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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

On the basis of their known fine specificities we evaluated the immunohistochemical marker qualities of two monoclonal antibodies (mabs) defining the tumor-associated TF disaccharide Gal beta 1-3 GalNAc. This antigen is expressed in certain tumors in correlation with prognosis and metastasis. The reactivity of one of these mabs (A78-G/A7) depends on clustered TF disaccharides (glycosylation at vicinal Ser/Thr positions) while the other--mab BW835--has been characterized to bind specifically to TF disaccharide linked to a motif within the MUC1 repeat. Therefore, mab BW835 represents an interesting tool for the identification of tumor-associated glycoforms of MUC1, which are involved in tumor progression and metastasis, but also in the recognition of tumor cells by cytotoxic T cells. As references the TF-binding lectins from peanut (PNA) and Artocarpus integrifolia (jacalin) were applied. The binding patterns of these immunoreagents were strikingly distinct. Mab BW835 showed a significantly stronger reactivity than mab A78-G/A7, especially in gastric, mammary, pancreatic, thyreoideal, renal and bladder carcinomas. PNA and jacalin receptors exhibited an expression in the majority of all cancer types, with the exception of seminoma and glioblastoma/sarcoma. These results can be explained by the broader fine specificities of the lectins. Furthermore, a strong expression of MUC1-bound TF antigen is indicated by the staining pattern of mab BW835. The marker qualities of both antigens, TF and MUC1, are combined in the binding specificity of BW835, and hence this antibody may have a high impact for the immunodetection of these tumor-associated antigens.
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PMID:Immunoreactivity of Thomsen-Friedenreich (TF) antigen in human neoplasms: the importance of carrier-specific glycotope expression on MUC1. 1050 31

Rac1 is a member of the Ras superfamily of small GTPases involved in signal transduction pathways that induce the formation of lamellipodia, stimulate cell proliferation and activate the JNK/SAPK protein kinase cascade. Here we describe that amplification by RT-PCR of the entire Rac1 coding sequence from a series of human adult and fetal tissues revealed beside the expected Rac1 cDNA, a variant product which contained additional 57 nucleotides between codons 75 and 76. This variant resulted in an in-frame insertion of 19 new amino acids immediately behind the switch II region, including two potential threonine phosphorylation sites for casein kinase II and protein kinase C. Primers designed within and downstream of the inserted nucleotide sequence allowed isolation of a genomic clone with intronic consensus sequences demonstrating that the insertion corresponds to a novel, yet undescribed exon 3b. This Rac1 splice variant, designated Rac1b, was predominantly identified in skin and epithelial tissues from the intestinal tract. Most notably, the expression of rac1b versus rac1 was found to be elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues. We suggest that the 19 amino acid-insertion following the switch II region may create a novel effector binding site in rac1b, and thus participate in signaling pathways related to the normal or neoplastic growth of the intestinal mucosa.
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PMID:Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. 1059 94

MUC1 mucin is a target protein for many monoclonal antibodies. Human MUC1 detected by a murine anti-KL-6 monoclonal antibody that recognizes a sialylated carbohydrate chain has been designated KL-6/MUC1. Given the heterogeneous antigenicity of KL-6/MUC1, we established a new murine monoclonal antibody, H9, that reacts with epitope DTRP (Asp-Thr-Arg-Pro) peptides within the immunodominant region of the tandem repeat of MUC1 mucin. The reactivity of the H9 antibody differs from that of other previously reported antibodies that recognize the tandem repeat region of MUC1. Immunohistochemical experiments indicate that the reactivity of the H9 antibody is similar to that of other antibodies directed against MUC1 core proteins. A new cancer-associated protein detected by a sandwich assay using the H9 antibody as a catcher and the KL-6 antibody as a tracer is designated HK9. Serum HK9 levels showed a high expression level in lung cancer: 51% (19/37 cases) for adenocarcinoma, 39% (11/28 cases) for squamous cell carcinoma, and 67% (10/15 cases) for small cell carcinoma. The HK9 expression in lung cancer increased with cancer progression. These findings suggest monoclonal antibody H9 to be a novel antibody that reacts with an epitope within the tandem repeat region of MUC1, and that the cancer-associated antigen HK9 may have useful tumor-associated properties.
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PMID:A novel monoclonal antibody, H9, directed against the core protein of MUC1 mucin. 1067 62

