Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05109 (S100A8)
 1,212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cross-talk between tumour cells and the surrounding supporting host cells (stroma) is a key regulator of cancer growth and progression. By undertaking 2-DE analysis of laser capture microdissected malignant and stromal components of pancreatic tumours and benign ductal elements, we have identified high levels of S100A8 and S100A9 in tumour-associated stroma but not in benign or malignant epithelia. Immunohistochemical analysis (n = 71 patients) revealed strong expression of both proteins in stromal myeloid cells, subsequently identified as CD14(+)/CD68(- )monocytes/macrophages. Co-immunofluorescence revealed that S100A8 was expressed in a subset of S100A9-positive cells. Correlation of the expression of S100A8 and S100A9 to patient parameters revealed that the microenvironments of tumours which lacked expression of the tumour suppressor protein, Smad4, had significantly reduced numbers of S100A8-immunoreactive (p = 0.023) but not S100A9-immunoreactive (p = 0.21) cells. The ratio of S100A8- to S100A9-positive cells within individual tumours was significantly lower in Smad4-negative tumours than in Smad4-positive tumours (p<0.003). Pancreatitic specimens also contained S100A8- and S100A9-expressing cells, although this was not observed in regions displaying extensive fibrosis. In conclusion, our study provides an extensive analysis of S100A8 and S100A9 in pancreatic disease and highlights a potentially important relationship between pancreatic cancer cells and their surrounding microenvironment.
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PMID:The expression of S100A8 in pancreatic cancer-associated monocytes is associated with the Smad4 status of pancreatic cancer cells. 1746 85

The S100 gene family, which is composed of at least 24 members carrying the Ca2+ binding EF-hand motif, has been implicated in both intracellular and extracellular functions, including enzyme activities, immune responses, cytoskeleton dynamics, Ca2+ homeostasis, cell growth and cell differentiation. Altered S100 protein levels are associated with a broad range of diseases, including cardiomyopathy, inflammatory and immune disorders, neurodegenerative disorders and cancer. Although the precise role of S100 protein in carcinogenesis is poorly understood, it seems that formation of homo- and hetero-dimers, binding of Ca2+ and interaction with effector molecules are essential for the development and progression of many cancers. Several studies have suggested that S100 proteins promote cancer progression and metastasis through cell survival and apoptosis pathways. In animal models of bladder cancer, several S100 proteins are differentially expressed in bladder tumors relative to normal urothelium. In human bladder cancer, overexpression of S100A4, S100A8 or S100A11 are associated with stage progression, invasion, metastasis and poor survival. This review summarizes these findings and evaluates their implications for human bladder cancer management.
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PMID:The S100 proteins for screening and prognostic grading of bladder cancer. 1752 80

Squamous cell carcinoma in the lung originates from bronchial epithelial cells that acquire increasingly abnormal phenotypes. Currently, no known biomarkers are clinically efficient for the early detection of premalignant lesions and lung cancer. We sought to identify secreted molecules produced from squamous bronchial epithelial cells cultured with organotypic culture methods. We analyzed protein expression patterns in the apical surface fluid (ASF) from aberrantly differentiated squamous metaplastic normal human tracheobronchial epithelial (NHTBE) and mucous NHTBE cells. Comparative two-dimensional PAGE analysis revealed 174 unique proteins in the ASF of squamous NHTBE cells compared with normal mucociliary differentiated NHTBE cells. Among them, 64 well-separated protein spots were identified by liquid chromatography-tandem mass spectrometry, revealing 22 different proteins in the ASF from squamous NHTBE cells. Expression of six of these proteins [SCC antigen 1 (SCCA1), SCC antigen 2 (SCCA2), S100A8, S100A9, Annexin I, and Annexin II] in the squamous NHTBE cells was further confirmed with immunoblot analysis. Notably, SCCA1 and SCCA2 were verified as being expressed in squamous metaplastic NHTBE cells but not in normal mucous NHTBE or normal bronchial epithelium. Moreover, SCCA1 and SCCA2 expression increased in in vitro lung carcinogenesis model cell lines with increasing malignancy. In summary, we identified proteins that are uniquely secreted from squamous metaplastic primary human bronchial epithelial cells cultured by the organotypic air-liquid interface method. These ASF proteins may be used to detect abnormal lesions in the lung without collecting invasive biopsy specimens.
Cancer Res 2007 Jul 15
PMID:Proteomics-based identification of proteins secreted in apical surface fluid of squamous metaplastic human tracheobronchial epithelial cells cultured by three-dimensional organotypic air-liquid interface method. 1763 65

