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

Tetraspanins are transmembrane adaptor proteins involved in the regulation of various fundamental cellular processes. For a number of malignant diseases, the level of expression of members of the tetraspanin family was found to correlate with tumor cell invasiveness, ability to form metastases, and poor clinical outcome. We describe the exact quantification of mRNAs coding for the tetraspanins CD9, CD63, CD82 and CD151 expressed by mammary carcinoma-derived cell lines that were classified as invasive or non-invasive according to their ability to penetrate collagen-fibroblast gels in vitro. The mean of beta2-microglobulin-normalized expression of CD9 was about 10-fold higher than the mean calculated for CD63 and about 20-fold higher than expression of CD82 and CD151. Direct comparison of tetraspanin expression of invasive and non-invasive cell lines with the Mann-Whitney test revealed a significant correlation for CD63. Grouping of cell lines in relation to threshold values of expression resulted in significant correlations for CD63 (Fisher's exact test p=0.004) and CD151 (p=0.02) but not for CD82 (p=0.065) and CD9 (p=0.168). Expression of CD9, C63 and CD151 was found to be coupled whereas CD82 was expressed independently. This highly significant association points to common mechanisms of gene regulation for this subgroup of tetraspanins. We showed that on basis of absolute amounts of tetraspanin mRNAs, at least in vitro invasiveness is clearly predictable. Our results support the assumption that downregulation of tetraspanins in breast cancer cells is an important step of tumor progression to more malignant phenotypes and underline their important role as mediators in multimolecular membrane protein complexes regulating cell adhesion and migration.
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PMID:Expression of tetraspanin adaptor proteins below defined threshold values is associated with in vitro invasiveness of mammary carcinoma cells. 1257 80

The metastatic subline of a rat pancreatic adenocarcinoma differs from the non-metastasizing subline by overexpression of 5 membrane molecules: CD44 variant isoforms, EpCAM, the tetraspanin D6.1A, an uPAR-related molecule and, as described here, the alpha6beta4 integrin. An antibody-defined molecule was identified by mass spectrometry and cloning as alpha6beta4 integrin. Transfection-induced expression of alpha6beta4 in the non-metastasizing subline did not support migration on laminin 5 or tumor progression. However, when the non-metastasizing subline was doubly transfected to express alpha6beta4 and the D6.1A tetraspanin, intraperitoneally injected tumor cells frequently formed liver metastasis. For the following reasons we assume that metastasis formation is supported by an interaction between alpha6beta4 and D6.1A. (i) The 2 molecules can associate and co-localize. (ii) Co-localization is strengthened by PKC stimulation. (iii) PKC stimulation, which induces a migratory phenotype, leads to a redistribution of alpha6beta4/D6.1A complexes. In resting cells, the molecules co-localize at the trail of the cell; during PKC stimulation they become transiently internalized and are (re-)expressed in the leading lamella. Thus, in the appropriate milieu, i.e. intraperitoneally, alpha6beta4 changes from an adhesion-supporting towards a migration-supporting molecule by its association with a tetraspanin. The findings provide a convincing experimental explanation for the repeatedly described involvement of alpha6beta4 in tumor progression.
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PMID:The association of the tetraspanin D6.1A with the alpha6beta4 integrin supports cell motility and liver metastasis formation. 1313 99

Factors that regulate alpha(1,3)fucosyltransferase activity are important to identify because FUT genes are up-regulated during inflammation, cancer progression, and tumor metastasis. FUT gene activation increases the expression of cell surface oncofetal antigens such as Lewis X, sialyl-Le X and VIM-2. The LEC11B gain-of-function glycosylation mutant displays these antigens and binds E-selectin because it expresses the Fut6B gene that is shown here to lie immediately downstream of the Fut6A gene. A retroviral strategy for expression cloning factors that suppress alpha(1,3)fucosylation in LEC11B cells was developed, and several cDNAs that reverted the LEC11B glycosylation phenotype were isolated. cDNAs that arose most frequently and independently encoded SLC35C2, a putative GDP-fucose transporter (also termed CGI-15 or Ovcov1); Cd63, a tetraspanin membrane protein; and Hdac5, a histone deacetylase. When transfected into LEC11B cells the SLC35C2 cDNA reduced Le X expression with no concomitant suppression of Fut6B gene transcripts. Transfection of the Cd63 cDNA induced low levels of ricin resistance and also did not suppress Fut6B gene transcripts in LEC11B. However, the Hdac5 cDNA induced ricin resistance, reduced fucosylated antigen expression, and essentially eliminated Fut6B gene transcripts. The Hdac5 cDNA isolated by expression cloning encoded the C-terminal region of hamster Hdac5. Overexpression of this partial Hdac5 cDNA or a full-length Hdac5 cDNA, suppressed Fut6B gene transcripts specifically. Thus the expression cloning strategy identified Hdac5 as a trans-acting repressor of the Chinese hamster ovary Fut6B gene and Cd63 and SLC35C2 as novel factors that suppress alpha(1,3)fucosylation by mechanisms unrelated to effects on Fut gene expression.
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PMID:Suppressors of alpha(1,3)fucosylation identified by expression cloning in the LEC11B gain-of-function CHO mutant. 1552 19