The mannose-6-phosphate/insulin-like growth factor 2 receptor (Man-6-P/IGFII receptor) is involved in lysosomal enzyme sorting, IGFII degradation and pro-TGFbeta activation. Genetic alterations in hepatocarcinomas and a few breast cancers suggest that this receptor behaves as a tumor suppressor. Moreover, hypersecretion and Man-6-P-independent targeting of cathepsins in breast and ovarian carcinomas also suggest alterations in this receptor. We studied the Man-6-P/IGFII receptor gene in 8 ovarian carcinomas, and 4 breast- and ovarian-cancer cell lines. The results confirmed a frequent loss of heterozygosity (LOH) in the 6q27-qter region in 5 out of 8 ovarian carcinomas. We used 23 overlapping RT-PCR fragments to sequence the whole coding region of the Man-6-P/IGFII receptor. The 2491 amino-acid sequence of this receptor was perfectly conserved in 9 out of 10 of our samples, including MCF7 and MDA-MB231 cells and 5 ovarian carcinomas with LOH. This allowed us to rectify the 2 previously published sequences which differed in several bases, and to propose a consensus amino-acid sequence. The only amino-acid change (Thr --> Ala) was in BG1 ovarian-cancer cells, and was due to an A-to-G substitution on one allele at nucleotide 2561. We found no bi-allelic alterations in the 9 ovarian carcinomas, but 3 silent nucleotide substitutions leading to a lower cordon usage in 2 ovarian carcinomas with LOH. No mutation of the Man-6-P/IGFII receptor coding sequence was found in breast-cancer cell lines to explain the cathepsin-D hypersecretion and Man-6-P-independent trafficking described. We propose that, in breast and ovarian cancers, the frequent loss of one allele, associated with over-expression of some of its ligands, might be sufficient to saturate the receptor protein, displace the ligands to other sites, and consequently facilitate tumor progression.
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PMID:Stable amino-acid sequence of the mannose-6-phosphate/insulin-like growth-factor-II receptor in ovarian carcinomas with loss of heterozygosity and in breast-cancer cell lines. 1069 16

Alterations of protein tyrosine kinase are often associated with uncontrolled cell growth and tumor progression. Knowledge of the overall expression pattern of tyrosine kinases should prove beneficial in understanding the signaling pathways involved in gastric cancer oncogenesis and in providing possible biomarkers for gastric cancer progression. To establish a general tyrosine-kinase expression profile, degenerated polymerase chain reaction primers designed from the consensus catalytic kinase motifs were used to amplify protein tyrosine kinase molecules from gastric cancer tissues. We observed more than 50 tyrosine and serine/threonine kinases from matching pairs of gastric cancer tissue and normal mucosa. Based on this new kinase profile information, we selected the MKK4 gene for further immunohistochemical studies. Statistical analysis of MKK4 protein expression and clinicopathological features indicated that MKK4 kinase expression could serve as a significant prognostic factor for relapse-free survival and for overall survival. We demonstrated a simple and sensitive method for establishing protein tyrosine-kinase expression profiles of human gastric cancer tissues as well as for discovering novel and useful clinical biomarkers from such kinase expression profiles.
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PMID:Human gastric cancer kinase profile and prognostic significance of MKK4 kinase. 1085 23

We have identified a human placenta cDNA coding for a new member of the matrix metalloproteinase (MMP) family. The isolated cDNA encodes a polypeptide of 261 amino acids, the smallest MMP identified to date, which contains several structural features of MMPs including the signal sequence, the prodomain involved in enzyme latency, and the catalytic domain with the zinc-binding site. However, it lacks the hinge region and hemopexin-domain present in most MMPs. According to these structural characteristics, the human MMP described herein has been called matrilysin-2 (MMP-26), because it exclusively shares with matrilysin this minimal domain organization required for secretion, latency, and activity. The amino acid sequence of matrilysin-2 also contains a threonine residue adjacent to the Zn-binding site that has been defined as a specific feature of matrilysin. Chromosomal location of the matrilysin-2 gene showed that it maps to the short arm of chromosome 11, a location distinct to that of other MMP genes. Matrilysin-2 was expressed in Escherichia coli, and, after purification and refolding, the recombinant protein was found to degrade synthetic substrates commonly used for assaying MMPs. Furthermore, this protein hydrolyzed type IV collagen, fibronectin, fibrinogen, and gelatin, which indicated that matrilysin-2 is a potent enzyme with a wide substrate specificity. In addition, it was found that matrilysin-2 is able to activate progelatinase B. Proteolytic activity of matrilysin-2 against all of these substrates was abolished by synthetic inhibitors and by tissue inhibitors of metalloproteinases. Expression analysis revealed that matrilysin-2 is detected not only in placenta and uterus but is widely expressed in malignant tumors from different sources as well as in diverse tumor cell lines. These data together with its broad spectrum of proteolytic activity, suggest that matrilysin-2 may play a role in some of the tissue-remodeling events associated with tumor progression.
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PMID:Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity. 1098 80

The DAP (Death Associated Protein) kinase family is a novel subfamily of pro-apoptotic serine/threonine kinases. All five DAP kinase family members identified to date are ubiquitously expressed in various tissues and are capable of inducing apoptosis. The sequence homology of the five kinases is largely restricted to the N-terminal kinase domain. In contrast, the adjacent C-terminal regions are very diverse and link individual family members to specific signal transduction pathways. There is increasing evidence that DAP kinase family members are involved in both extrinsic and intrinsic pathways of apoptosis and may play a role in tumor progression. This review will focus on structural composition and subcellular localization of DAP kinase family members and on signal transduction pathways leading to their activation. Potential mechanisms of DAP kinase family-mediated apoptosis will be discussed. BioEssays 23:352-358, 2001.
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PMID:The DAP kinase family of pro-apoptotic proteins: novel players in the apoptotic game. 1126 41

