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)

The identification of (gamma-glutamyl)polyamines in proteolytic digest of proteins from the cytosolic and particulate fractions of B16-F10 and B16-F10Lr6 cell lines, originating from a spontaneous tumor in C57BL/6 mice, indicates that polyamines are incorporated into melanoma cell proteins by transglutaminases (TGases-EC 2.3.2.13). The levels of spermidine-derived protein cross-links were found to be inversely related with the metastatic potential of the 2 melanoma lines. Characterization of TGase activity in the 2 tumor cell lines showed 3 types of enzyme. The soluble cellular TGase activity (TGase C) was higher, and increased more, during the growth of the least metastasizing clone B16-F10Lr6 than in the B16-F10 line, which is the most metastasizing. Consistently, N1,N8-bis(gamma-glutamyl) spermidine, which is responsible for protein cross-link formation, was present in greater amount in B16-F10Lr6 cells. The enhancement by theophylline of soluble-TGase activity and spermidine-dependent protein cross-links of B16-F10 cells reduced, with linear dose dependence, the ability of these cells to penetrate through human fibronectin-coated membrane in an in vitro assay of invasiveness. Our data confirm and extend earlier observations indicating that the propensity of a tumor to metastasize can be indirectly related to intracellular levels of TGase activity, and provide the basis for some speculation concerning the role of polyamines as modifiers of murine melanoma cell proteins in metastasis.
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PMID:Differences in the post-translational modification of proteins by polyamines between weakly and highly metastatic B16 melanoma cells. 809 90

In the normal striated muscle, tissue transglutaminase (TG2) content is vestigial. However, this protein's presence has been reported to occur in myoblasts and myotubes during the fetal period. Its increased expression has been also found in the muscle tissue in the course of sporadic inclusion body myositis, as well as in polymyositis (PM) and dermatomyositis (DM), which are considered to be diseases of immunological origin. Based on in vitro studies, a substantial TG2 role in the infiltration of some T cell subsets into inflamed tissues has been suggested lately. In this study, the immunohistochemical reactions in the guinea pig experimental myositis specimens and in the ones from PM/DM patients were compared. The guinea pig tissue specimens were taken from muscles affected by experimental myositis induced by intramuscular injections of: 1/sera from 30 neoplasm patients with no metastases; 2/sera from 10 healthy people; 3/sera from 2 DM patients; 4/neuropeptides (SP, NPY or VIP) and from 5/the muscles affected by the reversed passive Arthus reaction (RPAR). The immunostaining for TG2 revealed substantial presence of this protein in single, damaged muscle fibers and a weak reaction in regenerating fibers appearing in PM/DM patients' specimens. From among experimental myositis specimens, a very intensive reaction appeared only in the damaged and regenerating muscle fibers present in the slides from guinea pig muscles injected with DM patients' sera. Such results suggest some presence of a specific factor(s) (the one(s) responsible for TG2 expression in the damaged muscle fibers) in DM patients' sera. The results suggest that transglutaminase can be a marker of inflammatory myopathies. A probable correlation between TG2 expression in muscles and organismal immunological factors, including the complement activation status, requires additional studies.
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PMID:Can tissue transglutaminase be a marker of idiopathic inflammatory myopathies? 1575 64

Tissue transglutaminase (TG2, EC 2.3.2.13) is a ubiquitous enzyme that catalyzes Ca2+-dependent post-translational modification of proteins by inserting highly stable (epsilon-[gamma-glutamyl] lysine) isopeptide bonds or by conjugating polyamines at selected peptide-bound glutamine residues. The TG2-catalyzed cross-linked products (generally high molecular mass scaffold of proteins) are of great physiological significance; they are highly stable and resistant to mechanical, chemical and proteolytic degradation. The accumulation of isopeptide bonds can be observed in skin, hair and during blood clotting and wound healing. In addition to transamidation activity, TG2 also exhibits GTPase activity and in response to certain agonist hormones can serve as a signal transducing G protein. Although predominantly a cytosolic protein, TG2 can translocate to the nucleus with the help of importin alpha-3 protein or to the membranes in association with integrins. Moreover, TG2 can also be secreted outside the cell (by yet unknown mechanism) where it crosslinks proteins of the extracellular matrix (ECM) and promotes cell adhesion and spreading. Another important property of TG2 is that it has high binding-affinity for the ECM component protein, fibronectin and thus can promote interaction between cell surface integrin with fibronectin. In this review, we discuss the implications of increased TG2 expression in drug-resistant and metastatic cancer cells and that how TG2 expression can contribute in the development of these phenotypes.
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PMID:Tissue transglutaminase: from biological glue to cell survival cues. 1614 23

