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)

Tumor cell invasion and metastasis are the hallmark of malignant neoplasm. Despite advances in the management of thyroid carcinoma and other solid tumors, metastasis continues to be the most significant cause in cancer mortality. To gain new insights into this complex process in thyroid carcinoma, we established a thyroid carcinoma cell line (ARO-met2) with high metastatic capacity to the lung by sequential passage of a human anaplastic thyroid cancer cell line (ARO) through the lung of a nude mouse. Global patterns of gene expression were analyzed in cells of the parental ARO and the ARO-met2, using Atlas human cancer 1.2 array with 1176 cancer-related genes. In total, 184 genes were differentially expressed more than 1.5 times, and 64 genes were differentially expressed over two times. Among those 64 genes, 43 were overexpressed, and 21 genes were underexpressed. Many genes whose increased expression was thought to be related to tumor progression were identified, such as c-Met, ezrin, integrin, motility-related protein-1, cadherin, and S100A4. The most highly expressed gene is the S100A4 (8-fold higher than control), which is a member of a small calcium binding protein family and is involved in the cell proliferation and cancer progression. The S100A4 overexpression in the ARO-met2 cells was later confirmed by Northern blot and real-time reverse transcriptase-PCR. Analysis of 49 thyroid tumor specimens by real-time reverse transcriptase-PCR (eight benign goiters, 36 papillary, and five anaplastic carcinomas) revealed that S100A4 overexpression was present in most advanced thyroid carcinomas and lymph node metastases, and was associated with poor prognosis. None of the benign goiters was found to have S100A4 overexpression. These data suggest that S100A4 could be used as a prognostic marker for thyroid carcinoma. Given that S100A4 is involved in tumor progression and metastasis, it may be a potential target for therapeutic intervention.
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PMID:Microarray analysis of metastasis-associated gene expression profiling in a murine model of thyroid carcinoma pulmonary metastasis: identification of S100A4 (Mts1) gene overexpression as a poor prognostic marker for thyroid carcinoma. 1557 71

The S100A4(mts1) protein stimulates metastatic spread of tumor cells. An elevated expression of S100A4 is associated with poor prognosis in many human cancers. Dynamics of tumor development were studied in S100A4-deficient mice using grafts of CSML100, highly metastatic mouse mammary carcinoma cells. A significant delay in tumor uptake and decreased tumor incidences were observed in S100A4(-/-) mice compared with the wild-type controls. Moreover, tumors developed in S100A4(-/-) mice never metastasize. Immunohistochemical analyses of these tumors revealed reduced vascularity and abnormal distribution of host-derived stroma cells. Coinjection of CSML100 cells with immortalized S100A4(+/+) fibroblasts partially restored the dynamics of tumor development and the ability to form metastasis. These fibroblasts were characterized by an enhanced motility and invasiveness in comparison with S100A4(-/-) fibroblasts, as well as by the ability to release S100A4 into the tumor environment. Taken together, our results point to a determinative role of host-derived stroma cells expressing S100A4 in tumor progression and metastasis.
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PMID:Suppression of tumor development and metastasis formation in mice lacking the S100A4(mts1) gene. 1586 73

