Nuclear localization of the metastasis‐related protein S100A4 correlates with tumour stage in colorectal cancer

Flatmark, Kjersti; Boye, Kjetil; Nesland, Jahn M.; Rasmussen, Heidi; Aamodt, Geir; Mikalsen, Svein‐Ole; Björnland, Kristin; Fodstad, Øsystein; Mælandsmo, Gunhild Mari

doi:10.1002/path.1381

Cited by 75 publications

(76 citation statements)

References 27 publications

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“…S100 proteins are expressed both intra-, and extracellularly, in a cell-and tissue-specific manner (Donato, 2003), suggesting cell-and tissue-specific roles for the different family members. S100A4 has been found in the nucleus, cytoplasm, and in the extracellular microenvironment (Cabezon et al, 2007;Flatmark et al, 2003), and in normal human tissues expression of the protein has been reported in fibroblasts (Strutz et al, 1995), endothelial cells (Ambartsumian et al, 2001), hematopoietic cells (Cabezon et al, 2007;Grigorian et al, 1994) and now in the mammary gland (this study).…”

supporting

confidence: 56%

“…Additionally, S100A4 was one of only 25 genes found upregulated in three different mammary cancer stem cell expression signatures (Gupta et al, 2009). Numerous other reports on clinical material from breast (Ismail et al, 2008;Lee et al, 2004), bladder (Matsumoto et al, 2007), colorectal (Flatmark et al, 2003;Gongoll et al, 2002), melanoma and several other types of cancer (Garrett et al, 2006) have confirmed the association between S100A4 expression, and a more severe prognosis. Collectively these findings suggest S100A4 as a major determinant of breast cancer progression.…”

mentioning

confidence: 69%

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370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

Andersen¹,

Mori²,

Fata³

et al. 2010

European Journal of Cancer Supplements

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High levels of the S100 calcium binding protein S100A4 also called fibroblast specific protein 1 (FSP1) have been established as an inducer of metastasis and indicator of poor prognosis in breast cancer. The mechanism by which S100A4 leads to increased cancer aggressiveness has yet to be established; moreover, the function of this protein in normal mammary gland biology has not been investigated. To address the role of S100A4 in normal mammary gland, its spatial and temporal expression patterns and possible function in branching morphogenesis were investigated. We show that the protein is expressed mainly in cells of the stromal compartment of adult humans, and during active ductal development, in pregnancy and in involution of mouse mammary gland. In 3D culture models, topical addition of S1004 induced significant increase in the TGFα mediated branching phenotype and a concomitant increase in expression of a previously identified branching morphogen, metalloproteinase-3 (MMP-3). These events were found to be dependent on MEK activation. Downregulation of S100A4 using shRNA significantly reduced TGFα induced branching and altered E-cadherin localization. These findings provide evidence that S100A4 is developmentally regulated and that it plays a functional role in mammary gland development by, in concert with TGFα, activating MMP-3, thereby increasing invasion into the fat pad during branching. We suggest that S100A4-mediated effects during branching morphogenesis provide a plausible mechanism for how it may function in breast cancer progression.

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supporting

confidence: 56%

mentioning

confidence: 69%

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

Andersen¹,

Mori²,

Fata³

et al. 2010

European Journal of Cancer Supplements

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“…34 , 37 To further investigate the kinetics of S100A4 + cells during CRC development, which could not be studied using clinical samples, C57 BL/6 mice were administered AOM/DSS (Fig. 1A) that has been used to induce a two-stage carcinogenesis model for CRC.…”

Section: Resultsmentioning

confidence: 99%

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

Zhang

Hou

et al. 2018

OncoImmunology

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S100A4 plays important roles in tumor development and metastasis, but its role in regulating inflammation and colitis-associated tumorigenesis has not been well characterized. Here, we report that S100A4 expression was increased in azoxymethane (AOM) and dextran sulfate sodium (DSS) induced colorectal cancer (CRC) in mice. After AOM/DSS treatment, both S100A4-TK mice with the selective depletion of S100A4-expressing cells and S100A4-deficient (S100A4−/−) mice developed fewer and smaller tumors than wild-type (WT) control littermates. Furthermore, S100A4−/− mice were resistant to DSS-induced colitis, reduced infiltration of macrophages, and the diminished production of proinflammatory cytokines. Further studies revealed that reduced colon inflammation and colorectal tumor development in S100A4−/− mice were partly due to the dampening of nuclear factor (NF)-κB activation in macrophages. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly decreased AOM/DSS-induced colon inflammation and tumorigenesis. These results indicate that S100A4 amplifies an inflammatory microenvironment that promotes colon tumorigenesis and provides a promising therapeutic strategy for treatment of inflammatory bowel disease and prevention of colitis-associated colorectal carcinogenesis.

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“…Up-regulation of S100A4 (calcium binding) in MCS has previously been identified at both the transcript and protein level (Oloumi et al 2002), and in tumours increased expression correlates with an invasive, metastatic phenotype (Rosty et al 2002;Flatmark et al 2003;Moriyama-Kita et al 2004). Oloumi et al (2002) showed that S100A4 expression is up-regulated in V79 and C6 MCS, and that both are resistant to etoposide treatment.…”

Section: Mcr Relatedmentioning

confidence: 90%

Identification of three gene candidates for multicellular resistance in colon carcinoma

et al. 2004

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Solid tumours display elevated resistance to chemo-and radiotherapies compared to individual tumour derived cells. This so-called multicellular resistance (MCR) phenomenon can only be partly explained by reduced diffusion and altered cell cycle status; even fast growing cells on the surface of solid tumours display MCR. Multicellular spheroids (MCS) recapture this phenomenon ex vivo and here we compare gene expression in exponentially growing MCS with gene expression in monolayer culture. Using an 18,664 gene microarray, we identified 42 differentially expressed genes and three of these genes can be linked to potential mechanisms of MCR. A group of interferon response genes were also up-regulated in MCS, as were a number of genes that that are indicative of greater differentiation in three-dimensional cultures.

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Nuclear localization of the metastasis‐related protein S100A4 correlates with tumour stage in colorectal cancer

Cited by 75 publications

References 27 publications

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

370 The metastasis-promoting protein, S100A4, regulates mammary branching morphogenesis

S100A4 promotes colon inflammation and colitis-associated colon tumorigenesis

Identification of three gene candidates for multicellular resistance in colon carcinoma

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