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

In order to clarify the relationship between HLA-DR antigen expression of nasopharyngeal carcinoma (NPC) and the clinicopathology and prognosis of NPC, immunohistochemical studies on HLA-DR antigen expression in 77 NPC cases were performed. The results showed that the positive rate of HLA-DR was 44.2% in this series. Non-neoplastic epithelium did not express this antigen. A close association was found between expression of HLA-DR antigen and the clinical staging of NPC. The positive rate of HLA-DR gradually decreased with tumor progression, showing a remarkable difference among tumors in different clinical stages (P < 0.05). Analysis of patient survival demonstrated that the prognosis of NPC patients with HLA-DR expression was significantly better than those without (P < 0.01). The above results give support to the possibility of immunomodulation of tumors.
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PMID:[A study of HIA-DR antigen expression in nasopharyngeal carcinoma and its relation with clinical pathology and prognosis]. 927 72

It is well known that the expression level of the ICAM-1 and MHC is frequently altered in accordance with tumor progression, and the expression of oncogenes is significantly related to tumorigenesis, tumor progression, and/or metastatic potential. In this study, to investigate the relationship between the alteration in ICAM-1 and MHC expression with the tumor grade and/or cell differentiation, we examined the expression of ICAM-1 and HLA-DR before and after treatment with IFN-gamma in 4 human bladder cancer cell lines. We also analyzed the expression of c-Ha-ras and c-myc. Using flow cytometry, highly constitutive expression of ICAM-1 was detected in all cell lines tested except RT4 (grade I, well-differentiated, superficial). IFN-gamma was found to somewhat induce the expression of ICAM-1 in all cell lines except RT4. The constitutive expression of HLA-DR was not detected in any of the cell lines tested by flow cytometry and Northern blot. HLA-DR expression was induced by IFN-gamma in RT4 and J82 (grade III, anaplastic, invasive). Codon 12 point mutation of c-Ha-ras (GGC-->GTC; Gly-->Val) was detected in T24 (grade III, epidermoid, superficial) through single-strand conformation polymorphism, and sequencing analysis. Another point mutation at codon 27 was detected in TCCSUP (grade IV, distant metastatic), but this mutation was found to be silent (CAT-->CAC; His). Expression of c-myc was detected in J82 and TCCSUP by Northern blot. These findings, along with the clinical and pathological characteristics of the patients from whom the cell lines were established, might suggest that the expression of ICAM-1 seems to be associated with cell differentiation, and the inducibility of HLA-DR by IFN-gamma seems to be associated with the degree of malignancy. Expression of c-myc seems to be associated with invasiveness. However, a significant correlation between c-Ha-ras activation and tumor grade could not be observed.
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PMID:Induction of ICAM-1, HLA-DR molecules by IFN-gamma and oncogene expression in human bladder cancer cell lines. 939 53

We report a case of CD7+ stem cell lymphoma. A 47-year-old man presented with general malaise and lumbago in April 1997. The patient exhibited swollen left cervical lymph-nodes and an intra-abdominal bulky mass. He was referred to us because lymph-node biopsy specimens indicated a diagnosis of diffuse type malignant lymphoma. An abdominal CT scan disclosed large retroperitoneal, para-aortic, and mesenteric root masses. Bone marrow involvement was shown by bone marrow biopsy specimens, though no circulating blasts were detected at presentation. The patient was treated with high-dose CHOP therapy without any benefit. Though ESHAP therapy was performed as salvage chemotherapy, the abdominal masses did not shrink at all. The patient died of tumor progression in November 1997. In the terminal stage, the lymphoma cells emerged in the peripheral blood and thus became available for analysis. The cells expressed CD5, 7, 34, 38, 71, but were negative for CD1, 2, 3, 4, 8, 10, 13, 14, 16, 19, 20, 21, 25, HLA-DR, and EMA. An immunoglobulin heavy chain gene rearrangement band was detected by Southern blot analysis. However, no T cell receptor lambda or beta chain gene rearrangement bands were detected.
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PMID:[Chemotherapy-resistant CD7-positive stem cell lymphoma presenting with intra-abdominal mass]. 1002 52

Although melanocytes are devoid of the human major histocompatibility complex class II (HLA II) molecules, melanomas often display constitutive expression of these molecules, particularly HLA-DR. This constitutive expression of HLA-DR molecules is associated with tumor progression and poor prognosis but the molecular basis for this association remains poorly understood. Within the hypothesis of a role in immune escape, we analyzed the regulation of Fas-mediated apoptosis by HLA-DR signaling in the HLA-DR-positive malignant melanoma cell line A375. Our study demonstrates that engagement of HLA-DR molecules with anti-HLA-DR-specific monoclonal antibody L243 significantly reduces Fas-mediated apoptosis; DNA fragmentation and cell death were decreased by 50% and 40%, respectively. We found that while HLA-DR signaling does not affect Fas receptor expression, it significantly reduces Fas-induced activation of caspase-8 and Bid. Furthermore, inhibition studies and expression of dominant negative form of Mek-1 demonstrated that HLA-DR-mediated inhibition of caspase-8/Bid activation and apoptosis are dependent on the activation of the MAPK/Erk pathway. Together, our results provide evidence that HLA-DR signaling activates the MAPK/Erk pathway in A375 melanoma cells, which has a functional role in the resistance of these cells to Fas-mediated apoptosis. These observations underline the potential importance that HLA-DR signaling might have in melanoma immune escape and tumor progression.
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PMID:HLA-DR signaling inhibits Fas-mediated apoptosis in A375 melanoma cells. 1530 75

