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)

We found that human kinin-free high-molecular-weight kininogen (kf-HK) significantly inhibited vitronectin-mediated migration (haptotaxis) and invasive potentiation (haptoinvasion) of osteosarcoma (MG-63) cells but that HK, LK, the common heavy chain of HK and LK, and the light chain (D6(H)) of HK had no inhibitory effect. Recombinant GST-D5(H) (histidine-rich region of HK) obtained from Escherichia coli. (BL21) also inhibited both haptotaxis and haptoinvasion to about 30% of the control level in a dose-dependent manner. These findings suggest that a specific region of D5(H) is responsible for the inhibition of cell haptotaxis and haptoinvasion. Among the seven synthetic peptides covering D5(H), peptide H(479)KHGHGHGKHKNKGK(493) (P-5) inhibited both haptotaxis and haptoinvasion in a dose-dependent manner, suggesting that P-5 could possibly be utilized to prevent primary and secondary metastases of tumor cells.
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PMID:Inhibition of vitronectin-mediated haptotaxis and haptoinvasion of MG-63 cells by domain 5 (D5(H)) of human high-molecular-weight kininogen and identification of a minimal amino acid sequence. 1168 5

Metastasis-associated protein S100A4 (Mts1) induces invasiveness of primary tumors and promotes metastasis. S100A4 belongs to the family of small calcium-binding S100 proteins that are involved in different cellular processes as transducers of calcium signal. S100A4 modulates properties of tumor cells via interaction with its intracellular targets, heavy chain of non-muscle myosin and p53. Here we report identification of a new molecular target of the S100A4 protein, liprin beta1. Liprin beta1 belongs to the family of leukocyte common antigen-related (LAR) transmembrane tyrosine phosphatase-interacting proteins that may regulate LAR protein properties via interaction with another member of the family, liprin alpha1. We showed by the immunoprecipitation analysis that S100A4 interacts specifically with liprin beta1 in vivo. Immunofluorescence staining demonstrated the co-localization of S100A4 and liprin beta1 in the cytoplasm and particularly at the protrusion sites of the plasma membrane. We mapped the S100A4 binding site at the C terminus of the liprin beta1 molecule between amino acid residues 938 and 1005. The S100A4-binding region contains two putative phosphorylation sites by protein kinase C and protein kinase CK2. S100A4-liprin beta1 interaction resulted in the inhibition of liprin beta1 phosphorylation by both kinases in vitro.
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PMID:Liprin beta 1, a member of the family of LAR transmembrane tyrosine phosphatase-interacting proteins, is a new target for the metastasis-associated protein S100A4 (Mts1). 1183 60

Substantial effort has been invested into optimization of vector structure, DNA formulation, or delivery methods to increase the effectiveness of DNA vaccines. In contrast, it has been only insufficiently explored how the higher order structure of an antigenic protein influences immunogenicity of embedded epitopes in vivo. Potent CD8+ T cell responses specific for a single immunogenic epitope are induced upon electrovaccination with plasmid DNA encoding the full-length heavy chain of the human HLA-Cw3 molecule. Contrary to expectations, a minimal construct, which provoked a substantial release of IFN-gamma from specific CTLs in vitro, did not induce a significant response in vivo. Systematically altered variants of the Cw3 molecule were thus tested both in vivo and in vitro to determine which structural parts are responsible for this discrepancy. In complementation experiments the participation of trans-acting helper epitopes was ruled out. Successive C-terminal truncations, human/mouse domain swap variants, and subdomain modifications defined the alpha3 region of the HLA heavy chain and membrane anchoring as critical elements. Based on these data, refined minimal constructs were engineered that triggered very high in vivo responses. The most advanced variant consisted only of an adenoviral leader, antigenic epitope, alpha3 domain, and 16 aa of the transmembrane domain. When a tumor Ag epitope was incorporated into one of these high performer minimal constructs, protection against melanoma metastases was attained upon vaccination. Thus, structural elements of the Ag can dominantly influence immunogenicity in vivo. These elements can also markedly improve the immunogenicity of unrelated Ags and may form the basis of a new generation of DNA vaccines.
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PMID:Structural elements of a protein antigen determine immunogenicity of the embedded MHC class I-restricted T cell epitope. 1221 7

