Evaluation of Plasma and Tissue S100A4 Protein and mRNA Levels as Potential Markers of Metastasis and Prognosis in Clear Cell Renal Cell Carcinoma

Yang, Han; Zhao, Kai; Yu, Qing; Wang, X; Song, Young Woo; Li, R

doi:10.1177/147323001204000209

Cited by 21 publications

(16 citation statements)

References 32 publications

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“…These strategies include targeting S100A4 with specific antibodies or interfering with the interaction of S100A4 and its targets using small molecular inhibitors [35, 36]. However, S100A4 is often present at high concentrations in malignancies, and is also high in inflammatory disorders [37, 38], which complicates the use of antibodies to inhibit S100A4 signaling extracellularly and/or through blocking the intracellular action. Niclosamide, an anti-helminthic agent used for over 50 years to treat tapeworm infections in humans, is proposed to have a favorable safety profile due to poor systemic absorption from the gastrointestinal tract [15].…”

Section: Discussionmentioning

confidence: 99%

S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide

et al. 2016

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S100A4 (metastasin-1), a metastasis-associated protein and marker of the epithelial to mesenchymal transition, contributes to several hallmarks of cancer and has been implicated in the progression of several types of cancer. However, the impacts of S100A4 signaling in lung cancer progression and its potential use as a target for therapy in lung cancer have not been properly explored. Using established lung cancer cell lines, we demonstrate that S100A4 knockdown reduces cell proliferation, invasion and three-dimensional invasive growth, while overexpression of S100A4 increases invasive potential. In patient-derived tissues, S100A4 is preferentially elevated in lung adenocarcinoma. This elevation is associated with lymphovascular invasion and decreased overall survival. In addition, depletion of S100A4 by shRNA inhibits NF-κB activity and decreases TNFα-induced MMP9 expression. Furthermore, inhibition of the NF-κB/MMP9 axis decreases lung carcinoma invasive potential. Niclosamide, a reported inhibitor of S100A4, blocks expression and function of S100A4 with a reduction in proliferation, invasion and NF-κB-mediated MMP9 expression. Collectively, this study highlights the importance of the S100A4/NF-κB/MMP9 axis in lung cancer invasion and provides a rationale for targeting S100A4 to combat lung cancer.

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Section: Discussionmentioning

confidence: 99%

S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide

et al. 2016

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“…However, in the last years three clinical studies provided evidence that high expression of S100A4 in primary tumors correlates with metastasis and poor prognosis in RCC (Bandiera et al, 2009; Wang et al, 2012; Yang et al, 2012). It has been proposed that upregulation of S100A4 mediates epithelial-to-mesenchymal transition, an initial step in the development of metastasis.…”

Section: Discussionmentioning

confidence: 99%

“…S100A4 binds to several target proteins, among them the tumor suppressor p53 and the non-muscle myosin IIa. Recent studies suggest that S100A4 also plays a role in the development of RCC and may be useful as prognostic marker (Bandiera et al, 2009; Lopez-Lago et al, 2010; Wang et al, 2012; Yang et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

NFAT5-mediated expression of S100A4 contributes to proliferation and migration of renal carcinoma cells

Küper¹,

Beck²,

Neuhofer

2014

Front. Physiol.

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The osmosensitive transcription factor nuclear factor of activated T-cells (NFAT) 5, also known as tonicity enhancer binding protein (TonEBP), has been associated with the development of a variety of tumor entities, among them breast cancer, colon carcinoma, and melanoma. The aim of the present study was to determine whether NFAT5 is also involved in the development of renal cell carcinoma (RCC). The most common type of RCC, the clear cell RCC, originates from the proximal convoluted tubule. We tested our hypothesis in the clear cell RCC cell line CaKi-1 and the non-cancerous proximal tubule cell line HK-2, as control. Basal expression of NFAT5 and NFAT5 activity in CaKi-1 cells was several times higher than in HK-2 cells. Osmotic stress induced an increased NFAT5 activity in both CaKi-1 and HK-2 cells, again with significantly higher activities in CaKi-1 cells. Analysis of NFAT5-regulating signaling pathways in CaKi-1 cells revealed that inhibition of the MAP kinases p38, c-Jun-terminal kinase (JNK) and extracellular regulated kinase (ERK) and of the focal adhesion kinase (FAK) partially blunted NFAT5 activity. FAK and ERK were both constitutively active, even under isotonic conditions, which may contribute to the high basal expression and activity of NFAT5 in CaKi-1 cells. In contrast, the MAP kinases p38 and JNK were inactive under isotonic conditions and became activated under osmotic stress conditions, indicating that p38 and JNK mediate upregulation of NFAT5 activity under these conditions. siRNA-mediated knockdown of NFAT5 in CaKi-1 cells reduced the expression of S100A4, a member of the S100 family of proteins, which promotes metastasis. Knockdown of NFAT5 was accompanied by a significant decrease in proliferation and migration activity. Taken together, our results indicate that NFAT5 induces S100A4 expression in CaKi-1 cells, thereby playing an important role in RCC proliferation and migration.

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“…Finally, based on the evidence that S100A4 is secreted by tumor cells and tumor activated stromal cells [57], [58], [59], and that the determination of S100A4 in plasma derived from cancer patients is feasible [60], we extended the studies and analyzed the presence of S100A4 in plasma from mice bearing tumors developed from different human cell lines. Our data further indicate that S100A4 could be considered as a good plasmatic biomarker because it allowed us to discriminate between animals with or without tumors.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of Tumor Growth and Angiogenesis with a Novel Anti-S100A4 Monoclonal Antibody

et al. 2013

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S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.

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Evaluation of Plasma and Tissue S100A4 Protein and mRNA Levels as Potential Markers of Metastasis and Prognosis in Clear Cell Renal Cell Carcinoma

Cited by 21 publications

References 32 publications

S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide

S100A4 drives non-small cell lung cancer invasion, associates with poor prognosis, and is effectively targeted by the FDA-approved anti-helminthic agent niclosamide

NFAT5-mediated expression of S100A4 contributes to proliferation and migration of renal carcinoma cells

Therapeutic Targeting of Tumor Growth and Angiogenesis with a Novel Anti-S100A4 Monoclonal Antibody

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