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)

Endothelial cell adhesion molecules are partly responsible for the distinct organ distribution of cancer metastases. Dipeptidyl peptidase IV (DPP IV) expressed on rat lung capillary endothelia is shown here to be an adhesion receptor for rat breast cancer cells and to mediate lung colonization by these tumor cells. Fibronectin (FN) assembled on breast cancer cell surfaces into multiple, randomly dispersed globules from cellular and plasma FN is identified as the principal ligand for DPP IV. Ligand expression correlates quantitatively with the tumor cells' capabilities to bind to DPP IV and to metastasize to the lungs. DPP IV/FN-mediated adhesion and metastasis are blocked when tumor cells are incubated with soluble DPP IV prior to conducting adhesion and lung colony assays. Adhesion is also blocked by anti-DPP IV monoclonal antibody 6A3 and anti-FN antiserum. However, adhesion to immobilized FN is unaffected by soluble plasma FN and, thus, can happen during hematogenous spread of cancer cells at high plasma FN concentrations. The ability of many cancer cells to capture FN molecules on their surface and to augment such deposits by FN self-association during passage in the blood suggests that DPP IV/FN binding may be a relatively common mechanism for lung metastasis.
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PMID:Lung endothelial dipeptidyl peptidase IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface-associated fibronectin. 972 44

A novel adhesion receptor/ligand pair was shown recently to mediate lung vascular arrest and metastasis of rat breast cancer cells. The interacting adhesion molecules are endothelial dipeptidyl peptidase IV (DPP IV) and tumor cell surface-associated, polymeric fibronectin (FN). A truncated DPP IV (DPP IV(31-767): amino acids 31-767) in which the FN-binding site is preserved is shown here to mask the breast cancer cell surface-associated FN complexes, causing a dose-dependent inhibition of adhesion to endothelial DPP IV and impeding lung colony formation by approximately 80%. Since surface accumulation of FN is chiefly occurring during dissemination in the blood and since many cancer cell types have surface receptors by which they may initiate FN accumulation on their surfaces, the present anti-metastatic treatment modality may extend its efficacy farther than appreciated by this study.
Invasion Metastasis 1998
PMID:Truncated dipeptidyl peptidase IV is a potent anti-adhesion and anti-metastasis peptide for rat breast cancer cells. 1020 49

Fischer 344/CRJ rats harbor a G633R substitution in dipeptidyl peptidase IV (DPP IV) that leads to retention and degradation of the mutant protein in the endoplasmic reticulum (Tsuji E, Misumi Y, Fujiwara T et al. Biochemistry 1992; 31 (47): 11921-7). However, when these rats were used as a 'protein knock-out' model in further evaluating the previously established role of DPP IV in metastasis, lung colonization of the highly metastatic MTF7 rat breast cancer cell line was reduced by only 33% relative to normal Fischer 344 rats. To examine whether lung endothelia leak expression of mutant DPP IV and whether mutant DPP IV exhibits the same adhesion qualities as wild type DPP IV, detailed immunohistochemical, biochemical, transfection, and FACS analyses were performed to assess the surface expression of mutant DPP IV on lung endothelia and transfected HEK293 cells and adhesion assay to compare the adhesion qualities of wild-type and mutant DPP IV. Both endothelial and transfected HEK293 cells expressed mutant, enzymatically inactive DPP IV on their surfaces, albeit at greatly reduced levels when compared to expression of wild type DPP IV. Purified mutant DPP IV had identical adhesion qualities for lung-metastatic MTF7 cells as wild type DPP IV, and competitive inhibition of MTF7 lung colonization by truncated DPP IV confirmed involvement of mutant DPP IV in lung metastasis of Fischer 344/CRJ rats. Although metastasis appears to be mediated by several, often parallel mechanisms involving multiple tumor and host factors, these data indicate that altered expression of a single component can drastically change the outcome of metastatic disease.
Clin Exp Metastasis 1999
PMID:Is the Fischer 344/CRJ rat a protein-knock-out model for dipeptidyl peptidase IV-mediated lung metastasis of breast cancer? 1084 60