The survival and growth of tumor cells in a foreign environment is considered a rate-limiting step during metastasis. To identify genes that may be essential for this process, we isolated highly metastatic variants from a poorly metastatic human melanoma cell line and performed expression analyses of metastases and primary tumors from these cells. GPR56 is among the genes markedly down-regulated in the metastatic variants. We show that overexpression of GPR56 suppresses tumor growth and metastasis, whereas reduced expression of GPR56 enhances tumor progression. Levels of GPR56 do not correlate with growth rate in vitro, suggesting that GPR56 may mediate growth suppression by interaction with a component in the tumor microenvironment in vivo. We show that GPR56 binds specifically to tissue transglutaminase, TG2, a widespread component of tissue and tumor stroma previously implicated as an inhibitor of tumor progression. We discuss the mechanisms whereby GPR56-TG2 interactions may suppress tumor growth and metastasis.
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PMID:GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. 1675 64

Transglutaminase-2 is involved in the physiological regulation of cell growth, but has also been associated with a number of cancer-associated features such as cell adhesion, metastasis and extracellular matrix modulation. Despite its importance in tumor cell progression and survival, relatively little is known about its expression in human malignancies. We have therefore investigated the transglutaminase-2 expression pattern in breast and ovarian cancer by using tissue arrays which contained 57 invasive breast cancer biopsies and 62 ovarian cancers, and compared it to transglutaminase-2 protein levels in normal human tissues. By using immunohistochemistry, transglutaminase-2 protein was detected in 48 of 57 breast tumors (84%), with epithelial expression in 26 of 41 (63%) ductal invasive carcinomas and in all 6 (100%) lobular invasive carcinomas. Stromal transglutaminase-2 was present in 14 of 41 (34%) ductal subtypes and in 4 of 6 (67%) lobular subtypes, which is in sharp contrast to the infrequent expression in normal breast stroma (P<0.001, Mann-Whitney test) and somewhat also in normal breast epithelium (P = 0.065, Mann-Whitney test). In most other human tissues, transglutaminase-2 protein was less frequent and usually confined to either the epithelium or in adjacent stroma. In ovarian tumors, the protein was detected in 36 of the 62 cases (58%), and seen in all histological subtypes. Taken together, we have demonstrated increased transglutaminase-2 protein expression in both malignant breast epithelium and surrounding stroma, although its selective spatial expression pattern in normal tissues also indicates a physiological role in stromal-epithelial interactions.
Clin Exp Metastasis 2006
PMID:Tissue array-based expression of transglutaminase-2 in human breast and ovarian cancer. 1682 31

The transcription factor nuclear factor-kappaB (NF-kappaB) plays an important role in regulating cell growth, apoptosis, and metastatic functions. Constitutive activation of NF-kappaB has been observed in various cancers; however, molecular mechanisms resulting in such activation remain elusive. Based on our previous results showing that drug-resistant and metastatic cancer cells have high levels of tissue transglutaminase (TG2) expression and that this expression can confer chemoresistance to certain types of cancer cells, we hypothesized that TG2 contributes to constitutive activation of NF-kappaB. Numerous lines of evidence showed that overexpression of TG2 is linked with constitutive activation of NF-kappaB. Tumor cells with overexpression of TG2 exhibited increased levels of constitutively active NF-kappaB. Activation of TG2 led to activation of NF-kappaB; conversely, inhibition of TG2 activity inhibited activation of NF-kappaB. Similarly, ectopic expression of TG2 caused activation of NF-kappaB, and inhibition of expression of TG2 by small interfering RNA abolished the activation of NF-kappaB. Our results further indicated that constitutive NF-kappaB reporter activity in pancreatic cancer cells is not affected by dominant-negative I kappaB alpha. Additionally, coimmunoprecipitation and confocal microscopy showed that I kappaB alpha is physically associated with TG2. Lastly, immunohistochemical analysis of pancreatic ductal carcinoma samples obtained from 61 patients further supported a strong correlation between TG2 expression and NF-kappaB activation/overexpression (P = 0.0098, Fisher's exact test). We conclude that TG2 induces constitutive activation of NF-kappaB in tumor cells via a novel pathway that is most likely independent of I kappaB alpha kinase. Therefore, TG2 may be an attractive alternate target for inhibiting constitutive NF-kappaB activation and rendering cancer cells sensitive to anticancer therapies.
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PMID:Overexpression of tissue transglutaminase leads to constitutive activation of nuclear factor-kappaB in cancer cells: delineation of a novel pathway. 1695 Nov 95

Metastasis is a complex process that involves multiple levels of cell-cell interaction. Among these interactions, tumor-stroma interactions are being actively investigated. Metastatic cells are hypothesized to show gene expression changes that contribute to their survival and growth at the distant site. Such changes could contribute either to enhancement of growth or to evasion of growth inhibition by the normal tissue environment thus allowing growth as metastases. Our recent report that tumors from highly metastatic melanoma derivatives express low levels of a suppressor of tumor progression, GPR56, is consistent with such a model. GPR56 associates in a complex with Gaq and the tetraspanin protein CD81. We further identified a ligand that interacts with GPR56 in the extracellular matrix (ECM) as TG2, a major crosslinking enzyme in the matrix. TG2 also binds to fibronectin and integrins and affects their cell adhesion functions. TG2 itself has been implicated in suppression of tumor progression; therefore TG2 might serve as a host defense against the invading metastatic cells. The highly metastatic cells may escape from this inhibition by down-regulation of GPR56. Much future work will be needed to test this hypothesis and further our understanding of metastasis in general.
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PMID:GPR56 and TG2: possible roles in suppression of tumor growth by the microenvironment. 1731 16

