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)

Primary cultures of surgery samples from 9 human breast carcinoma cases were studied by double staining with fluorochrome labelled phalloidin for F-actin and immunofluorescence by tubulin, alpha-actinin or vinculin. Primary cultures of normal human mammary gland and benign breast tumors were used for comparison. Results showed that microfilament cables (stress fibers) and microtubules were reduced dramatically both in number and organization in most carcinoma cells. F-actin aggregates appeared. They are dot-like and 0.1-0.4 microns in size. These F-actin aggregates were co-stained with alpha-actinin and vinculin, located at (near) the innerface of cell membrane at the cell bottom (cell-substrate contact). In individual cells, the aggregates varied in number from 10 to more than 100 per cell, tended to group into pad-like patches. The percentage of F-actin aggregate positive cells in cell population of each case varied from < 5% to 90%. There was a positive correlation between the frequency of F-actin aggregates and the level of clinic and pathologically diagnosed invasion and subaxillary lymph node metastasis. These results suggest that aberrations of cytoskeletal organization of microfilaments and microtubules may be a common phenotype in human breast carcinoma cells. The varied frequency of F-actin aggregates may reflect the different potential capacity of malignant cells to invade and metastasize, thus provide a diagnostic clue as well as suggestions for further genetic diagnostic investigation studies.
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PMID:[F-actin aggregates and aberrations of cytoskeletal organization of microfilaments and microtubules in human breast carcinoma cells]. 839 30

Tumor cell adhesion to the extracellular matrix (ECM) is closely linked with tumor cell invasion and metastasis. In this study, we demonstrate that low levels of adriamycin, a widely used anticancer drug, can inhibit the invasion of highly metastatic K1735-M2 mouse melanoma cells in vitro through a reconstituted basement membrane extract. Adriamycin-induced inhibition of melanoma cell invasion occurred at levels of the drug (i.e. 1 ng/ml) that did not inhibit tumor cell growth, suggesting that the observed inhibition in tumor cell invasion was not due to the well-documented ability of adriamycin to interfere with DNA and/or RNA synthesis. Rather, these studies indicated that adriamycin-induced inhibition of melanoma cell invasion was accompanied by a corresponding decrease in the ability of adriamycin-treated tumor cells to migrate in response to several isolated ECM components including fibronectin, laminin and basement membrane (type IV) collagen. The decreased migration of adriamycin-treated tumor cells was not accompanied by a decrease in the adhesion or spreading of the adriamycin-treated cells on substrata coated with these ECM components. Instead, adriamycin-treated cells actually exhibited a slightly increased propensity (compared to untreated control cells) to adhere on fibronectin-, laminin-, and type IV collagen-coated substrata. Additionally, adriamycin treatment caused a dramatic increase in focal contact formation by these melanoma cells, as assessed by fluorescent microscopy of actin and vinculin. In addition to providing a useful model for which to study the molecular and cellular basis for focal contact formation, these results further emphasize the results of several other investigators that have suggested an important role for focal contacts in modulating tumor cell motility, invasion and metastasis.
Clin Exp Metastasis 1993 Jan
PMID:Adriamycin-induced inhibition of melanoma cell invasion is correlated with decreases in tumor cell motility and increases in focal contact formation. 842 10