Increased levels of interleukin (IL)-10 have been described as a negative prognostic indicator for survival in patients with various types of cancer. IL-10 exerts tolerogenic and immunosuppressive effects on dendritic cells, which are crucial for the induction of an antitumor immune response. Blood dendritic cell antigen (BDCA)-2 and BDCA-4 are specifically expressed by CD123(bright) CD11c- plasmacytoid dendritic cells; whereas BDCA-1 and BDCA-3 define 2 distinct subsets of CD11c+ myeloid dendritic cells. In this study, the T-helper cell (Th)1/Th2 cytokine serum profile of 65 hepatocellular carcinoma patients was assessed. We found that serum levels of IL-10 were substantially increased in hepatocellular carcinoma patients as compared with controls. Peripheral blood mononuclear cells from healthy volunteers were exposed to recombinant human (rh)IL-10 in vitro to additionally characterize its impact on distinct blood dendritic cell subsets. A dramatic decrease of all myeloid dendritic cell (MDC) and plasmacytoid dendritic cell (PDC) subsets was detectable after 24 hours of continuous rhIL-10 exposure. Moreover, the expression of HLA-DR, CD80 and CD86, was significantly reduced on rhIL-10-treated dendritic cell subsets. Direct ex vivo flow cytometric analysis of various dendritic cell subpopulations in peripheral blood from hepatocellular carcinoma patients revealed an immature phenotype and a substantial reduction of circulating dendritic cells that was associated with increased IL-10 concentrations in serum and with tumor progression. These findings confirm a predominantly immunosuppressive role of IL-10 for circulating dendritic cells in patients with hepatocellular carcinoma and, thus, may indicate novel aspects of tumor immune evasion.
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PMID:Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. 1553

Dendritic cell (DC) defects are an important component of immunosuppression in cancer. Here, we assessed whether cancer could affect circulating DC populations and its correlation with tumor progression. The blood DC compartment was evaluated in 136 patients with breast cancer, prostate cancer, and malignant glioma. Phenotypic, quantitative, and functional analyses were performed at various stages of disease. Patients had significantly fewer circulating myeloid (CD11c+) and plasmacytoid (CD123+) DC, and a concurrent accumulation of CD11c(-)CD123(-) immature cells that expressed high levels of HLA-DR+ immature cells (DR(+)IC). Although DR(+)IC exhibited a limited expression of markers ascribed to mature hematopoietic lineages, expression of HLA-DR, CD40, and CD86 suggested a role as antigen-presenting cells. Nevertheless, DR(+)IC had reduced capacity to capture antigens and elicited poor proliferation and interferon-gamma secretion by T-lymphocytes. Importantly, increased numbers of DR(+)IC correlated with disease status. Patients with metastatic breast cancer showed a larger number of DR(+)IC in the circulation than patients with local/nodal disease. Similarly, in patients with fully resected glioma, the proportion of DR(+)IC in the blood increased when evaluation indicated tumor recurrence. Reduction of blood DC correlating with accumulation of a population of immature cells with poor immunologic function may be associated with increased immunodeficiency observed in cancer.
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PMID:A population of HLA-DR+ immature cells accumulates in the blood dendritic cell compartment of patients with different types of cancer. 1635 94

Dendritic cells (DC) have been implicated in the defective function of the immune system during cancer progression. We have demonstrated that patients with cancer have fewer myeloid (CD11c+) and plasmacytoid (CD123(hi)) DC and a concurrent accumulation of CD11c(-)CD123- immature cells expressing HLA-DR (DR(+)IC). Notably, DR(+)IC from cancer patients have a reduced capacity to stimulate allogeneic T-cells. DR(+)IC are also present in healthy donors, albeit in smaller numbers. In this study, we assessed whether DR(+)IC could have an impact on the immune response by comparing their function with DC counterparts. For this purpose, DR(+)IC and DC were purified and tested in the presentation of antigens through major histocompatibility complex (MHC) II and MHC-I molecules. DR(+)IC were less efficient than DC at presenting antigens to T-cells. DR(+)IC induced a limited activation of T-cells, eliciting poor T-helper (Th) 1 and preferentially inducing Th2-biased responses. Importantly, despite DR(+)IC's poor responsiveness to inflammatory factors, in samples from healthy volunteers and breast cancer patients, CD40 ligation induced phenotypic maturation and interleukin 12 secretion, in turn generating more efficient T-cell responses. These data underscore the importance of inefficient antigen presentation as a mechanism for tumor evasion and suggest an approach to improve the efficacy of DC-based immunotherapy for cancer.
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PMID:HLA-DR+ immature cells exhibit reduced antigen-presenting cell function but respond to CD40 stimulation. 1635 95