Canonical TGF-beta is involved in cell differentiation, tissue maintenance, and wound healing, but also plays a central role in the pathogenesis of diseases such as cancer Here we describe a lentivirus-based reporter vector system expressing green fluorescent protein (GFP) or red fluorescent protein (RFP) under the control of a Smad3-responsive element (CAGA)12 that allows observation of the temporospatial pattern of endogeneous Smad3-mediated signaling on a cellular level. Use of this method will be valuable to identify cells with active Smad3 signaling and investigate the role of endogenous Smad3 signaling in complex systems such as co-cultures in vitro, or in tumors during tumor cell invasion and metastasis in vivo.
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PMID:Lentiviral reporter constructs for fluorescence tracking of the temporospatial pattern of Smad3 signaling. 1790 71

Activin is a member of the transforming growth factor beta superfamily that regulates mammary cell function during development, lactation, and in cancer. Activin slows the growth of breast cancer cells by inducing G(0)/G(1) cell cycle arrest. Estrogen is a steroid hormone that stimulates the proliferation of mammary epithelial cells in development and oncogenesis. The crosstalk between estrogen and activin that regulates activin ligand expression, activin and estrogen signal transduction, and cell cycle arrest was investigated in this study. Estrogen antagonized activin-dependent production of plasminogen activator inhibitor 1 (PAI-1) mRNA, while activin repressed estrogen-dependent transcription of trefoil factor 1. The repression of estrogen signaling by activin was recapitulated using a simple estrogen response element-luciferase construct and was enhanced in the presence of overexpressed estrogen receptor alpha (ERalpha). In contrast, estrogen-mediated repression of activin signaling could not be recapitulated on a simple CAGA Smad-binding element but did inhibit the short PAI-1 promoter, p3TP-luciferase, especially when ERalpha was overexpressed. Repression of both estrogen- and activin-regulated transcription was found to be ligand induced and Smad3 dependent. In addition to transcriptional repression, estrogen also reduced the amount of activin B mRNA and protein produced by MCF7 breast cancer cells. These studies demonstrate the importance of activin and estrogen crosstalk during mammary cell growth and cancer initiation.
Endocr Relat Cancer 2007 Sep
PMID:Activin and estrogen crosstalk regulates transcription in human breast cancer cells. 1791 98

S100 protein A8 and A9 naturally form a stable heterocomplex. Recently, we have proved that S100A9 overexpression in various adenocarcinomas is associated with poor tumor differentiation. In this study, we examined the relationship between the expression of each protein and the pathological parameters that reflect the aggressiveness of carcinoma, in invasive ductal carcinoma (IDC) of the breast. Serial paraffin-embedded tissue sections from 101 IDC cases were immunostained with respective monoclonal antibodies, and the results were as follows: 1) A positive correlation of immunoreactivity between S100A8 and S100A9 was noticed (r=0.873 and P<0.0001); 2) The percentage of S100A9-positive tumor cells was higher than that of S100A8-positive tumor cells (P<0.001), and S100A8 alone was not detected in any case; 3) Overlap between S100A8 and S100A9 staining patterns was found in the corresponding tissue areas, but S100A9 positivity was also observed in S100A8-negative tumor cells; 4) The immunopositivity for each protein also correlated with the mitotic activity, MIB-1 index, HER2 overexpression, node metastasis, and poor pT categories and pStage (P<0.05); 5) Co-expression of both proteins was associated with poor tumor differentiation, vessel invasion, node metastasis, and poor pStage (P<0.05). Furthermore, co-expression of the proteins was also observed in MCF-7 cells, and it was suggested that the immunolocalization is related with cell cycle. Our conclusions are as follows: 1) It is suggested that S100A8 is S100A9-dependently expressed and acquires the protein stability by S100A8/A9 heterocomplex formation; 2) S100A8 and S100A9 overexpression should be considered marker of poor prognosis in IDC.
Curr Cancer Drug Targets 2008 Jun
PMID:S100A8 and S100A9 overexpression is associated with poor pathological parameters in invasive ductal carcinoma of the breast. 1853 48

Doxorubicin is a DNA-damaging drug, commonly used for treatment of cancer patients. Doxorubicin causes not only cytotoxic and cytostatic effects, but also inhibits metastasis formation, while TGFbeta1 (Transforming Growth Factor-beta1) is a cytokine that is often up-regulated in human cancers and can promote metastasis formation. We have studied the influence of Doxorubicin on TGFbeta signaling in tumor cells. Here we have demonstrated that Doxorubicin inhibited TGFbeta-signaling in human lung adenocarcinoma A549 cells, namely, it blocked TGFbeta1-induced activation of Smad3-responsive CAGA(12)-Luc reporter, but did not affect c-myc-Luc reporter. That effect was observed as early as after 1-3 h of treating these cells with Doxorubicin, while the other drugs cisplatin or methotrexate did not alter activation of CAGA(12)-Luc reporter under the same conditions. Besides, after 1 h action, Doxorubicin abrogated TGFbeta-induced translocation of Smad3-protein from the cytoplasm to the nucleus. Down-regulation of expression of Smad2, Smad3, and Smad4 proteins, and up-regulation of inhibitory Smad7 protein upon Doxorubicin treatment, were found after 12-24 h of Doxorubicin treatment. Phosphorylation of Smad2/3 proteins was also affected by Doxorubicin. Summarizing, we have found that human tumor cells treatment with Doxorubicin resulted in the inhibition of TGFbeta-signaling at both early (1 h) and later (12 h) stages of the drug action. Such inhibition can be a new potential mechanism for Doxorubicin action towards tumor cells.
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PMID:Doxorubicin inhibits TGF-beta signaling in human lung carcinoma A549 cells. 1860 4