Tumor-reactive T cells play an important role in cancer immunosurveillance. Applying the multimer technology, we report here an unexpected high frequency of Melan-A-specific CTLs in a melanoma patient with progressive lymph node metastases, consisting of 18 and 12.8% of total peripheral blood and tumor-infiltrating CD8+ T cells, respectively. Melan-A-specific CTLs revealed a high cytolytic activity against allogeneic Melan-A-expressing target cells but failed to kill the autologous tumor cells. Loading of the tumor cells with Melan-A peptide reversed the resistance to killing, suggesting impaired function of the MHC class I antigen processing and presentation pathway. Mutations of the coding region of the HLA-A2 binding Melan-A26-35 peptide or down-regulation of the MHC class I heavy chain, the antigenic peptide TAP, and tapasin could be excluded. However, PCR and immunohistochemical analysis revealed a deficiency of the immunoproteasomes low molecular weight protein 2 and low molecular weight protein 7 in the primary tumor cells, which affects the quantity and quality of generated T-cell epitopes and might explain the resistance to killing. This is supported by our data, demonstrating that the resistance to killing can be partially reversed by pre-exposure of the tumor cells to IFN-gamma, which is known to induce the immunoproteasomes. Overall, this is the first report of an extremely high frequency of tumor-specific CTLs that exhibit competent T-cell-effector functions but fail to lyse the autologous tumor cells. Immunotherapeutic approaches should not only focus on the induction of a robust antitumor immune response, but should also have to target tumor immune escape mechanisms.
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PMID:High frequency of functionally active Melan-a-specific T cells in a patient with progressive immunoproteasome-deficient melanoma. 1534 21

Immunoproliferative small intestinal disease (IPSID) was recently added to the growing list of infectious pathogen-associated human lymphomas. Molecular and immunohistochemical studies demonstrated an association with Campylobacter jejuni. IPSID is a variant of the B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), which involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. Geographically, IPSID is most prevalent in the Middle East and Africa. IPSID lymphomas reveal excessive plasma cell differentiation and produce truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. The corresponding mRNA lacks the variable heavy chain (V(H)) and the constant heavy chain 1 (C(H)1) sequences and contains deletions as well as insertions of unknown origin. The encoding gene sequence reveals a deletion of V region and parts of C(H)1 domain. Cytogenetic studies demonstrated clonal rearrangements involving predominantly the heavy and light chain genes, including t(9;14) translocation involving the PAX5 gene. Early-stage IPSID responds to antibiotics (30%-70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma invading the intestinal wall and mesenteric lymph nodes, and may metastasize to a distant organ. IPSID lymphoma shares clinical, morphologic, and molecular features with MALT lymphoma, lymphoplasmacytic lymphoma, and plasma cell neoplasms.
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PMID:Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms. 1554 84

Combinatorial antibody libraries have the potential to display the entire immunological record of an individual, allowing one to detect and recover any antibody ever made, irrespective of whether it is currently being produced. We have termed this the "fossil record" of an individual's antibody response. To determine whether cancer patients have ever made antibodies with disease-fighting potential, we screened combinatorial antibody libraries from cancer patients for immunoglobulins that can identify metastatic tumor cells. This strategy yielded human antibodies specific for the activated conformation of the adhesion receptor integrin alphavbeta3 that is associated with a metastatic phenotype. In a remarkable example of convergent evolution, two of these antibodies were shown to contain the Arg-Gly-Asp integrin recognition motif of the natural ligand within the third complementarity-determining region of the heavy chain. These antibodies interfered with lung colonization by human breast cancer cells in a mouse model and inhibited existing metastatic disease. Our data imply that, at least at some time, these antibodies were part of a patient's surveillance system against metastatic cells, targeting the activated conformer of integrin alphavbeta3 and disrupting its functions. The ligand-mimetic nature of these antibodies, combined with specificity for a single receptor, is unique in the integrin-ligand repertoire. The convergent evolution of critical sequences in antibodies and other ligands that bind to the same target means that the immune response has sufficient power to find a best chemical solution for the optimization of binding energy, even though antibodies evolve in real time, as compared with billions of years for the natural ligand.
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PMID:Combinatorial antibody libraries from cancer patients yield ligand-mimetic Arg-Gly-Asp-containing immunoglobulins that inhibit breast cancer metastasis. 1556 90

We hypothesized that inducing display of the immunoglobulin Fc (IgFc) molecule on the tumor cell surface by gene transfer would promote tumor cell killing by the same mechanisms as antibody-based approaches but would alleviate some of the problems inherent in the use of antibodies for cancer therapy. We expressed the cDNA of the Fc portion of the murine IgG2a heavy chain on the surface of tumor cells such that its C terminus projected away from the tumor cell surface, mimicking a natural antibody-tagging event. In vitro, Fc receptor-positive natural killer (NK) cells specifically recognized and lysed B16 melanoma cells expressing surface IgFc. Macrophages bound to B16-Fc cells significantly more than to parental B16 cells and surface IgFc expression promoted formation of the terminal complement pore complex leading to cell lysis and death. Expression of IgFc dramatically delayed the ability of B16 cells to form tumors in vivo, attributable largely to the effects of NK cells. Furthermore, fluorescence-activated cell-sorting analysis showed that cells from outgrowth B16 IgFc tumors had lost all IgFc expression. When additional immunostimulatory signals were provided at the time of IgFc-mediated tumor cell killing through expression of heat shock protein 70 (hsp70), significant antitumor immunity was generated. Intratumoral delivery of an adenoviral vector expressing IgFc was effective at treating locally accessible tumors but did not impact metastatic disease. However, delivery of adenoviral vectors expressing both IgFc and hsp70 cured both local and metastatic tumors established for 6 days before viral treatment. These data suggest that it is possible to use gene transfer to mimic the beneficial properties of antibody therapy while alleviating some of the associated problems.
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PMID:Tumor cell surface display of immunoglobulin heavy chain Fc by gene transfer as a means to mimic antibody therapy. 1600 65