Aminopeptidase N (APN, CD13) and dipeptidyl peptidase IV (DPP IV, CD26) are transmembrane ectoenzymes occurring in a wide variety of cells. They are involved in tumour cell invasion and the formation of metastases. A basis for further information about these enzymes is the exact ultrastructural localization in normal and malignant cells. In this paper, we demonstrate the precise subcellular localization of the membrane peptidases APN and DPP IV on the cell surfaces in renal tissues, renal cell carcinoma, cultured renal parenchymal cells and cultured renal carcinoma cells. Using cryo-ultramicrotomy of weakly fixed tissues and cells in combination with indirect immunogold labelling, both membrane peptidases were detectable on the external cell surfaces. They showed different ultrastructural expression patterns. Both membrane peptidases were abundantly labelled on the external cell surfaces of human kidney proximal tubular cells. The expression pattern of APN/CD13 and DPP IV/CD26 in single labelling was confirmed by a successive double labelling technique. The immunolabelling of CD13 on cultured renal parenchymal cells showed a stronger expression then in cells in vivo, but CD26 could not be found. In renal cell cancer (mixed clear cell/chromophilic, poorly differentiated and clear cell type, moderately differentiated) CD13 and CD26 were labelled as in benign renal tissue, but CD26 appeared overexpressed. On the renal carcinoma cells Caki-1 and Caki-2, only one of the two peptidases could be found. CD13 was present non-homogeneously in Caki-1, where the enzyme appeared to form clusters. When CD26 on the cultured renal carcinoma cells Caki-2, is compared with renal proximal tubular cells and renal carcinoma cells in tissue sections, a reduced expression is observed. CD13 was not detected in Caki-2, and CD26 was not found in Caki-1. These small changes on the cell surfaces can only be detected by electronmicroscopic methods. The differences in the distribution of APN/CD13 and DPP IV/CD26 in normal and malignant cells are discussed in connection with literature. Further investigations, especially labelling studies on other neoplastic tissues and cells, will be necessary in order to explain the precise role these membrane peptidases in malignancies.
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PMID:Immunoelectron microscopic demonstration of the membrane proteases aminopeptidase N/CD13 and dipeptidyl peptidase IV/CD26 in normal and neoplastic renal parenchymal tissues and cells. 1096 63

Dipeptidyl peptidase IV (DPPIV) is a 110-kD, trans-membrane, ectoenzyme, with ubiquitous expression. DPPIV has numerous functions including involvement in T-cell activation, cell adhesion, digestion of proline containing peptides in the kidney and intestines, HIV infection and apoptosis, and regulation of tumorigenicity in certain melanoma cells. Constitutively expressed on numerous epithelial cell types, DPPIV is often disregulated in a variety of human malignancies. The most striking evidence of DPPIV down-regulation is found in transformed melanocytes. where nearly 100% of melanomas lack DPPIV expression. We have identified DPPIV as a gene that can alter the invasive potential of a number of melanoma cell lines. By transfecting the full-length cDNA of DPPIV, we have established stable melanoma cell lines that express comparable levels of the DPPIV protein as normal epidermal melanocytes. Matrigel invasion assays were utilized to study the effects of DPPIV expression on the invasive potential of these cells. The parental and vector transfectants readily migrated across the Matrigel while the invasiveness of DPPIV transfected cells was reduced by greater than 75%. The effects on cellular invasion are not attributed to overall growth characteristics, as both DPPIV expressing and non-expressing cells behave comparably in culture. We have also constructed mutants of DPPIV that lack either the extra-cellular serine protease activity or the six amino acid cytoplasmic domain. Both mutants were stably expressed in melanoma cells. Matrigel invasion assays performed with cells expressing the two mutant forms of the protein revealed phenotypic effects similar to wild type function. In this study. we have demonstrated that expression of a proteolytically active form of the DPPIV protein inhibits the invasiveness of malignant melanoma cell lines lacking endogenous DPPIV expression. Furthermore, we have shown that neither the protease activity nor the cytoplasmic domain of DPPIV is required for its anti-invasive activity.
Clin Exp Metastasis 2000
PMID:Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells. 1146 71