Drug resistance and metastasis are major impediments for the successful treatment of cancer. A common feature among drug resistant and metastatic tumor cells is that they exhibit profound resistance to apoptosis. This property enables cancer cells not only to grow and survive in stressful environments (metastasis) but also to display resistance against many anticancer agents. Therefore, perturbation of the intrinsic apoptotic pathways of cancer cells will affect their ability to respond to chemotherapy and to metastasize and survive in distant sites. Recent studies have demonstrated that cancer cells and cancer cell lines selected for resistance against chemotherapeutic drugs or isolated from metastatic sites, express elevated levels of the multifunctional protein, tissue transglutaminase (TG2). TG2 is the most diverse and ubiquitous member of the transglutaminase family of proteins that is implicated to play a role in apoptosis, wound healing, cell migration, cell attachment, cell growth, angiogenesis, and matrix assembly. TG2 can associate with certain beta members of the integrin family of proteins (beta1, beta3, beta4, and beta5) and promote stable interaction between cells and the extracellular matrix (ECM), resulting in increased cell survival, cell migration, and invasion. Additionally, TG2 forms a ternary complex with IkappaB/p65:p50 and results in constitutive activation of the nuclear transcription factor-kappaB (NF-kappaB). Moreover, TG2 expression in cancer cells leads to constitutive activation of the focal adhesion kinase (FAK) and its downstream PI3K/Akt survival pathway. Importantly, the inhibition of endogenous TG2 by small interfering RNA (siRNA) resulted in the reversal of drug resistance and the invasive phenotype. Conversely, ectopic expression of TG2 promoted cell survival, cell motility and invasive functions of cancer cells. This review discusses the current thinking and implications of increased TG2 expression in development of drug resistance and metastasis by cancer cells.
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PMID:Tissue transglutaminase-mediated chemoresistance in cancer cells. 1766 45

One of the most relevant problems in tumour treatment resides on the ability of the tumour to form metastasis and disseminate among the organism. The formation of metastases is a complex process, which requires the action of various effectors, not yet completely identified. The analysis of various types of tumours revealed a complex picture about the relationship between type 2 transglutaminase (TG2) expression and outcome and/or metastatic potential of the tumour itself. In some tumours, the transition to a highly invasive state is paralleled by an up-regulation of TG2 expression and/or activity while in some other a down-regulation has been reported. In addition, host tissues seem to react to tumour invasion by up-regulating TG2 expression. In order to analyse whether TG2 might be involved in the metastatic process in melanoma, we studied the metastases formation and development by means of the B16-F10 murine melanoma cell line and with TG2(-/-) mice as experimental model. Our results indicate that TG2 absence in the host is a favouring condition for the formation and development of the metastasis, while the presence of TG2 in the tumour's cell might be requested for the development of the metastasis.
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PMID:In vivo evaluation of type 2 transglutaminase contribution to the metastasis formation in melanoma. 1859 48

Despite major advances in diagnosis, surgical and postsurgical techniques and adjuvant therapies, 7.5 million individuals worldwide still die of cancer every year. Most cancer deaths result because tumor cells metastasize to distant organs and/or acquire resistance to conventional therapies. Therefore, elucidation of tumor-encoded genes whose expression contribute to the development of drug resistance and metastasis can be of great significance in revealing novel therapeutic targets for the effective control and treatment of cancer. Tissue transglutaminase (TG2) is an enzyme whose expression is up-regulated in a number of cancer cell types. TG2 is a ubiquitous member of the transglutaminase family of enzymes and is implicated in such diverse processes as inflammation, wound healing, apoptosis, neurodegenerative disorders and cancer. Depending on the cell type and its localization within the cell, TG2 can serve as an antiapoptotic or a proapoptotic protein. In general, the presence of high levels (>1 mM) of Ca(2+) induces its activation, which promotes inter- and intramolecular cross-linking of proteins and results in cell death. Indeed, the use of TG2-specific antisense RNA protects cells against stress-induced cell death. In contrast, low levels (<1 mM) of Ca(2+) and a high concentration (>9 microM) of guanosine triphosphate (the conditions that generally prevail inside cells) promotes TG2-mediated cell survival signaling. Many studies have reported increased TG2 expression in a number of cancer cell types that are known to have high resistance to chemotherapeutic drugs or are metastatic. Importantly, the increased expression of TG2 is associated with increased invasion and cell survival. Down-regulation of TG2 by small interfering RNA or inhibition by small molecule inhibitors can enhance therapeutic efficacy of anticancer drugs and inhibit metastatic spread. In this review, the contextual roles of TG2 in promoting and protecting normal versus tumor cells from death-induced signaling, its contributions in promoting the drug resistance and metastasis of cancer cells and its therapeutic potential for treating advanced cancer are discussed.
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PMID:Tissue transglutaminase promotes or suppresses tumors depending on cell context. 1952 47


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