Tumor growth and metastasis are affected by changes in membrane lipid composition, however, little is known regarding the role of specific fatty acids in these pathological events. We investigated the effects of the long-chain saturated fatty acids (LCSFA), myristate (C14:0), palmitate (C16:0) and stearate (C18:0) on two key steps of metastasis: cell adhesion and invasion into extracellular matrix (ECM). Using a new 72-hour ECM (Amgel) invasion assay, we demonstrated that the exposure of highly invasive human fibrosarcoma HT-1080 cells to 0.3 mM stearate inhibited their ability to traverse Amgel by 59.4 +/- 8%. In contrast, treatment of tumor cells with 0.3 mM myristate or palmitate had no effect. Microscopic examination revealed a time-dependent inhibition of tumor cell adhesion to the Amgel in the stearate-treated group. Cell adhesion assays further showed a series of rapid morphological cellular changes, i.e. retraction of processes, cell rounding, and subsequent detachment in the presence of stearate. These morphological events were both dose- and time-dependent. Viability of LCSFA-treated cells exceeded 80%. This stearate inhibition of HT-1080 cell adhesion was also observed with two other invasive human tumor cell lines. Similar treatment of HT-1080 cell with the unsaturated long-chain fatty acid oleate (C18:1) did not alter tumor cell adhesiveness. In contrast, nontransformed human fibroblasts (Hs-68) were unaffected by stearate treatment. This inhibition of cell adhesion by stearate was determined to be dependent upon laminin-containing ECM. Pretreatment of HT-1080 cells with stearate dramatically abolished their capacity to attach to laminin but not to collagen type IV or fibronectin matrices. Immunofluorescent studies with anti-beta 1 integrin receptor and antivinculin antibodies demonstrated beta 1 subunit and vinculin colocalization to focal adhesions in untreated HT-1080 cells adherent to laminin, in contrast to stearate-treated tumor cells. Further, stearate-induced changes were shown to be functionally coupled to integrins as an anti-beta 1 antibody markedly diminishes the adhesive ability of tumor cells to laminin. These data demonstrate stearate inhibits tumor cell adhesion, and therefore invasion, via a mechanism involving a laminin integrin receptor.
Invasion Metastasis 1995
PMID:Stearate inhibits human tumor cell invasion. 862 Dec 70

Cancer cell surface glycosphingolipids are considered to play a critical role in tumor growth and metastasis. However, the implications of glycoconjugates in the control of cell motility, which is considered to be involved in tumor invasion, are not fully understood. In this study, the effects of a series of synthetic sphingosine derivatives, obtained by the chemical transformation of azidosphingosines, on directional migration of K1735-M2 melanoma cells grown on type I collagen-coated surfaces were investigated. Following the application of 60 microM (2R, 3S, 4E)-2, 3-epimino-4-octadecen-3-ol (S4) the migration rate was 94 +/- 10 microns/day, compared with 377 +/- 22 microns/day in the control experiment. Six other analogues were not as potent. S4 also considerably down-modulated melanoma single cell motility. Inhibition of motile activity was associated with changes in the actin filament organization as well as with changes in the number and distribution of vinculin plaques. Moreover, the compound reduced the attachment abilities of melanoma cells to basement membrane Matrigel. Tumor cell invasion, however, was less affected and proliferation remained unimpaired after treatment with S4. These data suggest at least one intracellular mode of action of this particular synthetic sphingosine derivative by modulation of cytoskeletal organization. Melanoma cell motility and growth may be controlled independently via glycosphingolipids.
Clin Exp Metastasis 1996 Nov
PMID:Differential effects of synthetic sphingosine derivatives on melanoma cell motility, growth, adhesion and invasion in vitro. 897 May 78

The cells of various normal and malignantly transformed tissues are connected by "adhering junctions"-plasma membrane domains characterized by close membrane-membrane contact, a dense cytoplasmic plaque and, in most cases, the attachment of cytoskeletal filaments. On the basis of their specific ultrastructural organization and molecular composition, three major types of intercellular adhering junctions can be distinguished: 1. Adherens junctions appear in different shapes and sizes (zonula adhaerens, fascia adh., punctum adh.) and contain the transmembrane glycoprotein E-cadherin. The cytoplasmic portion of E-cadherin forms complexes with alpha-, beta-, and gamma-catenin and plakoglobin which, together with other proteins such as vinculin and radicin, constitute a plaque at which actin microfilaments insert. 2. Desmosomes (maculae adhaerentes) are mostly isodiametric (diameters up to approximately 0.5 micron) membrane domains traversed by representatives of two types of desmosomal cadherins, the desmogleins (Dsg) and desmocollins (Dsc), whose cytoplasmic tails contribute to a dense plaque containing plakoglobin and desmoplakin I (with or without an alternative splice form, desmoplakin II) which anchor IFs. The specific Dsc and Dsg subtypes can differ in different cell types and up to three different human genes have so far been identified for each desmosomal cadherin. 3. Complexus adhaerentes are junctions of variable size and shape that occur in lymphatic endothelia. They have a desmoplakin- and plakoglobin-rich plaque, whose specific transmembrane proteins have not yet been fully elucidated but can include endothelial cadherin-5. In their most elaborate subform- the "syndesmos" connecting the retothelial cells of lymph node sinus-these junctions can occupy extended portions of the cell surface. The molecular arrangements in desmosomes and complexus adhaerentes have been studied to understand the assembly and disappearance of these structures. The diagnostic potential of their constituent proteins for cell typing in tumor diagnosis is emphasized, as is the role of transient junction dissociation during invasion and metastasis of carcinomas and the general importance of tumor cell interactions with the retothelial cell system in the formation of lymph node metastases.
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PMID:The desmosome and the syndesmos: cell junctions in normal development and in malignancy. 898 60

