Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucose-regulated protein 94 (GRP94/gp96), the endoplasmic reticulum heat shock protein 90 paralog, elicits both innate and adaptive immune responses. Regarding the former, GRP94/gp96 stimulates APC cytokine expression and dendritic cell maturation. The adaptive component of GRP94/gp96 function reflects a proposed peptide-binding activity and, consequently, a role for native GRP94/gp96-peptide complexes in cross-presentation. It is by this mechanism that tumor-derived GRP94/gp96 is thought to suppress tumor growth and metastasis. Recent data have demonstrated that GRP94/gp96-elicited innate immune responses can be sufficient to suppress tumor growth and metastasis. However, the immunological processes activated in response to tumor Ag-negative sources of GRP94/gp96 are currently unknown. We have examined the in vivo immunological response to nontumor sources of GRP94/gp96 and report that administration of syngeneic GRP94/gp96- or GRP94/gp96-N-terminal domain-secreting KBALB fibroblasts to BALB/c mice stimulates CD11b(+) and CD11c(+) APC function and promotes bystander activation of CD4(+) T cell Th1 cytokine production. Only modest activation of CD8(+) T cell or NK cell cytolytic function was observed. The GRP94/gp96-dependent induction of CD4(+) T cell cytokine production was markedly inhibited by carrageenan, indicating an essential role for APC in this response. These results identify the bystander activation of CD4(+) T lymphocytes as a previously unappreciated immunological consequence of GRP94/gp96 administration and demonstrate that GRP94/gp96-elicited alterations in the in vivo cytokine environment influence the development of CD4(+) T cell effector functions, independently of its proposed function as a peptide chaperone.
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PMID:Glucose-regulated protein 94/glycoprotein 96 elicits bystander activation of CD4+ T cell Th1 cytokine production in vivo. 1503 32

There is a growing body of evidence that the occurrence of neuroendocrine (NE) differentiation in prostate carcinoma correlates with poor prognosis, tumor progression, and androgen-independence. In the present study, the expression of common NE markers, i.e., chromogranin A (ChGA), serotonin (5HT), neuron-specific enolase (NSE) and adrenomedullin (AM), was retrospectively examined in formalin-fixed, paraffin-embedded prostate tissue samples obtained from patients with adenocarcinoma and from patients with nodular hyperplasia of the prostatic gland (NHPG) (33 and 28, respectively). The statistical analysis of the results (tested the equality of matched pairs of observations using the Wilcoxon matched-pairs signed ranks test) revealed a more prominent expression of ChGA in benign epithelial cells adjacent to adenocarcinomatic lesions (Peri-PAC) than in the adenocarcinoma (PAC) (p = 0.0049). A similar pattern of expression was detected for 5HT (p = 0.000). When comparing the expression of ChGA and 5HT in tissue samples originating in cancer patients with those obtained from NHPG samples, more ChGA and 5HT were expressed in Peri-PAC than in NHPG (p = 0.0004 and 0.002, respectively). The results obtained raise the possibility that adenocarcinoma cells urge some adjacent benign epithelial cells to differentiate into NE cells, which, in turn, may promote tumor growth and invasion.
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PMID:Augmented expression of chromogranin A and serotonin in peri-malignant benign prostate epithelium as compared to adenocarcinoma. 1546 96

Heterogeneity in advanced colon cancer leads to different results from adjuvant chemotherapy. To identify groups of patients who may need adjuvant treatment, molecular staging and correlation with clinical data may be helpful in classifying histologically similar tumors. Colon cancer develops through a multistep process with an accumulation of multiple genetic alterations that are often the cause of a form of genomic instability. The 2 best known mechanisms of genomic instability are chromosomal instability (CIN) and microsatellite instability (MSI). The CIN phenotype is found in approximately 85% of sporadic colon cancers and is characterized by aneuploidy, multiple chromosomal rearrangements, and an accumulation of somatic mutations in oncogenes such as K-ras and tumor suppressor genes such as TP53 and APC. The MSI phenotype is associated with small insertions and deletions mainly in repetitive sequences (microsatellites) and is found in approximately 15% of cases. This instability, often referred to as high-frequency MSI (MSI-H), is caused by defects of the mismatch repair system, which is involved in repairing DNA errors that arise during DNA replication. Clear-cut correlations between the somatic genetic alterations in tumors and the clinical behavior of the tumor are rare. Only a few markers, such as MSI-H and TP53, seem to have a prognostic value. Mutations in the TP53 gene are associated with an aggressive tumor growth and subsequent reduced survival, whereas MSI-H seems to be correlated with a favorable outcome. In general, predicting biologic behavior of in particular stage III colon cancers is difficult and remains a great clinical problem.
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PMID:Genetic alterations in locally advanced stage II/III colon cancer: a search for prognostic markers. 1555 8

