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)

S100A4(mts1) protein expression has been strongly associated with metastatic tumor progression. It has been suggested as a prognostic marker for a number of human cancers. It is proposed that extracellular S100A4 accelerates cancer progression by stimulating the motility of endothelial cells, thereby promoting angiogenesis. Here we show that in 3D culture mouse endothelial cells (SVEC 4-10) respond to recombinant S100A4 by stimulating invasive growth of capillary-like structures. The outgrowth is not dependent on the stimulation of cell proliferation, but rather correlates with the transcriptional modulation of genes involved in the proteolytic degradation of extracellular matrix (ECM). Treatment of SVEC 4-10 with the S100A4 protein leads to the transcriptional activation of collagenase 3 (MMP-13) mRNA followed by subsequent release of the protein from the cells. Beta-casein zymography demonstrates enhancement of proteolytic activity associated with MMP-13. This observation indicates that extracellular S100A4 stimulates the production of ECM degrading enzymes from endothelial cells, thereby stimulating the remodeling of ECM. This could explain the angiogenic and metastasis-stimulating activity of S100A4(mts1).
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PMID:Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity. 1512 22

Mts1 (S100A4) is a calcium-binding protein of the EF-hand type, belonging to the S100 family of proteins. The mts1/S100A4 gene was originally isolated from tumor cell lines, and the protein is believed to play an important role in tumor progression. More recently, oligomeric, but not dimeric, forms of Mts1 have been shown to have a neuritogenic effect when added extracellularly to hippocampal neurons. Here we show increased neurite outgrowth in two other cell types, dopaminergic and cerebellar neurons, in response to treatment with Mts1 oligomers. Moreover, we demonstrate that Mts1 acts as a neuroprotectant in primary cerebellar, dopaminergic, and hippocampal neurons induced to undergo cell death. Interestingly, the survival of the cerebellar and hippocampal neurons increased as a result of treatment with Mts1 not only in oligomeric form but also--although to a lesser extent--in dimeric form. The inhibition of death in cerebellar neurons by Mts1 was accompanied by an inhibition of DNA fragmentation, but Mts1 did not affect the activity of caspases-3 and -6. In hippocampal neurons, cell death induced by the amyloid-beta peptide (Abeta(25-35)) was characterized by an increase in caspase-3 and -6 activity, but no DNA fragmentation was observed. As in cerebellar neurons, the induced increase in caspase activity in hippocampal neurons was not affected by Mts1.
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PMID:The Mts1/S100A4 protein is a neuroprotectant. 1533 97

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

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

Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription-polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P=0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P=0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P=0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P=0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P=0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4.
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PMID:Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes. 1636 3

S100A4 (Mts1) belongs to the S100 family of calcium binding proteins, which are involved in diverse biological regulatory activities. An association between S100A4 and tumor progression has been demonstrated in several studies. S100A4 binds to distinct intracellular target proteins and regulates specific functions involved in tumor progression such as cell motility, proliferation and apoptosis as well as remodelling of the extracellular matrix. Once released from the tumor or tumor-activated stromal cells, it may influence certain functions of target cells towards a more aggressive phenotype. Extracellular S100A4 has been demonstrated to contribute to angiogenesis and the increased production of matrix-degrading enzymes by both endothelial and tumor cells. Moreover, S100A4 might be responsible for TCRgammadelta T-cell mediated lysis and negative regulation of matrix mineralization. Increased expression of S100A4 mRNA has recently been found in proliferating rheumatoid arthritis synovial fibroblasts and synovial tissues from rheumatoid arthritis patients. Synovial hyperplasia in rheumatoid arthritis consists of inflammatory cells and activated synovial lining cells which contribute to the progressive destruction of the joints during the disease. Since several phenomena are similar between rheumatoid arthritis and malignant tumors it can be hypothesized that S100A4 contributes to the invasive and tumor-like behavior of rheumatoid arthritis synovium.
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PMID:S100A4 (Mts1): is there any relation to the pathogenesis of rheumatoid arthritis? 1643 43