DAP-kinase is a pro-apoptotic Ca(2+) calmodulin-regulated serine/threonine kinase that participates in a wide array of apoptotic systems initiated by interferon-gamma, TNF-alpha, activated Fas, and detachment from extracellular matrix. It was isolated by an unbiased functional approach to gene cloning aimed at hitting central mediators of the apoptotic process. This 160 Kd protein kinase is localized to actin microfilaments and carries interesting modules such as ankyrin repeats and the death domain. The death promoting effects of DAP-kinase depend on its intact catalytic activity, the correct intracellular localization, and on the presence of the death domain. A few mechanisms restrain the killing effects of the protein in healthy cells. The enzyme's active site is negatively controlled by an adjacent CaM regulatory domain whose effect is relieved by binding to Ca(2+)-activated calmodulin. A second mode of autoinhibition engages the serine-rich C-terminal tail, spanning the last 17 amino acids of the protein. A link between DAP-kinase and cancer has been established. It was found that the mRNA and protein expression is frequently lost in various human cancer cell lines. Analysis of the methylation status of DAP-kinase's 5' UTR in DNA extracted from fresh tumor samples, showed high incidence of hypermethylation in several human carcinomas and B cell malignancies. The anti-tumorigenic effect of DAP-kinase was also studied experimentally in mouse model systems where the re-introduction of DAP-kinase into highly metastatic mouse lung carcinoma cells who had lost the protein, strongly reduced their metastatic capacity. Thus, it appears that loss of DAP-kinase confers a selective advantage to cancer cells and may play a causative role in tumor progression. A few novel kinases sharing high homology in their catalytic domains with DAP-kinase have been recently identified constituting altogether a novel family of death promoting serine/threonine kinases.
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PMID:DAP-kinase: from functional gene cloning to establishment of its role in apoptosis and cancer. 1131 98

Thrombospondin-1 (TSP-1) is a 450 kDa matrix bound glycoprotein involved in tumor invasion, metastasis, and angiogenesis. One of the receptors involved in TSP-1 mediated tumor cell adhesion and metastasis is the cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) receptor. One mechanism of TSP-1 in promoting tumor cell metastasis involves the up-regulation of matrix metalloproteinase-9 (MMP-9) expression, specifically through the CSVTCG TSP-1 receptor. TSP-1 and its CSVTCG receptor has been implicated in tumor progression in a variety of cancers including breast adenocarcinomas, head and neck squamous cell carcinomas, and pancreatic carcinomas. In this study, we examined 99 cases of colorectal cancer by immunohistochemical analysis to investigate 1) the localization of TSP-1 and CSVTCG TSP-1 receptor, 2) the relationship with MMP-9, and 3) the correlation of expression with clinical staging. Strong expression of TSP-1 was observed in the submucosa or the serosa adjacent to the tumor. Positive staining for CSVTCG TSP-1 receptor was observed in tumor cells and microvessels. MMP-9 was also expressed in tumor cells. In addition, staining intensity of CSVTCG TSP-1 receptor was higher in poorly differentiated adenocarcinoma than well or moderately differentiated adenocarcinoma. Tumors in which inflammatory cells stained strongly for CSVTCG TSP-1 receptor correlated with decreased incidence of distant metastasis and angiogenesis. These data were consistent with our previous studies for breast, pancreatic, and head and neck carcinoma. They suggest an important role for TSP-1 and CSVTCG TSP-1 receptor in tumor progression in colorectal cancer.
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PMID:The localization of thrombospondin-1 (TSP-1), cysteine-serine-valine-threonine-cysteine-glycine (CSVTCG) TSP receptor, and matrix metalloproteinase-9 (MMP-9) in colorectal cancer. 1133 89

Grb7 family adaptor molecules consist of Grb7, Grb10 and Grb14, each of which has several splicing variants. Like other adaptor molecules, Grb7 family proteins function to mediate the coupling of multiple cell surface receptors to downstream signaling pathways in the regulation of various cellular functions. They share significant sequence homology with each other and a conserved molecular architecture including an amino-terminal proline-rich region, a central segment termed the GM region (for Grb and Mig) which includes a PH domain and shares sequence homology with the Caenorhabditis elegans protein, Mig-10, involved in embryonic migration, and a carboxyl-terminal SH2 domain. Grb7 family proteins are differentially expressed in a variety of tissues. They are phosphorylated on serine/threonine as well as tyrosine residues, although the kinases responsible have not been well characterized. Grb7 family proteins are mainly localized in the cytoplasm, but have been observed at the plasma membrane, focal contacts, or mitochondria under certain conditions. A large number of receptor tyrosine kinases and other signaling molecules can associate with Grb7 family proteins, mostly through the SH2 domains. Various isoforms of Grb10 have been shown to regulate cell proliferation and apoptosis, whereas Grb7 has been found to regulate cell migration and also implicated in tumor progression. Future studies of interests will include identification of potential downstream effectors of Grb7 family proteins as well as understanding of the mechanisms of specificity of the different family members in signal transduction.
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PMID:The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions. 1160 34


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