Because of the possible pathogenetic importance of aberrant class II expression, knowledge of the cis- and trans-acting elements controlling gene expression at either the transcriptional or posttranscriptional level may allow the development of strategies for immunointervention against these diseases.
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PMID:Control of MHC class II gene expression in autoimmune, infectious, and neoplastic diseases. 811 Mar 78

In tumor cells, abnormal proteins expression results from DNA mutations or fusion associated with carcinogenesis or tumor progression. Those abnormal, often clearly defined proteins should be recognized by the immune system and induce an immune response leading to tumor rejection. Actually, most tumors escape the immune response through a specific tolerance, able to suppress or to modify the immune response against tumor associated antigens. Factors which contribute to tumor immunological escape are not elucidated, but could involve a defect in tumor-antigen presentation to the host immune system. An effective immune response against tumor requires tumor-associated antigens to be processed into immunogenic peptides which are presented to T lymphocytes in association with MHC molecules. T-cell fonctional activation requires also a costimulatory signal delivered to the CD28 receptor on T cells by the B7 family of molecules expressed by the antigen-presenting cells. Most tumor cells express MHC class I molecules, a minority also express MHC class II molecules and only a few lymphoma have been reported to express B7. So, tumor cells are not able to present efficiently their specific antigens to competent T cells. Most tumors are yet infiltrated by inflammatory cells, some of them possessing the capacity to process tumor antigens and to present them to competent T cells, either inside the tumor itself, or after migration into the draining lymph nodes. Among antigen-presenting cells, dendritic cells, unlike B lymphocytes and macrophages, are the only cells able to stimulate naive T lymphocytes. They present effectively antigens in situ and stimulate naive and memory T lymphocytes into secondary lymphoid organs. Actually, dendritic cells are supposed to take place in the antitumor immune response, and dendritic cells infiltration inside numerous neoplasms is often associated to an immune response against tumor. However, many questions still underline the failure to recognize stimuli involved in the mobilization (and the retention?) of dendritic cells inside tumor, or which incite them to migrate out of it to ensure their antigen presenting cell function effectively. The secretion of immunosuppressive factors like IL-10, either by tumor cells and by tumor-infiltrating leukocytes represents one of the mechanisms involved in the modulation of the antigen-presenting cell function and in tumor immunological escape. Recent works were undertaken to increase tumor cells immunogenicity. B7.1 molecule transfection allows tumor cells to present directly their antigens and leads to their eradication in vivo. Those results suggest that tumor-antigens presentation is limited in tumor-bearing hosts.
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PMID:[Dendritic cells and immune function in cancer]. 878 96

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

Multiple myelomas produce tumor-specific antigen (TSA) in the form of idiotype (Id) on monoclonal Ig. CD4(+) T cells can recognize Id-peptide on MHC class II molecules and protect against challenges with MOPC315 cells, which are, as common for myelomas, class II-negative. The present study explains these previous results by demonstrating that Id can be transferred from myeloma cells to antigen-presenting cells (APC), which present processed Id-peptide on their class II molecules to Id-specific T cell receptor-transgenic (TCR-TG) CD4(+) T cells. Id-primed tumor APC were heterogeneous, the majority being dendritic cells with class II(+), CD11b(+) CD11c(+) CD40(+) CD80(+) CD86(+) markers. The APC were localized beneath CD31(+) endothelial cells of tumor microvessels, and their frequency declined with tumor progression. The APC could stimulate Id-specific naive TCR-TG, short-term polarized TCR-TG, and cloned CD4(+) T cells to proliferate and produce cytokines in vitro. Furthermore, small MOPC315 tumors established in Id-specific TCR-TG mice contained clusters of activated (CD69(+)CD25(+)) and proliferating (BrdUrd(+)) Id-specific transgenic CD4(+) blasts. The activated Id-specific T cells were located adjacent to Id-primed dendritic cells in the tumor. Thus, a TSA can be transferred in vivo from myeloma, and possibly other types of cancer cells to APC for MHC class II presentation to CD4(+) T cells.
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PMID:Dendritic cells purified from myeloma are primed with tumor-specific antigen (idiotype) and activate CD4+ T cells. 1070 28