The acquisition of an invasive or metastatic phenotype in malignant neoplasms is often correlated with reduced cellular adhesiveness. We investigated the expression of the adhesion-associated cytoplasmic protein, vinculin, in normal and neoplastic human squamous epithelia, as well as in metastases of squamous cell carcinomas, and correlated the results with invasiveness and metastatic potential. Tissue samples from various tumors were examined, including basal cell carcinomas (BCC), keratoacanthomas, and squamous cell carcinomas (SCC). In addition, lymph node metastases from nine of the SCC were tested in this study. Our results indicate that most BCC, keratoacanthomas, and in situ SCC display strong positive staining for vinculin. The level of immunolabeling for vinculin and its pattern of distribution in the low malignant, nonmetastasizing lesions was similar to those observed in normal squamous epithelia. In contrast, in SCC, which are invasive and possess metastatic potential, as well as in their metastases, vinculin labeling was negative or poor, irrespective of their degree of differentiation. In conclusion, poor vinculin labeling in tumors of squamous epithelial origin examined here appears to be related to the metastatic potential of the tumor. Vinculin immunostaining of primary tumors originating in stratified squamous epithelia may thus be of value in helping to determine the metastatic potential of these neoplasms.
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PMID:Expression of the adherens junction protein vinculin in human basal and squamous cell tumors: relationship to invasiveness and metastatic potential. 938 27

Intercellular communication and the active movement of malignant cells into and through host tissue barriers play a critical role during the complex process of tumor invasion. Motile activity, cytoskeletal actin and vinculin organization as well as gap junctional communication of in vivo benign and malignant melanocytes were compared and related to in vitro invasiveness. Normal melanocytes, Melan-a, showed significantly less motile activity, a higher organization of the actin cytoskeleton and more vinculin-containing cell-substratum adhesion plaques than highly metastatic melanoma cells, K1735-M2. There was no pronounced difference in gap junctional communication under comparable culture conditions. However, cultivation of Melan-a cells in a conventional melanocyte growth medium containing the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced intercellular communication. Melanocytes were less invasive than melanoma cells both in the embryonic chick heart model and in the Matrigel invasion assay. The least invasive activity was determined for melanocytes cultivated in TPA-deficient medium indicating that the medium supplement TPA stimulates invasion. The comparison of certain in vitro properties of both melanocytic cell lines revealed a positive correlation of motility with in vitro invasion, whereas an inverse correlation was found for the degree of actin filament organization as well as for the number of vinculin plaques. Gap junctional communication was not directly related to in vitro invasiveness.
Invasion Metastasis 1997
PMID:Interrelation of motility, cytoskeletal organization and gap junctional communication with invasiveness of melanocytic cells in vitro. 942 22

