Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Osteopontin (OPN) is a GRGDS-containing phosphoglycoprotein that is capable of facilitating cell adhesion and modulating gene expression via integrin receptors. Three hammerhead ribozymes designed to target three different regions of OPN mRNA were shown to cleave the message catalytically in vitro. Plasmid vectors that had been engineered to express the ribozymes in mammalian cells were used to generate stably transfected T24 H-ras-transformed NIH3T3 cells that normally express OPN at high levels. Northern and Western blot analyses showed that OPN mRNA and protein expression were reduced in a subset of these anti-OPN ribozyme-expressing cell lines. Cells whose ability to produce OPN had been impaired exhibited greater sensitivity to the cytotoxic action of activated RAW264.7 macrophage-like cells; they were also less effective at suppressing macrophage NO production. In agreement with previous reports, they were also less tumorigenic and metastatic in an experimental metastasis assay. These results are consistent with the hypothesis that OPN serves as a defense against NO-mediated host cell cytotoxicity and thereby augments the metastatic phenotype.
Clin Exp Metastasis 1995 Nov
PMID:Osteopontin (OPN) may facilitate metastasis by protecting cells from macrophage NO-mediated cytotoxicity: evidence from cell lines down-regulated for OPN expression by a targeted ribozyme. 758 3

Transformation of nontumorigenic NIH 3T3 fibroblasts with an activated ras oncogene produces malignant cells that can metastasize. This induction of malignant behavior is due to changes in gene expression induced by Ras-mediated signal transduction. Osteopontin expression is induced in response to Ras, due to increased osteopontin transcription mediated by Ras-responsive regions in the osteopontin gene promoter. The increased expression of osteopontin contributes functionally to the malignant ability of the cells. Ras-transformed cells that express antisense osteopontin RNA show markedly reduced ability to form tumors and to metastasize in experimental animals. Increased osteopontin expression in human tumors thus may also contribute to increased malignancy. Site-directed mutagenesis of recombinant osteopontin protein indicates that an intact RGD sequence is required for cell adhesion and induction of chemotaxis, consistent with the idea that integrin-mediated signal transduction is a consequence of osteopontin binding to cells. Osteopontin may contribute to malignancy by inducing responses in host and/or tumor cells.
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PMID:Regulation and function of osteopontin in ras-transformed cells. 778 89

Microcalcifications are a common phenomenon associated with breast cancer and are often the only mammographic sign of a malignant breast disease. Although microcalcifications are not restricted to breast cancer and can be also associated with benign lesions, it is noteworthy that they are composed exclusively of hydroxyapatite in breast carcinoma. Hydroxyapatite is the bone-associated phosphocalcic crystal the deposition of which in bone tissue requires the coordinated expression of several molecules such as osteonectin (OSN) and osteopontin (OPN), synthesized by cells of the osteoblastic lineage. In this study, we evaluated the expression of these two bone matrix proteins, using an immunoperoxidase technique and specific antibodies, in 79 breast lesions including 28 benign and 51 cancerous specimens. We found that normal mammary tissue associated with the lesions examined expressed generally undetectable or lightly detectable (0 or 1+) amounts of OSN and OPN (92 and 81%, respectively). Benign breast lesions, including fibroadenoma and fibrocystic dysplasia, were generally weakly stained (0 or 1+) with both anti-OSN and anti-OPN antibodies (96.4 and 60.7%, respectively). Interestingly, the majority of both in situ and invasive breast carcinoma lesions showed a strong expression (2+ or 3+) for OSN or OPN (74.5 and 84.3%, respectively). High expression of these two bone matrix proteins was associated with frequent microcalcification deposition in the lesion. This study is the first extensive study of OSN and OPN expression in mammary cancers. Our data suggest that OSN and OPN could play a role in the formation of ectopic microcalcifications often associated with breast cancer. It is also tempting to speculate that the expression of these two glycoproteins by breast cancer cells play a role in the preferred bone homing of breast metastases.
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PMID:Increased expression of osteonectin and osteopontin, two bone matrix proteins, in human breast cancer. 785 41