Patients with inflammatory bowel diseases are at increased risk for colorectal cancer, but the molecular mechanisms linking inflammation and cancer are not well defined. We earlier showed that carboxylated N-glycans expressed on receptor for advanced glycation end products (RAGE) and other glycoproteins mediate colitis through activation of nuclear factor kappa B (NF-kappaB). Because NF-kappaB signaling plays a critical role in the molecular pathogenesis of colitis-associated cancer (CAC), we reasoned that carboxylated glycans, RAGE and its ligands might promote CAC. Carboxylated glycans are expressed on a subpopulation of RAGE on colon cancer cells and mediate S100A8/A9 binding to RAGE. Colon tumor cells express binding sites for S100A8/A9 and binding leads to activation of NF-kappaB and tumor cell proliferation. Binding, downstream signaling and tumor cell proliferation are blocked by mAbGB3.1, an anti-carboxylate glycan antibody, and by anti-RAGE. In human colon tumor tissues and in a mouse model of CAC, we found that myeloid progenitors expressing S100A8 and S100A9 infiltrate regions of dysplasia and adenoma. mAbGB3.1 administration markedly reduces chronic inflammation and tumorigenesis in the mouse model of CAC and RAGE-deficient mice are resistant to the onset of CAC. These findings show that RAGE, carboxylated glycans and S100A8/A9 play essential roles in tumor-stromal interactions, leading to inflammation-associated colon carcinogenesis.
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PMID:RAGE, carboxylated glycans and S100A8/A9 play essential roles in colitis-associated carcinogenesis. 1868 72

Keratinocytes can be induced to produce cytokines by exogenous stimuli, such as UVB, and dysregulation of this production has been described in various skin diseases, including cancer. In this study, we compared the effect of UVB on the secretion of several cytokines involved in inflammation by human keratinocytes immortalized or not with human papillomavirus (HPV)16 or HPV38 at the mRNA and protein levels. We show that expression of the HPV E6/E7 oncoproteins influences not only the basal cytokine secretion profile of keratinocytes, but also its modulation upon UVB irradiation. In particular, UVB upregulates interleukin (IL)-6, IL-8 and transforming growth factor (TGF)-beta in HPV-immortalized cells to a higher extent than in control keratinocytes. Moreover, expression of other pro-inflammatory molecules such as S100A8/9 and interferon (IFN)-kappa was downregulated in HPV-immortalized cells. These data support the functional similarity between HPV16 and 38, and suggest an active role of these viruses in modulation of the inflammatory process.
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PMID:Altered expression of UVB-induced cytokines in human papillomavirus-immortalized epithelial cells. 1879 14

Chronic inflammation is a complex process that promotes carcinogenesis and tumor progression; however, the mechanisms by which specific inflammatory mediators contribute to tumor growth remain unclear. We and others recently demonstrated that the inflammatory mediators IL-1beta, IL-6, and PGE(2) induce accumulation of myeloid-derived suppressor cells (MDSC) in tumor-bearing individuals. MDSC impair tumor immunity and thereby facilitate carcinogenesis and tumor progression by inhibiting T and NK cell activation, and by polarizing immunity toward a tumor-promoting type 2 phenotype. We now show that this population of immature myeloid cells induced by a given tumor share a common phenotype regardless of their in vivo location (bone marrow, spleen, blood, or tumor site), and that Gr1(high)CD11b(high)F4/80(-)CD80(+)IL4Ralpha(+/-)Arginase(+) MDSC are induced by the proinflammatory proteins S100A8/A9. S100A8/A9 proteins bind to carboxylated N-glycans expressed on the receptor for advanced glycation end-products and other cell surface glycoprotein receptors on MDSC, signal through the NF-kappaB pathway, and promote MDSC migration. MDSC also synthesize and secrete S100A8/A9 proteins that accumulate in the serum of tumor-bearing mice, and in vivo blocking of S100A8/A9 binding to MDSC using an anti-carboxylated glycan Ab reduces MDSC levels in blood and secondary lymphoid organs in mice with metastatic disease. Therefore, the S100 family of inflammatory mediators serves as an autocrine feedback loop that sustains accumulation of MDSC. Since S100A8/A9 activation of MDSC is through the NF-kappaB signaling pathway, drugs that target this pathway may reduce MDSC levels and be useful therapeutic agents in conjunction with active immunotherapy in cancer patients.
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PMID:Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. 1880 69


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