A group of type II integral serine proteases, including dipeptidyl peptidase IV (DPP4/CD26), seprase/fibroblast activation protein alpha (FAPalpha) and related type II transmembrane prolyl serine peptidases, exert their mechanisms of action on the cell surface. DPP4 and seprase exhibit multiple functions due to their abilities to form complexes with each other and to interact with other membrane-associated molecules. Localization of the protease complexes at cell surface protrusions, called invadopodia, may have a prominent role in processing soluble factors (including chemokines and neuropeptide Y) and in degrading locally extracellular matrix components, that are essential to the cell migration and matrix invasion occurring during tumor invasion, angiogenesis and metastasis.
Cancer Metastasis Rev
PMID:Seprase complexes in cellular invasiveness. 1278

The association between CD26 expression, tumor cell adhesion, metastasis, and natural killer (NK) cell function was investigated in a CD26 mutant Fischer 344 (F344/DuCrj) substrain from Japanese breeders (F344JAP) in comparison with wild-type F344 substrains from US (F344/Crl) and Hannover (HAN; F344/Ztm) breeders. F344JAP rats lack the dipeptidyl peptidase IV activity of CD26 and show a reduced cell surface expression of the mutated CD26 glycoprotein. In vivo adhesion of vital dye-labeled MADB106 tumor cells, tumor colonization, CD26 enzymatic activity, and CD26 immunoreactivity in lungs and soluble CD26-like protein expression in serum were markedly reduced in F344JAP rats. These findings demonstrate that CD26 protein expression exerts a key role in lung metastasis. In addition, NK cell cytotoxicity against MADB106 cells was diminished in the mutant F344 substrain, suggesting that CD26 enzymatic activity sustains NK cytotoxicity. Interestingly, tumor cells lacked CD26 immunoreactivity in vitro, but displayed CD26 immunoreactivity in situ after in vivo inoculation as well as after incubation with rat serum, indicating that soluble CD26-like protein assembles in tumor cells during in vivo passage, which may interact with the process of tumor adhesion and metastasis. Overall, these findings indicate that altered expression and function of a single enzyme-the CD26 protein--can drastically change the outcome of metastatic disease.
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PMID:CD26 expression determines lung metastasis in mutant F344 rats: involvement of NK cell function and soluble CD26. 1462 26

Tetraspanins are integral membrane proteins involved in a variety of physiological and pathological processes. In cancer, clinical and experimental studies have reported a link between tetraspanin expression levels and metastasis. Tetraspanins play a role as organizers of multimolecular complexes in the plasma membrane. Indeed each tetraspanin associates specifically with one or a few other membrane proteins forming primary complexes. Thus, tetraspanin-tetraspanin associations lead to a molecular network of interactions, the "tetraspanin web." We performed a proteomic characterization of the tetraspanin web using a model of human colon cancer consisting of three cell lines derived from the primary tumor and two metastases (hepatic and peritoneal) from the same patient. The tetraspanin complexes were isolated after immunoaffinity purification using monoclonal antibodies directed against the tetraspanin CD9, and the associated proteins were separated by SDS-PAGE and identified by mass spectrometry using LC-MS/MS. This allowed the identification of 32 proteins including adhesion molecules (integrins, proteins with Ig domains, CD44, and epithelial cell adhesion molecule) (EpCAM), membrane proteases (ADAM10, TADG-15, and CD26/dipeptidyl peptidase IV), and signaling proteins (heterotrimeric G proteins). Importantly some components were differentially detected in the tetraspanin web of the three cell lines: the laminin receptor Lutheran/B-cell adhesion molecule (Lu/B-CAM) was expressed only on the primary tumor cells, whereas CD26/dipeptidyl peptidase IV and tetraspanin Co-029 were observed only on metastatic cells. Concerning Co-029, immunohistofluorescence showed a high expression of Co-029 on epithelial cells in normal colon and a lower expression in tumors, whereas heterogeneity in terms of expression level was observed on metastasis. Finally we demonstrated that epithelial cell adhesion molecule and CD9 form a new primary complex in the tetraspanin web.
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PMID:Profiling of the tetraspanin web of human colon cancer cells. 1646 80