The calcium-binding protein, S100A4, with an inverse association of E-cadherin, is known to correlate with prognosis in various cancers. In this study, we investigated the expression of the S100A4 and E-cadherin status in relation to the clinicopathological parameters of pancreatic cancer. The expression status of these two proteins was examined in 72 specimens of primary pancreatic carcinoma with immunohistochemistry. Fifty-six of 72 (78%) surgical specimens of primary pancreatic cancer were positive for S100A4 according to immunohistochemistry. Thirty-one (43%) specimens of pancreatic cancer showed positive expression of E-cadherin. The inverse association of S100A4 and E-cadherin expression was significant in the cancers (p < 0.0001). The S100A4 expression correlated significantly with the pathological T stage and poorer prognosis (p = 0.024). The 41 E-cadherin-negative cases showed poorer prognoses and a higher incidence of liver metastasis (p = 0.0344, p = 0.027). The 10 cases with S100A4-negative/E-cadherin-positive cancers showed a significantly better prognosis than the others (p < 0.05). The histological grade (p = 0.004), nodal status (p < 0.0001) and S100A4-positive status (p = 0.048) were highly significant independent prognostic predictors (p < 0.05). These results suggest that S100A4 overexpression combined with reduced E-cadherin expression play important roles in tumor progression and metastasis in pancreatic cancer. The combined examination of these two molecules is useful in evaluating the outcome of pancreatic cancer patient.
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PMID:Increased S100A4 expression combined with decreased E-cadherin expression predicts a poor outcome of patients with pancreatic cancer. 1686 43

A remarkable change has occurred in the thinking about epithelial-derived cancer in recent years: From almost entirely focusing on oncogenes and tumor suppressor genes has come the realization that the tumor microenvironment is a coconspirator in the carcinogenic process. Many types of stromal cells, including fibroblasts, adipocytes, macrophages, mast cells, and cells of the vascular system, are crucial contributors to epithelial carcinogenesis. Here, we focus on the fibroblast's role in cancer progression and the molecules involved in the communications between the fibroblasts and the cancer cells, including fibroblast secreted protein 1 (FSP-1 or S100A4), transforming growth factor beta (TGF-beta), the chemokine CXCL-12 (stromal derived factor 1 alpha, SDF-1alpha), type I collagen, and matrix metalloproteinase 13 (MMP-13).
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PMID:The fibroblastic coconspirator in cancer progression. 1686 75

Identification of in vivo secreted peptides/proteins (secretomes) in tumor masses has the potential to provide important biomarkers and therapeutic targets for cancer therapy. However, limitations of existing technologies have made obtaining these secretomes for analysis extremely difficult. Here we employed an in vivo sampling technique using capillary ultrafiltration (CUF) probes to collect secretomes directly from tumor masses. Mass spectrometric proteomics approaches were then used to identify the tumor secretomes. A UV-induced skin fibrosarcoma cell line (UV-2240) was subcutaneously injected into C3H/NeH mice, resulting in tumor masses that initially progressed, then regressed and eventually eradicated. We then implanted CUF probes into tumor masses at the progressive and regressive stage. Five secreted proteins (cyclophilin-A, S100A4, profilin-1, thymosin beta 4 and 10), previously associated with tumor progression, were identified from tumor masses at the progressive stage. Five secreted proteins including three protease inhibitors (fetuin-A, alpha-1 antitrypsin 1-6, and contrapsin) were identified from tumor masses at the regressive stage. The technique involving CUF probes linked to mass spectrometric proteomics reinforces systems biology studies of cell-cell interactions and is potentially applicable to the discovery of in vivo biomarkers in human disease.
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PMID:Mass spectrometric proteomics profiles of in vivo tumor secretomes: capillary ultrafiltration sampling of regressive tumor masses. 1705 43


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