Tumor xenografts in immune-deficient mice (athymic nude mice and SCID mice) are well-established animal models for the study of human cancer. Several human melanoma cell lines were reported to metastasize in the immune-deficient mice models. However, metastatic rates were extremely low in spite of large numbers of injections of cancer cells, more than 1 x 10(6) cells/mouse. The NOD/SCID/gamma(C)(null) (NOG) mouse shows multiple immunological dysfunctions, including cytokine production capability, in addition to the functional incompetence of T, B and natural killer (NK) cells. However, the immune-deficient mice, with preserved NK cell activity, might interfere with engraftment efficiency. We examined the distant metastasis of the human melanoma cell lines (A2058, A375, G361 and HMY-1, 1 x 10(4) cells/mouse) in the 6 weeks after intravenous inoculation. All four melanoma cell lines showed metastasis in the NOG mice, while no metastatic lesions were observed in the NOD/SCID mice. Metastatic lesions were noted in the liver and lung of 6/6 (100%) mice at A2058, 8/9 (89%) at A375, 2/6 (33%) at G361 and 2/8 (25%) at HMY-1. A2058 and A375 cell lines with high metastatic potentials show increased gene expression of S100A4. Western blot assay confirmed the increased protein levels of S100A4 in the A2058 and A375 cell lines. E-cadherin gene expression was conversely inhibited in these cell lines. The increased expression of S100A4 combined with inhibited E-cadherin expression resulted in high metastatic potentials of the human melanoma cell lines in vivo.
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PMID:S100A4 expression with reduced E-cadherin expression predicts distant metastasis of human malignant melanoma cell lines in the NOD/SCID/gammaCnull (NOG) mouse model. 1607 66

Tumour cell invasion and metastasis are the hallmark of malignant neoplasm. S100A4 is a member of small calcium-binding protein family and is involved in the cell proliferation and cancer progression. S100A4 is capable of inducing metastasis in animal models and is associated with aggressive phenotype of human tumours. We previously identified S100A4 as a candidate gene involved in anaplastic thyroid cancer metastasis by microarray analysis. To further determine whether S100A4 overexpression is associated with thyroid tumour invasion and metastasis, in the present study, we examined S100A4 gene expression in six benign multinodular goitres (MNG) and 28 matched samples of adjacent normal thyroid tissue (N), primary (T) and metastatic (M) papillary thyroid carcinomas (PTC) by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. This gave us the advantage of directly comparing levels of S100A4 expression within the same genetic background. Using immunohistochemistry, we found that high levels of S100A4 were detected in 24 of 28 (86%) PTC specimens and their local regional lymph node or distant metastases. No S100A4 staining was observed in normal thyroid tissues and simple MNG. However, in MNG coexistent with PTC, moderate focal staining could be found in 11 of 15 MNG adjacent to PTC. The S100A4 was stained more intensely in invading fronts than in central portions of both T and M. Real-time RT-PCR analysis of primary tumours and their matched lymph node metastasis demonstrated that significantly higher S100A4 transcripts were present in metastatic tumours as compared to the primary tumours (P<0.01). These data suggest that overexpression of S100A4 is associated with thyroid tumour invasion and metastasis and it may be a potential target for therapeutic intervention.
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PMID:S100A4 (Mts1) gene overexpression is associated with invasion and metastasis of papillary thyroid carcinoma. 1626 47

To study the effect of RAB5A gene on microfilaments in human lung adenocarcinoma cells, AGZY83-a cells were stained with fluorescein isothiocyanate (FITC)-phalloidin. Microfilament bundles in RAB5A gene over-expressed AGZY83-a cells were shown to be denser than in control cells using confocal laser scanning microscope (CLSM). According to the analysis of Tumor Metastasis Microarray on RAB5A gene, three genes related to the regulation of cytoskeleton were identified, including NM23H1, Rac1 (downregulated in RAB5A over expressing cells), and S100A4 (upregulated in RAB5A overexpressing cells). Previous studies demonstrated that S100A4 gene functioned to suppress the expression of NM23H1 gene. To test if this elevated expression of S100A4 results in the down-regulation of NM23H1, RNAi was applied to silence the expression of S100A4 in AGZY83-a cells. Our data indicated that expression of NM23H1 was increased following the inhibition of S100A4 expression. Altogether, the results indicated that RAB5A gene was involved in the suppression of expression of NM23H1 by promoting the expression of S100A4.
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PMID:The effect of RAB5A gene on rearrangement of microfilaments in human lung adenocarcinoma cells. 1645 50