Osteopontin (OPN) is a secreted phosphoglycoprotein abundant in secretory luminal epithelia (Brown et al., 1992) and in bone (Reinholt et al., 1990). It contains a functional gly-arg-gly-asp-ser (GRGDS) integrin binding domain (Oldberg et al., 1986), promotes the adhesion of a variety of cell types (Somerman et al., 1989; Brown et al., 1992) and is a ligand for the vitronectin binding integrin alpha v beta 3 (Miyauchi et al., 1991). Elevated expression of OPN correlates with tumorigenic transformation in a great variety of stromal and epithelial cell lines (Senger et al., 1980, 1983, 1989; Craig et al., 1988; Chambers et al., 1992; Chang & Prince, 1993). The protein is also present in excess in the blood of patients with metastatic disease (Senger et al., 1988). To find whether OPN contributes significantly to the tumorigenic phenotype, we expressed antisense mRNA to OPN in high OPN producing malignant B77-Rat1 fibroblasts. This caused a reduction in their OPN secretion and reduced their ability to form both lung tumors in nude mice after intravenous injection, and colonies in soft agar. Antisense transfectants also showed increased spreading on vitronectin. These observations suggest that OPN overproduction is advantageous to the metastatic phenotype, possibly by altering adhesion via, or signal transduction from, vitronectin receptors.
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PMID:Specific reduction in osteopontin synthesis by antisense RNA inhibits the tumorigenicity of transformed Rat1 fibroblasts. 803 14

We have examined tumor progression and metastatic properties of three clonal murine mammary tumor cell lines of recent origin (D2A1, D2.OR and D2.1). These lines were derived from spontaneous mammary tumors which originated from a D2 hyperplastic alveolar nodule (HAN) line. D2A1 cells were more malignant than D2.OR or D2.1 cells, whether measured by experimental metastasis assays after intravenous injection in nude mice or chick embryos, in vivo growth rate of primary tumors following mammary fat pad injection in nude mice, or spontaneous metastasis assay from primary tumors growing in mammary fat pads. D2A1 cells also were more invasive in vitro in a Matrigel invasion assay than D2.1 cells, while the D2.OR cells were non-invasive in this assay. The increased invasiveness and malignancy of D2A1 cells were associated with increased levels of mRNA for the cysteine proteinase cathepsin L. Levels of osteopontin (OPN), nm23, int-1 and int-2 mRNAs were also examined. Nm23 levels were highest in the most malignant cell line. These cell lines provide a model for studying the tumorigenic and metastatic ability of mammary tumor cells and offer several advantages: they were cloned from mammary tumors that originate from a common source of preneoplastic cells (D2HAN); they are of relatively recent origin; and they have spontaneously arrived at different stages of tumor progression.
Clin Exp Metastasis 1993 Jan
PMID:Tumor progression and metastasis in murine D2 hyperplastic alveolar nodule mammary tumor cell lines. 842 1

The rat mammary epithelial cell line, Rama 37, yields benign, non-metastasizing adenomatous tumours in syngeneic Furth-Wistar rats. Transfection of this stably diploid cell line with genomic DNA fragments from a human metastasizing breast cancer cell line yields cells which, when injected subcutaneously in syngeneic rats, give rise to secondary tumours in a number of the animals. From one such secondary lung tumour, a cell line was established designated Ca2-5-LT1. This cell line, when introduced into the syngeneic rat host, also showed the ability to metastasise. To determine key changes in gene expression that occur during the progression from Rama 37, the benign tumour-inducing cell line, to the metastatic derivative Ca2-5-LT1, a general method of subtractive hybridization has been employed. This procedure in conjunction with Northern blotting and nucleic acid sequencing has been used to identify mRNAs expressed differentially between the metastatic and nonmetastatic cell lines described above. So far, of the subtracted cDNAs that have been identified which represent differentially expressed mRNAs, a large proportion of these cDNAs corresponded to the mRNA for rat osteopontin (OPN). The mRNA for OPN was expressed at a ninefold higher level in the metastatic Ca2-5-LT1 cell line when compared to the nonmetastatic parental Rama 37 cell line. Rama 37 cells transfected with DNA from a human benign cell line failed to show elevated levels of OPN mRNA. Following transfection of Rama 37 cells with an expression-construct producing elevated levels of OPN, the newly-transfected cells, when introduced into the rat host, developed metastases in 55% of the animals that produced primary tumours. These experiments show that increasing the expression of OPN in a previously benign cell tine is sufficient to produce a metastatic phenotype in this particular rat mammary model.
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PMID:The identification of osteopontin as a metastasis-related gene product in a rodent mammary tumour model. 870 May 59