The magnitude of response elicited by CTL-inducing vaccines correlates with the density of MHC class I (MHC-I)-peptide complexes formed on the APC membrane. The MHC-I L chain, beta2-microglobulin (beta2m), governs complex stability. We reasoned that genetically converting beta2m into an integral membrane protein should exert a marked stabilizing effect on the resulting MHC-I molecules and enhance vaccine efficacy. In the present study, we show that expression of membranal human beta2m (hbeta2m) in mouse RMA-S cells elevates MHC-I thermal stability. RMA-S transfectants bind an exogenous peptide at concentrations 10(4)- to 10(6)-fold lower than parental RMA-S, as detected by complex-specific Abs and by T cell activation. Moreover, saturation of the transfectants' MHC-I by exogenous peptide occurs within 1 min, as compared with approximately 1 h required for parental cells. At saturation, however, level of peptide bound by modified cells is only 3- to 5-fold higher. Expression of native hbeta2m only results in marginal effect on the binding profile. Soluble beta2m has no effect on the accelerated kinetics, but the kinetics of transfectants parallel that of parental cells in the presence of Abs to hbeta2m. Ab inhibition and coimmunoprecipitation analyses suggest that both prolonged persistence of peptide-receptive H chain/beta2m heterodimers and fast heterodimer formation via lateral diffusion may contribute to stabilization. In vivo, peptide-loaded transfectants are considerably superior to parental cells in suppressing tumor growth. Our findings support the role of an allosteric mechanism in determining ternary MHC-I complex stability and propose membranal beta2m as a novel scaffold for CTL induction.
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PMID:Membrane-anchored beta 2-microglobulin stabilizes a highly receptive state of MHC class I molecules. 1569 42

The activation of naive CD4+ T cells requires both TCR engagement and a second costimulatory signal mediated by the interaction of CD28 with CD80/CD86 expressed on professional APC. However, the situation for naive CD8+ T cells is less clear. Although evidence indicates that induction of CD8+ T cell responses is also dependent on professional APC, the ability of some tumors, which do not express CD80/CD86, to induce CTL suggests that other pathways of costimulation exist for the activation of CD8+ T cells. We examined the ability of tumor cells expressing different levels of a tumor-specific Ag to directly prime CD8+ T cells. We demonstrate that CD8+ T cells are directly activated by tumor cells in a CD80/CD86-CD28 independent manner. In this system, costimulation requires ICAM-1/LFA-1 interaction. This results in the generation of CTL capable of inhibiting tumor growth in vivo, and maintaining long-term survival.
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PMID:The role of intercellular adhesion molecule-1/LFA-1 interactions in the generation of tumor-specific CD8+ T cell responses. 1574 73

Angiogenesis, a complex, coordinated process resulting in the assembly and maturation of new blood vessels, is critical for the growth of tumors. Several lines of evidence argue for angiogenesis inhibition in the treatment of colorectal cancer (CRC) : 1) angiogenesis (as measured by microvessel count), and the expression of pro-angiogenesis factors, such as vascular endothelial growth factor (VEGF), the key regulator of normal and pathological angiogenesis, have been reported to correlate with advanced disease and a worse prognosis ; 2) the expression of VEGF has been shown to correlate with RAS mutations, alterations in the APC-WNT signaling pathway, and overexpression of cyclo-oxygenase-2, which all are frequent in CRC ; 3) bevacizumab, a humanized anti-VEGF monoclonal antibody, is a potent inhibitor of tumor growth of various CRC cell lines in murine xenografts ; 4) the addition of bevacizumab to systemic chemotherapy has been shown to be significantly superior to chemotherapy alone in terms of objective tumor response rate, progression-free survival, and overall survival in patients with metastatic CRC, in the frontline, and more recently in the second-line setting, without worsening of chemotherapy-related toxicity. However, several potential specific adverse events, such as thrombosis, hemorrhages, proteinuria, arterial hypertension, and bowel perforations have been described. Whether the antitumoral efficacy of bevacizumab could be increased when combined to low-dose (metronomic) chemotherapy, or radiotherapy (in rectal cancer), is under development, as well other VEGF-targeted approaches (e.g., dominantnegative mutants, antisense oligonucleotides, antibodies directed against VEGF receptors (VEGFR), VEGFR tyrosine kinase inhibitors, soluble VEGFR,...), or other anti-angiogenesis agents (e.g., thalidomide, celecoxib, angiozyme...).
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PMID:[Therapeutic strategies using VEGF inhibitors in colorectal cancer]. 1638 67