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 a molecular network of interactions, the "tetraspanin web". Here, we have performed a proteomic characterization of the tetraspanin web using a model of human colon cancer consisting of two cell lines derived from primary tumor and metastasis from the same patient. The tetraspanin complexes were isolated after immunoaffinity purification and the proteins were identified by MS using LC-ESI-MS/MS and MALDI-FTICR. The high resolution and mass accuracy of FTICR MS allowed reliable identification using mass finger printing with only two peptides. Thus, it could be used to resolve the composition of complex peptide mixtures from membrane proteins. Different types of membrane proteins were identified, including adhesion molecules (integrins, Lu/B-CAM, GA733 proteins), receptors and signaling molecules (BAI2, PKC, G proteins), proteases (ADAM10, TADG15), and membrane fusion proteins (syntaxins) as well as poorly characterized proteins (CDCP1, HEM-1, CTL1, and CTL2). Some components were differentially detected in the tetraspanin web of the two cell lines. These differences may be relevant for tumor progression and metastasis.
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PMID:Proteomic analysis of the tetraspanin web using LC-ESI-MS/MS and MALDI-FTICR-MS. 1640 22

CD9, a tetraspanin protein, makes crucial contributions to sperm egg fusion, other cellular fusions, epidermal growth factor receptor signaling, cell motility, and tumor suppression. Here we characterize a low affinity anti-CD9 antibody, C9BB, which binds preferentially to homoclustered CD9. Using mAb C9BB as a tool, we show that cell surface CD9 homoclustering is promoted by expression of alpha3beta1 and alpha6beta4 integrins and by palmitoylation of the CD9 and beta4 proteins. Conversely, CD9 is shifted toward heteroclusters upon expression of CD9 partner proteins (EWI-2 and EWI-F) or other tetraspanins, or upon ablation of CD9 palmitoylation. Furthermore, unpalmitoylated CD9 showed enhanced EWI-2 association, thereby demonstrating a previously unappreciated role for tetraspanin palmitoylation, and underscoring how depalmitoylation and EWI-2 association may collaborate to shift CD9 from homo- to heteroclusters. In conclusion, we have used a novel molecular probe (mAb C9BB) to demonstrate the existence of multiple types of CD9 complex on the cell surface. A shift from homo- to heteroclustered CD9 may be functionally significant because the latter was especially obvious on malignant epithelial tumor cells. Hence, because of its specialized properties, C9BB may be more useful than other anti-CD9 antibodies for monitoring CD9 during tumor progression.
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PMID:Contrasting effects of EWI proteins, integrins, and protein palmitoylation on cell surface CD9 organization. 1653 45

Tissue inhibitors of metalloproteinases (TIMPs) are endogenous inhibitors of matrix metalloproteinases (MMPs) and the balance between MMPs/TIMPs regulates the extracellular matrix (ECM) turnover and remodeling during normal development and pathogenesis. Increasing evidence indicates a much more complex role for TIMPs during tumor progression and angiogenesis, in addition to their regulation of MMP-mediated ECM degradation. In this article, we review both the MMP-dependent and -independent actions of TIMPs for the regulation of cell death, cell proliferation, and angiogenesis, with a particular emphasis on TIMP-1 in the regulation of tetraspanin/integrin-mediated cell survival signal transduction pathways.
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PMID:Novel functions of TIMPs in cell signaling. 1668 May 76