Integrins are transmembrane glycoproteins that mediate cell-cell and cell-matrix interactions. Altered integrin expression may contribute to tumor progression, invasiveness and metastases. The alpha-V/beta-3 (alpha v beta 3; osteopontin/ vitronectin receptor) has recently been implicated in neovascularization and tumor-induced angiogenesis. alpha v-Subunit also associates with beta 5 to form an alpha v beta 5-complex, another vitronectin receptor. We studied tissue distribution of alpha v beta 3-and alpha v beta 5-integrins, as well as alpha 1- and beta 1-subunits in nephrectomy samples from 7 subjects with localized renal cell carcinoma. Grossly and histologically uninvolved regions ('normal') from the same nephrectomy specimens were used for comparison. Integrin expression was studied with specific monoclonal antibodies and the immunoperoxidase technique. alpha v beta 3 was expressed in the glomerular epithelial cells, Bowman's capsule, vascular endothelium, and weakly in tubular epithelial cells. alpha v beta 5 had a similar distribution except for minimal expression on vascular endothelium. alpha 1-Expression was observed in mesangium and but weakly in Bowman's capsule. beta 1-Expression was seen in glomerular epithelial cells, Bowman's capsule, vascular epithelium and tubular epithelial cells. Unlike in 'normals', neoplastic expression was more heterogeneous alpha v beta 3 was expressed in tumor cells in 4/7 cases, vascular endothelium in 6/6, and in stroma in 4/7. alpha v beta 5 was weakly expressed in tumor cells in 4/5, vascular endothelium in 5/5, and stroma in 4/5 cases. alpha 1-Expression was seen in tumor cells in 3/7, vascular endothelium in 4/7 and in stroma in 7/7 cases. beta 1-Expression was seen in tumor cells in 7/7 cases, vascular endothelium in 7/7, and in stroma in 4/7 cases. This study delineates the pattern of expression of the alpha v beta 3-and alpha v beta 5-integrins in 'normal' and neoplastic human kidney. Variations in alpha v beta 3-and alpha v beta 5-integrin expression may play a role in normal and neoplastic processes of the kidney.
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PMID:Alpha-V/beta-3 and alpha-V/beta-5 integrin distribution in neoplastic kidney. 888 77

CD44 is a ubiquitous multistructural and multifunctional cells surface adhesion molecule involved in cell-cell and cell-matrix interactions. Twenty exons are involved in the genomic organization of this molecule. The first five and the last 5 exons are constant, whereas the 10 exons located between these regions are subjected to alternative splicing, resulting in the generation of a variable region. Differential utilization of the 10 variable region exons, as well as variations in N-glycosylation, O-glycosylation, and glycosaminoglycanation (by heparan sulfate or chondroitin sulfate), generate multiple isoforms (at least 20 are known) of different molecular sizes (85-230 kDa). The smallest CD44 molecule (85-95 kDa), which lacks the entire variable region, is standard CD44 (CD44s). As it is expressed mainly on cells of lymphohematopoietic origin, CD44s is also known as hematopoietic CD44 (CD44H). CD44s is a single-chain molecule composed of a distal extracellular domain (containing, the ligand-binding sites), a membrane-proximal region, a transmembrane-spanning domain, and a cytoplasmic tail. The molecular sequence (with the exception of the membrane-proximal region) displays high interspecies homology. After immunological activation, T lymphocytes and other leukocytes transiently upregulate CD44 isoforms expressing variant exons (designated CD44v). A CD44 isform containing the last 3 exon products of the variable region (CD44V8-10, also known as epithelial CD44 or CD44E), is preferentially expressed on epithelial cells. The longest CD44 isoform expressing in tandem eight exons of the variable region (CD44V3-10) was detected in keratinocytes. Hyaluronic acid (HA), an important component of the extracellular matrix (ECM), is the principal, but by no means the only, ligand of CD44. Other CD44 ligands include the ECM components collagen, fibronectin, laminin, and chondroitin sulfate. Mucosal addressin, serglycin, osteopontin, and the class II invariant chain (Ii) are additional, ECM-unrelated, ligands of the molecule. In many, but not in all cases, CD44 does not bind HA unless it is stimulated by phorbol esters, activated by agonistic anti-CD44 antibody, or deglycosylated (e.g., by tunicamycin). CD44 is a multifunctional receptor involved in cell-cell and cell-ECM interactions, cell traffic, lymph node homing, presentation of chemokines and growth factors to traveling cells, and transmission of growth signals. CD44 also participates in the uptake and intracellular degradation of HA, as well as in transmission of signals mediating hematopoiesis and apoptosis. Many cancer cell types as well as their metastases express high levels of CD44. Whereas some tumors, such as gliomas, exclusively express standard CD44, other neoplasms, including gastrointestinal cancer, bladder cancer, uterine cervical cancer, breast cancer and non-Hodgkin's lymphomas, also express CD44 variants. Hence CD44, particularly its variants, may be used as diagnostic or prognostic markers of at least some human malignant diseases. Furthermore, it has been shown in animal models that injection of reagents interfering with CD44-ligand interaction (e.g., CD44s- or CD44v-specific antibodies) inhibit local tumor growth and metastatic spread. These findings suggest that CD44 may confer a growth advantage on some neoplastic cells and, therefore, could be used as a target for cancer therapy. It is hoped that identification of CD44 variants expressed on cancer but not on normal cells will lead to the development of anti-CD44 reagents restricted to the neoplastic growth.
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PMID:CD44: structure, function, and association with the malignant process. 911 68