Our knowledge of the mechanisms underlying tumor-specific immune response and tumor escape has considerably increased. HLA class I antigen defects remain an important tumor escape mechanism since they influence the interactions between tumor cells and specific T and NK cells in the course of malignant disease. We have studied here HLA class I expression in six subcutaneous metastases obtained from a melanoma patient immunized with an autologous melanoma cell vaccine (M-VAX). We report in this paper that HLA class I antigen expression on these metastatic lesions strongly correlated with the course of the disease. The three metastases that were partially regressing at the time of their excision showed a strong HLA class I expression, whereas the progressing ones showed a very weak or negative staining with most of the anti-HLA class I mAbs used. Real-time quantitative PCR of the samples obtained from microdissected tumor tissue revealed a significant difference in the mRNA levels of HLA-ABC heavy chain and beta2m between the two types of metastases, i.e., lower levels in progressing metastases and high levels in regressing ones, confirming the immunohistological findings. This is, to our knowledge, the first report where the clinical outcome of different HLA class I positive and negative melanoma metastases can be clearly correlated with the regression and progression of the disease, respectively.
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PMID:HLA class I expression in metastatic melanoma correlates with tumor development during autologous vaccination. 1696 Jun 91

Vascular endothelial growth factor (VEGF) produced by tumor cells plays a central role in stimulating angiogenesis required for solid tumor growth. VEGF-specific antibodies inhibit tumor cell line growth in animal models and a humanized monoclonal anti-VEGF antibody (bevacizumab [Avastin]) is approved as a treatment for metastatic cancer. We hypothesized that administration of an adenoviral (Ad) vector expressing the murine monoclonal antibody equivalent of bevacizumab would suppress human tumor growth in vivo. The Ad vector (AdalphaVEGF) encodes the light chain and heavy chain cDNAs of monoclonal antibody A.4.6.1, a murine antibody that specifically recognizes human VEGF with the same antigen-binding site as bevacizumab. AdalphaVEGF efficacy in vivo was evaluated with A-673 rhabdomyosarcoma and DU 145 prostate carcinoma cells in human tumor cell xenografts in SCID mice. For both tumor models, AdalphaVEGF directed the expression of high anti-human VEGF IgG antibody titers in vivo, the numbers of mitotic nuclei and blood vessels in the tumor were significantly decreased (p < 0.05), tumor growth was suppressed (p < 0.05), and there was increased survival (p < 0.005). Thus, AdalphaVEGF, encoding a murine monoclonal antibody that is the equivalent of bevacizumab, effectively suppresses the growth of human tumors, suggesting gene therapy as an alternative to bevacizumab monoclonal antibody therapy.
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PMID:Genetic delivery of the murine equivalent of bevacizumab (avastin), an anti-vascular endothelial growth factor monoclonal antibody, to suppress growth of human tumors in immunodeficient mice. 1832 12

Regressive changes (RC) have been described in malignant melanoma, carcinomas of the prostate and cervix. The presence of RC in these neoplasms may signify some degree of host response to tumor and seems to be a sign of poor prognosis for some neoplasms. RC in breast cancer is vaguely defined in the older literature. We have observed periodically similar RC in a subset of high-grade ductal carcinoma in situ (HGDCIS) in breast specimens. The aim of our study is to demonstrate how to recognize RC in the diagnostic setting and an attempt to understand the biologic behavior in this subset of HGDCIS cases. Fifty-nine cases of HG-DCIS (35 cases with RC and 24 cases without RC) were included. We defined RC in our study as demonstrating thick periductal fibrosis, dense lymphocytic infiltrate, and a thin rim of intact neoplastic cells. A short panel of immunomarkers to study this entity included myoepithelial markers. Reduced expression of myoepithelial markers (p63 and smooth muscle heavy chain myosin) were seen more frequently in the HGDCIS group with RC than without RC cases. Invasion as well as metastatic disease was seen in association with HGDCIS with RC nearly 4 times as often. It is also critically important to recognize HGDCIS-RC for diagnostic purposes, as the differential diagnosis of RC includes, benign associations such as papilloma, fibrocystic changes and periductal mastitis. HGDCIS-RC may also be a sign of an aggressive phenotype than other HGDCIS subtypes. Further outcome studies are necessary to determine if it has a clinical impact akin to other tumors with RC.
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PMID:Characterization of high-grade ductal carcinoma in situ with and without regressive changes: diagnostic and biologic implications. 1940 54


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