Balb/c 3T3 cell adhesion on substrata coated with fibronectin's (FN) alternatively-spliced EDb, implicated in some tumor cell systems, and its neighboring type III repeats (III7 and III8) induced intracellular signaling coincident with morphological responses. These events were analysed using minigene-expressed proteins containing various permutations of type III repeats of FN. Cells adherent to the tri-repeat protein 7-EDb-8 were compared to those attached to the tri-repeat 8-9-10 which can interact with integrins through RGD and its synergistic sequences. Cell adhesion to 7-EDb-8 generated rapid tyrosine phosphorylation of several intracellular proteins (particularly the complex at 120-130 kD), with the overall phosphorylation level and its sensitivity to tyrosine kinase inhibitors similar to responses on the 8-9-10 tri-repeat. This similarity contrasted with the differential morphological responses of cells mediated by these proteins. Further analysis of the kinetics of phosphorylation through immunoblotting of two focal adhesion proteins, p125FAK and pl30cas, revealed a profile for Balb/c 3T3 adhesion to 7-EDb-8 distinct from that on 8-9-10. EDb mono-repeat was also more potent for inducing both limited cell spreading and FAK tyrosine phosphorylation than its neighboring repeats III7 or III8. Examination of cellular localization of FAK and vinculin showed that cells spread on the 7-EDb-8 substratum displayed vinculin-positive focal complex-like structures at the cell periphery, in contrast to the classical focal adhesions seen in 8-9-10-adherent cells. These results suggest that EDb induces cell signaling events, leading to tyrosine phosphorylation of focal adhesion proteins, through a mechanism different from that mediated by integrins recognizing sequences in III8-9-10. EDb-dependent signaling may have special significance in some tumor systems.
Clin Exp Metastasis 1998 Jan
PMID:Adhesion to fibronectin's EDb domain induces tyrosine phosphorylation of focal adhesion proteins in Balb/c 3T3 cells. 950 75

Genes that mediate breast cancer metastasis to lung are different from those which mediate bone metastasis. However, which markers accounts for the diversity of breast cancer metastasis remains unknown. The aim of this study was identify proteins associated with the soft-tissue metastatic ability of breast cancer tumors in metastases, coupling microarray data from clinical metastases and immunohistochemistry, for further screening for early detection at the first diagnosis in patients. We use a bioinformatic program to create and analyze protein interaction networks from protein experimental data, and to translate RNA expression analysis of breast cancer human metastases to protein, in a search for the phenotype associated with soft-tissue metastases. The pre-validated proteins constituted the protein signature for each metastasis: 37 (8.9%) from liver, 92 (8.5%) from lung and 167 (13%) from bone. Pleiotrophin, BAG 2, HSP 60 and vinculin were pre-validated in liver and lung metastases performing the soft-tissue phenotype. After IHC validation, we conclude that HSP 60, one of the best-known mitochondrial chaperone machines, is a key protein in soft-tissue metastases phenotype interacting with BAG 2, which competes for binding to GRP 75, the other mitochondrial chaperone. The relationship between HSP 60/GRP 75 and BAG 2 might result in the activation of several transcription pathways, different in liver from in lung metastases, as a nodal point coupling positive and negative actuators in the multiple survival-signal pathways and so achieving metastatic growth.
Clin Exp Metastasis 2007
PMID:Functional pathways shared by liver and lung metastases: a mitochondrial chaperone machine is up-regulated in soft-tissue breast cancer metastasis. 1800 73

Dissemination of primary cancer cells to distant sites is an early event in breast cancer. These cells can invade the bone marrow, rest there, and many years later disseminated tumor cells (DTC) can grow out to form overt metastases. Epithelium specific cytokeratins are commonly used as marker proteins for sensitive detection of metastatic lesions. However, due to difficulties in the detection of DTC, the question arises if DTC necessarily have the same protein expression profile as advanced tumors. On that account, we analyzed the previously uncharacterized breast cancer DTC cell line BC-M1 by 2-D DIGE. Special protein concentration and purification protocols for 2-DE were developed which resulted in high recovery rates and increased display of alkaline proteins. A broad range reference map of metastasis relevant proteins was compiled including the cytokeratins 5, 7, 8, 17, 18, and 19 and several classes of cytoskeleton proteins involved in metastasis like ezrin, gelsolin, vinculin, or vimentin. BC-M1 shows the rare and highly metastatic vimentin/cytokeratin 5 positive and cytokeratin 8/18 negative breast cancer phenotype and expresses Her-2, which is also found in stem cells/progenitor cells of primary tumors. Supported by the detection of several other epithelium-derived proteins, the example BC-M1 indicates that the protein expression profile of DTC might be reminiscent of the expression profile of the early tumor, which differs from the advanced tumor. Hence, DTC from breast cancer patients' bone marrow expressed cytokeratin 5, which further supports our hypothesis.
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PMID:Two-dimensional differential gel electrophoresis of a cell line derived from a breast cancer micrometastasis revealed a stem/ progenitor cell protein profile. 1971 17


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