We used cDNA microarrays to study gene expression in fresh frozen papillary thyroid carcinoma (PTC) specimens. Seven clinically aggressive carcinomas were included, comprising poorly differentiated PTC and tumors with extensive local invasion or synchronous distant metastases. Ten differentiated (classic) papillary thyroid carcinomas (PTC) and non-neoplastic thyroid tissues were also investigated. TaqMan quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridization, and immunohistochemistry verified the differential gene expression. The B-Raf gene was mutated with a T-->A transversion at nucleotide 1799 (V600E) in 8 of 10 differentiated PTC, and in 4 of 7 aggressive carcinomas. Among genes markedly and equally over-expressed in carcinomas of both the aggressive and classic PtC groups, compared to normal thyroid tissue, were CBP/p300 transactivator (CItED1), fibronectin, growth/differentiation factor 15, potassium inwardly rectifying channel KCNJ2, glutaminyl peptide cyclotransferase, WNT7A, and dipeptidyl peptidase IV. A marked upregulation in carcinomas of P-cadherin mRNA and protein concomitant with E-cadherin downregulation, indicates a possible P-E cadherin "switch" in PTC. The growth factor homologue Nel-like 2, dual specificity phosphatase 5, the serine protease kallikrein 10, and also the tight junction genes claudin 1 and claudin 16, were upregulated in classic PTC but not in aggressive tumors, which may be consistent with altered cell polarity in the dedifferentiated PtC. The aggressive, poorly differentiated PtC group was specifically characterized by marked upregulation of several genes related to cell proliferation such as cell division cycle 2 (CDC2), CDC7, kinesin-like 5, ubiquitin conjugating enzyme E2C, and topoisomerase IIalpha, and by upregulation of genes encoding extracellular matrix proteins such as seprase, extracellular matrix protein 1, and several collagens. These aggressive tumors were also characterized by overexpression of the integrin ligand periostin, and in some biopsies also of osteopontin and of the upstream Rac-regulator dedicator of cytokinesis 10 (DOCK10). These data are interpreted to be consistent with altered cell motility, extracellular matrix remodeling and increased cell proliferation, as important processes in PTC tumor progression.
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PMID:Gene expression in poorly differentiated papillary thyroid carcinomas. 1667 2

CD26 is a 110 kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity that is expressed on numerous cell types and has a multitude of biological functions. An important aspect of CD26 biology is its peptidase activity and its functional and physical association with molecules with key roles in various cellular pathways and biological programs. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T-lymphocyte activation as well as antigen presenting cell-T-cell interaction. Recent work also suggests that CD26 has a significant role in tumor biology, being both a marker of disease behavior clinically as well as playing an important role in tumor pathogenesis and development. In this paper, we will review emerging data that suggest CD26 may be an appropriate therapeutic target for the treatment of selected neoplasms and immune disorders. Through the use of various experimental approaches and agents to influence CD26/DPPIV expression and activity, such as anti-CD26 antibodies, CD26/DPPIV chemical inhibitors, siRNAs to inhibit CD26 expression, overexpressing CD26 transfectants and soluble CD26 molecules, our group has shown that CD26 interacts with structures with essential cellular functions. Its association with such key molecules as topoisomerase IIalpha, p38 MAPK, and integrin beta1, has important clinical implications, including its potential ability to regulate tumor sensitivity to selected chemotherapies and to influence tumor migration/metastases and tumorigenesis. Importantly, our recent in vitro and in vivo data support the hypothesis that CD26 may indeed be an appropriate target for therapy for selected cancers and immune disorders.
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PMID:CD26/dipeptidyl peptidase IV as a novel therapeutic target for cancer and immune disorders. 1734 18


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