IL-10 is assumed to be a major immunosuppressive factor produced by most B-cell tumors. The immunosuppressive role of tumor-derived IL-10 was analyzed using the MHC class II-negative BALB/c plasmacytoma ADJ-PC-5 as a model tumor. Immune monitoring of tumor-bearing mice was based on the measurement of tumor burden, tumor-specific CTL cytotoxicity and intracellular cytokine staining using FACS. ADJ-PC-5 tumor progression in syngeneic recipients is associated with strong, concomitant, tumor-specific CTL responses during early stages of tumor progression which are sufficient to cause rejection of small s.c. autologous test tumors. These initial CTL responses gradually decline during later tumor stages. Blocking of IL-10 in vivo did not abolish CTL suppression or retard tumor growth. More strikingly, application of anti-IL-10 antibodies during early tumor stages abrogated CTL induction and markedly accelerated tumor growth. In contrast to anti-IL-10 treatment, application of cyclo-oxygenase inhibitors to ADJ-PC-5 tumor-bearing mice led to enhanced tumor-specific CTL responses throughout all stages of tumor progression, paralleled by retarded tumor growth and a significantly delayed onset of suppression. Both findings contradict a dominant immunosuppressive role of IL-10 during B-cell tumor progression. Tumor-derived IL-10 must therefore be considered an immunostimulating factor, which accounts for the high immunogenicity of B-cell tumors, whereas prostaglandins, which are not produced by the tumor cells themselves, are the dominant immunosuppressors in this system.
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PMID:Prostaglandins, but not tumor-derived IL-10, shut down concomitant tumor-specific CTL responses during murine plasmacytoma progression. 1126 84

Most B-cell malignancies are incurable diseases and therefore warrant new therapeutic approaches. In a pilot study, we tested the feasibility and safety of combined immunotherapy consisting of adoptive transfer of autologous tumour-specific T cells, low-dose interleukin 2 (IL-2) and a cellular vaccine of CD40-activated plasma cell leukaemia (PCL) cells in a patient who failed tandem repeat stem cell transplantation and idiotype vaccination. Autologous tumour-specific T cells for adoptive T-cell transfer were propagated in vitro by repetitive stimulation with autologous ex vivo CD40-activated PCL cells. CD40-activated PCL cells for vaccination were similarly generated ex vivo by co-culture with CD40 ligand transfectants. Autologous T cells (5 x 108 and 2.5 x 109 for two separate treatment cycles) generated ex vivo and cytotoxic against autologous tumours were infused and well tolerated by the patient. Fever and myalgias were closely related to IL-2 injections and no other adverse effects were observed. A temporary decrease of PCL cells in peripheral blood was seen after the first cycle of adoptive T-cell therapy, tumour cell vaccination and low-dose IL-2. Tumour progression was associated with tumour cells that (1) expressed a complex karyotype, (2) demonstrated loss of MHC class II, and (3) did not induce autologous tumour-specific T-cell lines ex vivo. We demonstrated the safety and feasibility in combining autologous tumour-specific T-cell therapy with low-dose IL-2 and that clinical trials based on the use of CD40-activated autologous tumour cell vaccines are warranted in patients with CD40-activated autologous tumour cells, either as a vaccine or for ex vivo stimulation of autologous T cells.
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PMID:A pilot study of combined immunotherapy with autologous adoptive tumour-specific T-cell transfer, vaccination with CD40-activated malignant B cells and interleukin 2. 1138 Apr 16

The development of an effective antitumor immune response to control tumor growth is influenced by the tumor cell itself and/or by the tumor microenvironment. Tumor invasion and tumor cell spreading require a finely tuned regulation of the formation and loosening of adhesive contacts of tumor cells with the extracellular matrix (ECM). In our laboratory, a rat tumor cell line derived from a spontaneous rat sarcoma revealed, by flow cytometry, a high frequency of intercellular adhesion molecule-1 (ICAM-1, 70.1 +/- 8.7%) and urokinase-type plaminogen activator receptor (uPAR, 51.2 +/- 5.2%) positive cells, while a weak expression of MHC class II (IA, 2.2 +/- 0.2% and IE, 17.4 +/- 3.7%) and B7 (12.1 +/- 2.2%) antigens was detected. In our tumor experimental model, after implantation of tumor cells, visible tumor masses were present at days 5-7 with a relatively fast tumor growth until day 15 (progressive phase) followed by a suppression of the tumor growth (regressive phase). Here we present data that correlates a significant decrease in the frequency of ICAM-1 and uPAR expressing tumor cells with the appearance of tumor cells in sites distant from that of the primary tumor. In addition we describe the development of a cellular immune response which controls the tumor progression and is associated with an increase in the expression of major histocompatibility complex (MHC) class II IA antigen during tumor development. The histological examination at tumor progressive and regressive time points revealed the relevant presence of polymorphonuclear neutrophils (PMNs) evidencing colliquative necrosis in tumor growth areas. Taken together, these results support the idea that the balance between adhesive interactions, proteolytic activity and tumorigenicity may lead to a tumor invasive phenotype.
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PMID:Decreased expression of intercellular adhesion molecule-1 (ICAM-1) and urokinase-type plasminogen activator receptor (uPAR) is associated with tumor cell spreading in vivo. 1219 72