Tumors of the gastrointestinal tract -- gastric, colorectal, pancreatic and liver tumors -- account for over 50 % of cancer worldwide. The 5-year survival rate varies from > 50 % in colorectal to < 1 % in pancreatic cancer. The high cancer death rate strikingly correlates with the high metastasizing capacity of most gastrointestinal tumors. Therefore and because during the last decade several important hypotheses on metastasis formation could be settled on solid experimental ground, this review will first provide a brief outline on the currently most accepted view of tumor progression and then discuss whether and how the rather new family of tetraspanin molecules might contribute to cancer progression. Notably, some members of this family, in particular, CD82/KAI1 are known as metastasis suppressor genes, while others like CD151 and CO-029 are supposed to promote metastasis formation. The underlying mechanisms are beginning to become unraveled. Tetraspanins assemble complexes of different tetraspanins, integrins and additional transmembrane molecules in microdomains that serve as signaling platform. By creating proximity, tetraspanins modulate functional activity of the associating molecules. In addition, tetraspanins actively contribute to the intracellular traffic of the associating molecules that includes vesicular budding and formation of exosomes that are particularly rich in tetraspanins. Accordingly, the association of certain tetraspanins with the metastatic phenotype as well as the definition of other tetraspanins as metastasis suppressor genes has to be viewed from the perspective of molecular complexes rather than the individual tetraspanin.
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PMID:Gastrointestinal tumors: metastasis and tetraspanins. 1682 99

Biological membranes are compartmentalized into microdomains that exhibit particular lipid and protein compositions. Membrane microdomains, such as tetraspanin-enriched microdomains and lipid rafts, have been suggested to play a role in a variety of physiological and pathological processes. Therefore, the characterization of the protein compositions of these microdomains, which is the focus of this review, appears to be a crucial step to better understanding their function. Proteomics has recently allowed the characterization of tetraspanin-enriched microdomains in colon cancer cells. This demonstrated the presence of different categories of membrane proteins and suggested a variation in the composition of tetraspanin-enriched microdomains during tumor progression. On the other hand, proteomics has permitted the identification of hundreds of proteins in lipid rafts of different origins. However, the diversity of methodologies in sample preparation and of strategies in protein identification led to a broad variability in the data obtained. These methodological issues are discussed. Moreover, proteomics has revealed that different sets of proteins were present in tetraspanin-enriched microdomains as compared with lipid rafts, strengthening the idea that these microdomains are distinct structures.
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PMID:Membrane microdomains and proteomics: lessons from tetraspanin microdomains and comparison with lipid rafts. 1710 80

High expression of EpCAM and the tetraspanin CO-029 has been associated with colorectal cancer progression. However, opposing results have been reported on CD44 variant isoform v6 (CD44v6) expression. We recently noted in rat gastrointestinal tumors that EpCAM, claudin-7, CO-029, and CD44v6 were frequently coexpressed and could form a complex. This finding suggested the possibly that the complex, rather than the individual molecules, could support tumor progression. The expression of EpCAM, claudin-7, CO-029, and CD44v6 expression was evaluated in colorectal cancer (n = 104), liver metastasis (n = 66), and tumor-free colon and liver tissue. Coexpression and complex formation of the molecules was correlated with clinical variables and apoptosis resistance. EpCAM, claudin-7, CO-029, and CD44v6 expression was up-regulated in colon cancer and liver metastasis. Expression of the four molecules did not correlate with tumor staging and grading. However, coexpression inversely correlated with disease-free survival. Coexpression was accompanied by complex formation and recruitment into tetraspanin-enriched membrane microdomains (TEM). Claudin-7 contributes to complex formation inasmuch as in the absence of claudin-7, EpCAM hardly associates with CO-029 and CD44v6 and is not recruited into TEMs. Notably, colorectal cancer lines that expressed the EpCAM/claudin-7/CO-029/CD44v6 complex displayed a higher degree of apoptosis resistance than lines devoid of any one of the four molecules. Expression of EpCAM, claudin-7, CO-029, and CD44v6 by themselves cannot be considered as prognostic markers in colorectal cancer. However, claudin-7-associated EpCAM is recruited into TEM and forms a complex with CO-029 and CD44v6 that facilitates metastasis formation.
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PMID:A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression. 1757 17

CD9, a member of the tetraspanin family of proteins, is involved in a variety of cellular interactions with many other proteins and molecules. Although CD9 has been implicated in cell fusion, migration and cancer progression, the detailed function of this protein is not completely understood and likely depends on interactions with different protein partners, which are not yet all known. Using co-immunoprecipitation and mass-spectrometric protein sequencing, we have identified in prostate cancer cells, a novel CD9 partner, the 75-kDa protein HSPA9B, also known as mortalin. We further show that introduction and overexpression of wild-type CD9 into human PC-3 prostate cancer cells induces mitotic catastrophe. We also demonstrate, by immunocolocalisation studies, the interaction of CD9 and mortalin in PC-3 cells undergoing mitotic catastrophe. Our results not only identified mortalin as a new CD9 partner, but also clarify the mechanisms by which CD9 may control prostate cancer progression.
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PMID:Colocalisation of CD9 and mortalin in CD9-induced mitotic catastrophe in human prostate cancer cells. 1784 53


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