CD44 is a family of transmembrane glycoproteins that act mainly as a receptor for hyaluronan. It can also bind some other extracellular matrix ligands (chondroitin sulphate, heparan sulphate, fibronectin, serglycin, osteopontin) with lower affinity. CD44 is encoded by a single gene containing 20 exons, 10 of which (v1-v10) are variant exons inserted by alternative splicing. The standard, ubiquitously expressed isoform of CD44, does not contain sequences encoded by these variant exons. Numerous variant isoforms of CD44 containing different combinations of exons v1-v10 inserted into the extracellular domain can be expressed in proliferating epithelial cells and activated lymphocytes. CD44 plays a significant role in lymphocyte homing. Both alternative splicing and glycosylation influence receptor function of the molecule, usually reducing its affinity to hyaluronan. The cytoplasmic domain of CD44 communicates with the cytoskeleton via ankyrin and proteins belonging to the ezrin-moesin-radixin family. Relatively little is known about the intracellular events following interactions of CD44 with its ligands. Some variant isoforms, especially those containing sequences encoded by v6-v10, are overexpressed in both human and animal neoplasms. In a rat pancreatic adenocarcinoma model one of the variant CD44 isoforms was proved to be determinant in the metastatic process. For some human neoplasms (carcinomas of the digestive tract, non-Hodgkin's lymphomas, thyroid carcinomas, and others) correlations have been made between the particular pattern of CD44 variants produced by neoplastic cells and clinicopathological parameters of tumours, such as grade, stage, presence of metastases, and survival. In vitro studies indicate that modifications of CD44 expression result in different ligand recognition and influence cell motility, invasive properties, and metastatic potential of experimental tumours. Investigation of CD44 neoexpression can be useful both in early cancer diagnosis and in predicting tumour behaviour. It can also contribute to better understanding of molecular mechanisms leading to neoplastic transformation.
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PMID:CD44 and the adhesion of neoplastic cells. 923 Nov 52

Tumor cells exposed to a growth stress such as low pH, glucose starvation and hypoxia have been shown to exhibit a transient increase in experimental metastatic potential, particularly when allowed to recover under normal growth conditions for a period of 24-48 h. In this study we examined whether this increase in metastatic ability could be explained by changes in the expression of a number of different metastasis-associated genes, when the cells were exposed to similar conditions (24-48 h exposure to the stress condition followed by 0-48 h recovery under normal growth conditions). Although the cell lines used (KHT fibrosarcoma, SCC VII squamous cell carcinoma, and B16F1 melanoma) demonstrated altered metastatic ability after the treatment, no overall temporal correlation between changes in the mRNA levels for cathepsin B, cathepsin L, nm23, TIMP-1, osteopontin, or VEGF and metastatic ability in the three cell lines was observed. The production of gelatinase A (72 kDa collagenase) and gelatinase B (92 kDa collagenase) was also measured by gelatin zymography. There was an increase in production of these enzymes with increasing recovery time, but it did not parallel changes in metastatic potential. Although these results suggest that the products of most of the genes studied may not be involved in the transient metastatic changes, further studies are required to establish whether changes in protein levels track with changes in mRNA levels for these genes.
Clin Exp Metastasis 1997 Sep
PMID:An examination of the effects of hypoxia, acidosis, and glucose starvation on the expression of metastasis-associated genes in murine tumor cells. 924 50


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