Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer

Davies, Barry R.; O’Donnell, Marie; Durkan, Garrett; Rudland, Philip S.; Barraclough, Roger; Neal, David E.; Mellon, J. Kilian

doi:10.1002/path.1051

Cited by 102 publications

(76 citation statements)

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“…In humans, an increase in S100A4 expression has been correlated with aggressiveness and worse prognosis for patients with different types of carcinoma, including colorectal, gallbladder, pancreas, bladder, gastric, breast, non-small cell lung, and prostate cancers. [11][12][13][14][15][16][17][18] The exact mechanism for the metastasis-promoting activity by S100A4 is poorly understood. S100A4 may influence growth regulation, remodeling of the extracellular matrix, angiogenesis, cell detachment, and cell motility.…”

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confidence: 99%

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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Expression of various S100 genes has been associated with clinically aggressive subtypes in a variety of different cancers. We hypothesized that S100A4 would be overexpressed in endometrial carcinoma compared to benign endometrium. Quantitative real-time RT-PCR (qRT-PCR) was used to quantify the mRNA level of S100A4 in benign endometrium (n ¼ 19), endometrioid adenocarcinoma (n ¼ 87), and non-endometrioid tumors (n ¼ 21). Immunohistochemistry was used to verify the results of qRT-PCR and to assess protein localization. Possible mechanisms of S100A4 gene regulation were also examined. S100A4 was overexpressed in the grade 3 endometrioid tumors, uterine papillary serous carcinoma, and uterine malignant mixed mü llerian tumor. Expression in grade 1 and grade 2 endometrioid tumors was comparable to that of normal endometrium, which was quite low. Expression was significantly higher in stage III and IV tumors compared with stage I. By immunohistochemistry, S100A4 was expressed in the tumor cell cytoplasm of poorly differentiated tumors, but was not detected in normal endometrial glandular epithelium. In benign endometrium, S100A4 expression was confined to stromal cells. S100A4 was not regulated by estrogen or progesterone, and its expression in tumors was not significantly correlated to estrogen receptor or progesterone receptor content. However, methylation of the S100A4 gene was detected in benign endometrium and grade 1 tumors with low S100A4 expression. In contrast, grade 3 endometrioid tumors with high S100A4 mRNA and protein expression showed no methylation of the gene. These methylation results were verified in endometrial cancer cell lines with differential baseline levels of S100A4 protein. These results suggest that hypomethylation is an important mechanism of regulating the expression of the S100A4 gene. These results support the emerging concept that hypomethylation may play a role in the upregulation of genes during later stages of tumorigenesis. Keywords: endometrial cancer; S100A gene family; S100A4; methylation Endometrial carcinoma is the most common malignant neoplasm of the female genital tract and the fourth most frequently diagnosed cancer in women, following cancers of the breast, lung, and colon. 1 On the basis of histological and clinical features, endometrial carcinoma has been classified into two types. 2-4 Type I tumors (approximately 80% of all endometrial carcinomas) are typically low-grade (grade 1 or grade 2) endometrioid adenocarcinoma, most of which are confined to the uterus and have a favorable prognosis. Type II tumors (approximately 20%) are comprised of uterine papillary serous carcinoma, malignant mixed mü llerian tumors, and clear cell carcinoma. The nature of high-grade (grade 3) endometrioid adenocarcinoma is more controversial, as a subset may behave more like the Type II tumors. Type II cancers are associated with extrauterine spread and carry a high mortality rate. Previous studies have documented interesting molecular differences between endometrioid and nonendometrioid ...

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Hypomethylation-induced expression of S100A4 in endometrial carcinoma

et al. 2007

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“…The presence of the EF-hand-containing calcium-binding protein S100A4 in carcinoma cells has been associated with a poor prognosis in patients with carcinomas of the bladder, colorectum, gall bladder, oesophagus and lung (Kimura et al, 2000;Ninomiya et al, 2001;Davies et al, 2002;Gongoll et al, 2002;Nakamura et al, 2002). In an archival set of 349 breast cancer patients, less than 20% of patients with S100A4 in their carcinoma cells were alive after 20 years, whereas greater than 90% of patients with less than 1% S100A4 positive carcinoma cells survived over the same period .…”

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Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

et al. 2004

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Increased levels of the homodimeric calcium-binding protein, S100A4, have been shown to cause a metastatic phenotype in at least three independent model systems of breast cancer and its presence in carcinoma cells has been shown to be associated with a reduction in the survival of patients suffering from a range of different cancers. S100A4 has been shown to interact in vitro with another member of the S100 family of proteins, S100A1. The purpose of the present study was to find out whether S100A1 could affect S100A4 function. Fluorescence resonance energy transfer was used to show the interaction of S100A4 and S100A1 in living cells and the binding affinities between S100A4 and S100A1 were determined using a biosensor. S100A1 reduced the S100A4 inhibition of nonmuscle myosin A self-association and phosphorylation in vitro. S100A1 reduced S100A4 induced motility and growth in soft agar and metastasis in vivo. The results show for the first time that interactions between different S100 proteins can affect cancer-related activity, and that the presence of S100A1 protein in carcinoma cells might modulate the effect of S100A4 on their metastatic abilities.

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“…Stimulation of tumor metastasis was demonstrated in two transgenic mouse models with overexpression of the S100A4 gene Davies et al, 1996). In a number of human cancers of different origin, the enhanced expression of S100A4 was associated with poor prognosis (Platt-Higgins et al, 2000;Yonemura et al, 2000;Davies et al, 2002;Rosty et al, 2002). S100A4 protein belongs to the S100 family of Ca 2 þ -binding proteins.…”

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confidence: 99%

Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity

et al. 2004

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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. b-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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Expression of S100A4 protein is associated with metastasis and reduced survival in human bladder cancer

Cited by 102 publications

References 11 publications

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

Hypomethylation-induced expression of S100A4 in endometrial carcinoma

Mutually antagonistic actions of S100A4 and S100A1 on normal and metastatic phenotypes

Extracellular S100A4(mts1) stimulates invasive growth of mouse endothelial cells and modulates MMP-13 matrix metalloproteinase activity

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