Vaccine immunotherapy must induce helper and cytotoxic cell-mediated immunity to generate the powerful antitumor immune responses needed to suppress cancer progression. We reported previously that a 16-amino acid peptide analogue derived from pigeon cytochrome c can bind broad ranges of MHC class II types and activate helper T cells in mice. To determine whether DNA encoding the Pan-MHC class II IA peptide (Pan-IA) can increase the efficacy of tumor suppression by DNA vaccine immunotherapy targeting tumor antigens, Pan-IA DNA was administered with ovalbumin (OVA) DNA to C57BL/6 mice bearing the OVA-expressing tumor cell line E.G7. Specific proliferative responses to and cytotoxic activities against OVA-expressing targets were induced in mice vaccinated with both OVA and Pan-IA DNA but not in those vaccinated with OVA DNA alone or control DNA plus Pan-IA DNA. Growth of E.G7 cells was suppressed only by combined vaccination with OVA and Pan-IA DNA, and tumors in five of the nine mice that received this combined vaccination were eradicated completely. In those mice, the frequency of CD8-positive T cells reactive with OVA(257-264) peptides in the context of H-2K(b) was significantly increased in the tumor site. Furthermore, immunofluorescent study of the inoculated tumors revealed increased accumulation of both CD4- and CD8-positive T cells producing IFN-gamma in the tumor only by this vaccine protocol. The data suggest that Pan-IA DNA can augment suppressive effects of DNA vaccines on tumor growth by increasing numbers of antigen-specific CTLs and helper T cells. This is the first study in which established tumors have been eradicated successfully by vaccination with DNA corresponding to CTL epitopes and helper T cell epitopes. Our animal model may contribute to the development of therapeutic DNA vaccines against cancer.
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PMID:Deoxyribonucleic acid (DNA) encoding a pan-major histocompatibility complex class II peptide analogue augmented antigen-specific cellular immunity and suppressive effects on tumor growth elicited by DNA vaccine immunotherapy. 1463 22

The carcinoembryonic antigen (CEA) is an attractive target for immunotherapeutic purposes because of its expression profile, its role in tumor progression, and its immunogenicity. However, CEA belongs to the CD66 immunoglobulin super-gene family that comprises highly homologous molecules expressed on leukocytes, making CEA a potential autoantigen expressed on hematopoietic cells. We used a MHC class II epitope prediction algorithm (TEPITOPE) to select 11 sequence segments of CEA that could form promiscuous CD4(+) T-cell epitopes and used synthetic peptides corresponding to the predicted sequences to propagate in vitro CD4(+) T cells from healthy donors and colon cancer patients. CD4(+) T cells from all subjects strongly recognized the sequence segment (LWWVNNQSLPVSP), repeated at residues 177-189 and 355-367. Importantly, we demonstrated that this highly immunodominant region contains a naturally processed epitope(s). Cross-recognition experiments with peptide analogues present on the CD66 homologous proteins showed that CEA(177-189/355-367)-specific CD4(+) T cells did not recognize the analogues, demonstrating that recognition of the immunodominant epitope is CEA specific. These data suggest that the repertoire of CEA(177-189/355-367)-specific CD4(+) T cells might have been shaped by a selective process to exclude CD4(+) T cells specific for CD66 homologues expressed on leukocyte, while preserving the CEA-specific repertoire. The features of strong immunogenicity and immunodominance in the absence of potential induction of autoimmunity make the identified CEA epitope of particular interest for the development of antitumor vaccines.
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PMID:CD4(+) T cells from healthy subjects and colon cancer patients recognize a carcinoembryonic antigen-specific immunodominant epitope. 1467 13

S100A7 (psoriasin) is highly expressed in preinvasive breast carcinomas and in a subset of poor prognosis invasive tumors. To determine the influence of S100A7 expression on ERalpha negative breast cancer, we profiled mRNA gene expression by Microarray and SAGE analysis, using the ERalpha negative MDA-MB-231 cell line model. Statistically significant transcripts of genes with very high differential expression were further validated by QPCR in both MDA-MB-231 and MDA-MB-468 cell lines expressing exogenous and endogenous S100A7. S100A7 expression correlated with increases in genes associated with MHC class II receptor activity, antigen processing and antigen presentation, and immune cell activation. The transcription factors (TFs) prediction tool CARRIE confirmed an association between TFs reported to be upregulated by S100A7 (NF-kappaB, AP-1, and HIF1) and the regulation of many genes in this dataset. The relationship between S100A7 up-regulation and the MHC class II and HLA-class II molecule coding gene CD74 was examined further in a cohort of ERalpha negative breast tumors by tissue microarray (TMA) and immunohistochemistry (IHC), confirming a significant association in vivo (p=0.042, n=149). These results are consistent with a role for S100A7 in modulating the immune response which may be a factor in early breast tumor progression.
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PMID:S100A7 (psoriasin) influences immune response genes in human breast cancer. 1756 May 71


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