The carcinoembryonic Ag (CEA) is an attractive target for immunotherapy because of its expression profile and role in tumor progression. To verify the existence of spontaneous anti-CEA CD4+ T cells in lung cancer patients, we first identified CEA sequences forming naturally processed epitopes, and then used the identified epitopes to test their recognition by CD4+ T cells from the patients. We had previously identified CEA(177-189/355-367) as an immunodominant epitope recognized by CD4+ T cells in association with several HLA-DR alleles. In this study, we identified four additional subdominant CEA sequences (CEA(99-111), CEA(425-437), CEA(568-582), and CEA(666-678)), recognized in association with one or more HLA-DR alleles. Peptide-specific CD4+ T cells produced proinflammatory cytokines when challenged with the native protein and CEA-expressing tumor cells, thus demonstrating that the identified CEA sequences contain naturally processed epitopes. However, CEA is expressed in the thymus and belongs to the CD66 family that comprises highly homologous molecules expressed on hemopoietic cells, raising concerns about tolerance interfering with the in vivo development of anti-CEA immunity. We thus tested the spontaneous reactivity to the identified epitopes of peripheral blood CD4+ T lymphocytes from eight early-stage lung cancer patients bearing CEA-positive tumors. We found GM-CSF- and IFN-gamma-producing CD4+ T cells in two patients. Our data indicate that CD4+ immune responses against CEA develop in neoplastic patients, suggesting that tolerance toward CEA or cross-reactive CD66 homologous molecules might be either not absolute or be overcome in the neoplastic disease.
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PMID:Identification of novel subdominant epitopes on the carcinoembryonic antigen recognized by CD4+ T cells of lung cancer patients. 1658 7

Matrix metalloproteinase-9 is involved in inflammation and tumor progression. We previously demonstrated that interferon type I (alpha/beta) and II (gamma) inhibit matrix metalloproteinase-9 (92kDa) gene expression on lymphocytes from patients with B chronic lymphocytic leukemia and human monocytes. Since all-trans retinoic acid (ATRA) can regulate some interferon -responsive genes, we studied here the effects of all-trans retinoic acid onto matrix metalloproteinase-9 levels in these cells. By using RT-PCR, ELISA and zymography experiments, we showed that all-trans retinoic acid down-regulated matrix metalloproteinase-9 synthesis (mRNA,protein) and secretion. The inhibitory action of all-trans retinoic acid toward matrix metalloproteinase-9 was however not associated with the STAT1/IRF-1 pathway involved in interferon-mediated matrix metalloproteinase-9 inhibition indicating that all-trans retinoic acid did not bypass IFN receptor signaling. Using flow cytometry, we detected on the surface of monocytes low expression of matrix metalloproteinase-9 and Fc-gammaRI, and high expression of HLA-DR, beta1 and beta2 integrins. Enhancement of Fc-gammaRI and HLA-DR on monocytes by interferon-gamma, but not by all-trans retinoic acid, was accompanied by up-regulation of surface matrix metalloproteinase-9. Furthermore, we showed that all-trans retinoic acid down-regulated matrix metalloproteinase-9 expression in lymphocytes of untreated patients with early stage B chronic lymphocytic leukemia. Together, our data suggest the potential relevance of all-trans retinoic acid as a pharmacological tool to attenuate matrix metalloproteinase-9 secretion in pathological situations.
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PMID:Comparative effects of interferon-gamma and all- trans retinoic acid on secreted and surface-associated matrix metalloproteinase-9 expression of human monocytes. 1691 95

Studies aimed at elucidating the immunological and prognostic significance of HLA-DR expression on breast carcinoma cells have yielded contradictory results. To expand on previous studies, we have investigated the associations of tumor cell expression of HLA-DR and its related co-chaperones, invariant chain (Ii) and HLA-DM, with infiltrating inflammatory cells, in situ cytokine mRNA levels and prognosis and outcome in 112 breast carcinoma patients with a median follow-up of 59 months. While the majority of HLA-DR+ tumors co-express Ii, only a minority express HLA-DM. Tumor cell expression of HLA-DR and co-chaperones positively associated with both infiltrating CD4+ and CD8+ T-cell subsets (P < 0.01). Expression of HLA-DR and Ii associated with decreased estrogen receptor alpha levels and younger age at diagnosis, suggesting a role for hormones in the control of HLA class II expression in breast carcinoma. Patients with DR+Ii+DM- tumors had markedly decreased recurrence-free and disease-specific survival as compared with patients with DR+Ii+DM+ tumors (P < 0.05) and HLA-DR/co-chaperone expression was an independent predictor of survival by multivariate Cox regression analysis, controlling for standard prognostic indicators. Tumors that co-express HLA-DR, Ii and HLA-DM have increased levels of IFN-gamma, IL-2 and IL-12 mRNA, suggesting improved survival of patients with DR+Ii+DM+ tumors may be attributable to Th1-dominated immunity. We conclude that expression of determinants of the immune response by tumor cells may influence breast tumor progression and patient outcome.
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PMID:Tumor cell expression of HLA-DM associates with a Th1 profile and predicts improved survival in breast carcinoma patients. 1698 35


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