Colorectal cancer is a major cause of cancer death worldwide. A number of key oncogenes and tumor suppressor genes have been proposed to drive progression from healthy colonic epithelia to malignant tumors, including members of the Wnt/beta-catenin pathway. Recently, CpG island promoter hypermethylation was shown to cause inactivation of two extracellular Wnt inhibitors in colon cancer: secreted frizzled-related proteins (sFRPs) and Wnt inhibitory factor-1 (WIF-1). Here, we show for the first time that another extracellular Wnt inhibitor, the DICKKOPF-1 (DKK-1) gene, is transcriptionally silenced by CpG island promoter hypermethylation in colon cancer cell lines (n=9), whereas treatment with the DNA-demethylating agent 5-aza-2-deoxycytidine restored DKK-1 expression. Restoration of DKK-1 function in non-expressing cells bearing a truncated APC (Adenomatous Polyposis Coli) gene had no effect on beta-catenin/T-cell factor-dependent transcription, but induced tumor suppressor-like features such as reduced colony formation density and tumor growth inhibition in nude mice. These results suggest additional functions for DKK-1 other than inhibiting canonical Wnt signaling. In primary colorectal tumors, DKK-1 was found hypermethylated in 17% (nine of 54) of cases. Furthermore, while for both SFRP-1 and WIF-1 methylation-associated silencing occurred across the whole spectrum of colorectal tumorigenesis, DKK-1 promoter was selectively hypermethylated in advanced colorectal neoplasms (Duke's C and D tumors).
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PMID:Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. 1649 Nov 18

Renal cancer is a relatively uncommon solid tumor, accounting for about 3% of all adult malignancies, however this rate incidence is rising. The most common histological renal cell carcinoma (RCC) subtype is clear cell carcinoma that makes up approximately 70-80% of all renal neoplasms and appears to be the only histological subtype that is responsive to immunotherapeutic approaches with any consistency. Therefore, it has been hypothesized that immune-mediated mechanisms play important roles in limiting tumor growth and that dendritic cells (DC), the most potent APC in the body, and T cells are the dominant effector cells that regulate tumor progression in situ. In this context, the development of clinically effective DC-based vaccines is a major focus for active specific immunotherapy in renal cancer. In the current review we have not focused on the results of recently published RCC clinical trials, as several excellent reviews have already performed this function. Instead, we turned our attention to how the perception and practical application of DC-based vaccinations are evolving.
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PMID:Translational mini-review series on vaccines: Dendritic cell-based vaccines in renal cancer. 1730 87

Stem cells are defined by their intrinsic capacity to self-renew and differentiate. Cancer stem cells retain both these features but have lost homeostatic mechanisms which maintain normal cell numbers. The canonical Wnt/beta-catenin signaling pathway plays a central role in modulating the delicate balance between stemness and differentiation in several adult stem cell niches such as the hair follicles in the skin, the mammary gland, and the intestinal crypt. Accordingly, constitutive Wnt signaling activation, resulting from mutations in genes encoding its downstream components, underlies tumorigenesis in these tissues. In the majority of sporadic colorectal cancer cases, the rate-limiting event is either loss of APC function or oncogenic beta-catenin mutations. However, although the presence of these initiating mutations would predict nuclear beta-catenin accumulation throughout the tumor mass, heterogeneous intracellular distributions of this key Wnt signaling molecule are observed within primary tumors and their metastases. In particular, tumor cells located at the invasive front and those migrating into the adjacent stromal tissues show nuclear beta-catenin staining. Hence, different levels of Wnt signaling activity reflect tumor heterogeneity and are likely to account for distinct cellular activities such as proliferation and epithelial-mesenchymal transitions, which prompt tumor growth and malignant behavior, respectively. Several intrinsic (cell-autonomous and/or autocrine) and extrinsic (paracrine, derived from the tumor microenvironment) factors may explain this heterogeneity of Wnt/beta-catenin signaling activity within the tumor mass.
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PMID:Wnt/beta-catenin signaling in cancer stemness and malignant behavior. 1730 71

Cytotoxic T lymphocytes (CTL) are crucial in viral clearance and tumor growth control. Thus the induction of CTL activity is an important aim in vaccine development. We investigate an innovative delivery system for peptide transfer to the MHC class I processing pathway of APC with the aim to trigger CTL in the context of an antitumoral response. The strategy relies on a novel antigen delivery system termed "chimeric immunopotentiating reconstituted influenza virosomes" (CIRIV) targeting plasmacytoid dendritic cells (PDC). By using virosomes containing encapsulated Melan-A peptide and a PDC line developed in our laboratory, we evaluated the response of Melan-A specific T cells. Virosomes have the capacity to bind PDC and are endocyted within vesicles in the cytosol. This endocytosis is inhibited by neuraminidase, suggesting that it is mediated by sialic acid present on cell surface. Furthermore, PDC loaded with Melan-A virosomes can induce a Melan-A specific T cell activation. Interestingly, they activate T cells with a better efficiency than PDC loaded with a free peptide and when PDC where previously activated by a TLR ligand. These results indicate that virosomes could be a suitable delivery system for tumor peptide in immunotherapy of cancer.
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PMID:Virosome-mediated delivery of tumor antigen to plasmacytoid dendritic cells. 1733 32


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