Metastatic breast cancer cells exhibit the selective ability to seed and grow in the skeleton. We and others have previously reported that human breast tumors which metastasize to the skeleton overexpress bone matrix extracellular proteins. In an attempt to reveal the osteoblast-like phenotype of osteotropic breast cancer cells, we performed a microarray study on a model of breast cancer bone metastasis consisting of the MDA-MB-231 human cell line and its variant B02 selected for its high capacity to form bone metastases in vivo. Analysis of B02 cells transcriptional profile revealed that 11 and 9 out of the 50 most up- and down-regulated mRNAs, respectively, corresponded to genes which expression has been previously associated with osteoblastic differentiation process. Thus, osteoblast specific cadherin 11 which mediates the differentiation of mesenchymal cells into osteoblastic cells is up-regulated in B02. While S100A4, recently described as a key negative regulator of osteoblast differentiation, is the most down-regulated gene in B02 cells. RT-PCR and western blotting experiments allowed the validation of the modulation of several genes of interest. Using immunohistochemistry, performed on human breast primary tumors and their matched liver and bone metastases, we were able to confirm that the osteoblast-like pattern of gene expression observed in our model holds true in vivo. This is the first report demonstrating a gene-expression pattern corresponding to the acquisition of an osteomimetic phenotype by bone metastatic breast cancer cells.
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PMID:Transcriptome analysis reveals an osteoblast-like phenotype for human osteotropic breast cancer cells. 1702 89

The detection of papillary microcarcinomas of the thyroid is increasing due to frequent use of ultrasound and fine-needle aspiration biopsy. Although most of the papillary microcarcinomas remain quiescent and follow an indolent clinical course, some behave aggressively and metastasize early, giving rise to clinically significant disease. There have been few studies concerning factors predictive of lymph node metastasis in papillary microcarcinomas. We analyzed the expression of S100A4, cyclin D1, p27 and MUC1, the presence of the BRAF V600E mutation and the clinicopathological features of the tumors, including patient age, tumor size (>or=5 vs <5 mm), extrathyroidal extension, multifocality, histological subtype, sclerosis and encapsulation, in a series of 198 papillary microcarcinomas in relation to lymph node metastasis to determine the predictive factors of lymph node metastasis. On univariate analysis, tumor size of 5 mm or more, extrathyroidal extension, multifocality, sclerosis and the expression of S100A4 and cyclin D1 predicted lymph node metastasis, whereas patient age, expression of p27 and MUC1 and the BRAF V600E mutation did not. Moreover, tumor size 5 mm or more, multifocality and expression of S100A4, especially its strong expression in the invasive fronts, were significantly associated with macrometastasis and lateral node metastasis. On multivariate analysis, multifocality and expression of S100A4 were found to be common independent predictive factors of lymph node metastasis, macrometastases, and lateral node metastasis. In conclusion, S100A4 expression in papillary microcarcinomas may indicate the presence of nodal metastasis. Thus, S100A4 immunohistochemistry may be valuable for predicting metastatic potential in papillary microcarcinomas.
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PMID:S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid. 1836 Mar 53

S100A4 promotes cancer metastasis, but its overall status and splicing manner during gastrocarcinogenesis remains less known. We therefore examined S100A4 frequencies, splicing pattern(s) and the underlying reason(s) for S100A4 expression in gastric cancers. Immunohistochemistry revealed frequent S100A4 expression in intestinal gastric cancers (37/45; 82%) and diffuse gastric cancers (12/20; 60%), but uncommon in noncancerous epithelia (0/12), chronic gastritis (2/24; 8%), and intestinal metaplasia (3/15; 20%). Of 65 primary tumors, 18 were found with focal S100A4 expression, while their LN metastases showed homogenous distribution. S100A4-oriented reverse transcription-polymerase chain reaction yielded a transcript containing exons 1, 3, and 4 (AS1) in 20% of noncancerous, 84% premalignant, and 92% tumor tissues and a transcript harboring exons 1 to 4 (AS2) in 65% of gastric cancers (GCs), 26% premalignant but none in noncancerous tissues. Further analyses found AS1 expression in stromal but not epithelial cells of premalignant tissues, absence of AS2 in endoscopic inflammatory mucosa, and the coexistence of AS1/AS2 in the cultured fibroblasts. Methylation DNA sequencing revealed hypermethylation of four critical CpG sites within S100A4 intron first among S100A4-negative gastric tissues and hypomethylation in S100A4-expressing GC tissues/cell lines. E-cadherin reduction and Wnt activation were common in gastric cancers, which were closely correlated but unnecessarily overlapped with S100A4 expression. Our findings suggest that S100A4 expression is closely related with GC formation, which, as a hypomethylation event, is accompanied with E-cadherin reduction and Wnt activation. The preferential S100A4 AS2 expression in GC cells would have potential values in GC surveillance and prognostic assessment.
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PMID:Frequent S100A4 Expression with Unique Splicing Pattern in Gastric Cancers: A Hypomethylation Event Paralleled with E-cadherin Reduction and Wnt Activation. 1904 27

The present study analyzed the site-specific expression and clinical role of S100A4 in advanced-stage ovarian carcinoma (OC). S100A4 expression was analyzed in 161 effusions, 67 primary carcinomas and 127 solid metastases using immunohistochemistry. S100A4 levels were additionally measured in 20 effusion supernatants using the immunofluorometric assay IFMA. Cytoplasmic and nuclear S100A4 was detected in cancer cells at all anatomic sites, while myofibroblasts in solid tumors expressed only cytoplasmic S100A4. Nuclear expression was higher in solid tumors than in effusions (p < 0.001), while stromal cell expression was higher in metastases than primary tumors (p = 0.001). IFMA analysis detected S100A4 in all 20 supernatants. Nuclear S100A4 expression in primary carcinomas (p = 0.049), FIGO stage IV (p = 0.019) and poor response to chemotherapy at diagnosis (p < 0.001) were associated with worse overall survival. All three parameters were independent prognosticators in Cox analysis (S100A4: p = 0.048, FIGO stage: p = 0.015, response to chemotherapy: p < 0.001). S100A4 is frequently expressed in tumor and host cells in OC, with upregulated stromal expression in solid metastases. Tumor cell nuclear S100A4 expression is higher in solid tumors than in effusions, and is associated with more aggressive clinical disease in primary carcinoma, suggesting that the tumor-promoting role of this molecule is predominantly exerted at this anatomic site.
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PMID:Different expression and clinical role of S100A4 in serous ovarian carcinoma at different anatomic sites. 1919 11

Integrin alpha6beta4 is linked to cancer cell motility and invasion in aggressive and metastatic cancer cells. In this study, we showed that expression of the beta4 integrin in MDA-MB-435 cancer cells (MDA-MB-435/beta4) leads to a dramatic increase in expression of a metastasis-promoting factor, S100A4, as determined by affymetrix gene chip microarray, quantitative real-time PCR, and Western blot analysis. Alternatively, knocking down beta4 integrin expression in MDA-MB-231 breast carcinoma cells by shRNA reduced the level of S100A4 expression. The mechanism by which alpha6beta4 enhances S100A4 expression involves Src, Akt, and NFAT. We have further shown that Y1494, a tyrosine residue of the ITIM motif in the cytoplasmic domain of the beta4 integrin subunit, is essential for alpha6beta4-dependent S100A4 expression. Reduction of S100A4 expression by shRNA blocked migration, invasion, and anchorage-independent growth of MDA-MB-435/beta4, SUM-159, and MDA-MB-231 cells. These studies define a novel mechanism by which integrin alpha6beta4 promotes cancer cell motility and invasion, and provides insight into how S100A4 expression is regulated in cancer cells.
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PMID:Integrin (alpha6beta4) signals through Src to increase expression of S100A4, a metastasis-promoting factor: implications for cancer cell invasion. 1980 5


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