S100A8 and S100A9: New Insights into Their Roles in Malignancy

Srikrishna, Geetha

doi:10.1159/000330095

Cited by 216 publications

(226 citation statements)

References 115 publications

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“…Based on recent observation, it is possible to speculate that additional neutrophil-derived factors affect the activity of NK cells (26). Because in vivo major sources of S100A8/A9 are myeloid cells, including neutrophils (27), this study suggests that neutrophils give a significant signal to NK cells by secreting S100A8/A9 proteins in the presence of NKG2D stimulus, following NK cell activation. Alternatively, there is a possibility that a direct interaction between tumor cells and NK cells is more important for activation than neutrophils, because tumor cells are able to give a dual stimulus of NKG2D ligand-NKG2D and S100A8/A9-RAGE to NK cells at the same time in the same place.…”

Section: Discussionmentioning

confidence: 62%

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Narumi¹,

Miyakawa²,

Ueda³

et al. 2015

The Journal of Immunology

101

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S100A8/A9, a proinflammatory protein, is upregulated in inflammatory diseases, and also has a tumor-promoting activity by the recruitment of myeloid cells and tumor cell invasion. However, whether the expression of S100A8/A9 in tumors predicts a good or poor prognosis is controversial in the clinical setting. In this study, to clarify the in vivo role of S100A8/A9 in the tumor microenvironment, we s.c. inoculated Pan02 cells stably expressing S100A8 and S100A9 proteins (Pan02-S100A8/A9) in syngeneic C57BL/6 mice. Unexpectedly, after small tumor nodules were once established, they rapidly disappeared. Flow cytometry showed that the number of NK cells in the tumors was increased, and an administration of anti-asialoGM1 Ab for NK cell depletion promoted the growth of Pan02-S100A8/A9 s.c. tumors. Although the S100A8/A9 proteins alone did not change the IFN-γ expression of NK cells in vitro, a coculture with Pan02 cells, which express Rae-1, induced IFN-γ production, and Pan02-S100A8/A9 cells further increased the number of IFN-γ+ NK cells, suggesting that S100A8/A9 enhanced the NK group 2D ligand-mediated intracellular activation pathway in NK cells. We then examined whether NK cell activation by S100A8/A9 was via their binding to receptor of advanced glycation end product (RAGE) by using the inhibitors. RAGE antagonistic peptide and anti-RAGE Ab inhibited the IFN-γ production of NK cells induced by S100A8/A9 proteins, and an administration of FPS-ZM1, a RAGE inhibitor, significantly enhanced the in vivo growth of Pan02-S100A8/A9 tumors. We thus found a novel activation mechanism of NK cells via S100A8/A9–RAGE signaling, which may open a novel perspective on the in vivo interaction between inflammation and innate immunity.

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Section: Discussionmentioning

confidence: 62%

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Narumi¹,

Miyakawa²,

Ueda³

et al. 2015

The Journal of Immunology

101

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“…In concordance, our data shows that high-level S100A8/ S100A9 expression not only correlates with glucocorticoid resistance, but in itself seems to accurately predict an inferior outcome in MLL-rearranged infant ALL. As high-level S100A8/ S100A9 expression has been associated with tumor development, invasion, and metastasis in several types of human cancers, 43 a role in MLL-fusion-driven leukemogenesis might be plausible, at least in a subset of MLL-rearranged infant ALL patients.…”

Section: Discussionmentioning

confidence: 99%

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

et al. 2012

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MLL-rearranged acute lymphoblastic leukemia (ALL) in infants is characterized by a poor clinical outcome and resistance to glucocorticoids (for example, prednisone and dexamethasone). As both the response to prednisolone in vitro and prednisone in vivo are predictive for clinical outcome, understanding and overcoming glucocorticoid resistance remains an essential step towards improving prognosis. Prednisolone-induced apoptosis depends on glucocorticoid-evoked Ca 2 þ fluxes from the endoplasmic reticulum towards the mitochondria. Here, we demonstrate that in MLL-rearranged infant ALL, over-expression of S100A8 and S100A9 is associated with failure to induce free-cytosolic Ca 2 þ and prednisolone resistance. Furthermore, we demonstrate that enforced expression of S100A8/S100A9 in prednisolone-sensitive MLL-rearranged ALL cells, rapidly leads to prednisolone resistance as a result of S100A8/S100A9 mediated suppression of prednisolone-induced free-cytosolic Ca 2 þ levels. In addition, the Src kinase inhibitor PP2 markedly sensitized MLL-rearranged ALL cells otherwise resistant to prednisolone, via downregulation of S100A8 and S100A9, which allowed prednisolone-induced Ca 2 þ fluxes to reach the mitochondria and trigger apoptosis. On the basis of this novel mechanism of prednisolone resistance, we propose that developing more specific S100A8/S100A9 inhibitors may well be beneficial for prednisolone-resistant MLL-rearranged infant ALL patients.Leukemia ( Keywords: prednisolone resistance; S100A8 and S100A9; calcium signaling; MLL-rearranged infant leukemia INTRODUCTIONSince the early 1960s, treatment results for childhood acute lymphoblastic leukemia (ALL) began to improve steadily and continued to progress ever since. Consequently, the survival chances for childhood ALL, in general, nowadays exceed 85%. 1 Unfortunately, this tremendous step forward has not been equally beneficial for all patients. This is especially true for infants (o1 year of age) with ALL carrying leukemia-specific chromosomal translocations involving the MLL gene, which occur in B80% of the infant ALL cases. 2,3 Depending on the treatment protocol, survival chances for MLL-rearranged infant ALL patients are at best B40%. 3 Considerably contributing to this poor outcome is cellular resistance to multiple chemotherapeutic drugs, in particular to glucocorticoids like prednisone and dexamethasone, which form the cornerstone of childhood ALL treatment regimes. Prednisolone (the biologically active metabolite of prednisone) dosages needed to eliminate 50% of infant ALL cells in vitro typically are B500 --fold higher than the dosages required to eradicate similar amounts of precursor B-ALL cells from children older than one year of age (that is, non-infants). 4 Moreover, approximately 30% of infants with MLL-rearranged ALL show a poor prednisone response in vivo, compared with only B10% of non-infant pediatric precursor B-ALL cases. 5 As the in vitro prednisolone response and the prednisone response in vivo represent important prognostic factors, 6 --8 ...

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“…Although S100A8 and S100A9 are able to form homodimers, they typically exhibit pro-and anti-inflammatory properties (2) by forming heterodimers of S100A8/A9, alternatively known as calprotectin (3,4). High serum levels of S100A8/A9 correlate with inflammatory response in a number of chronic diseases, including rheumatic arthritis, inflammatory bowel disease and atherosclerosis (5).…”

Section: Introductionmentioning

confidence: 99%

S100A8/A9 is associated with estrogen receptor loss in breast cancer

Bao

Wang

2016

Oncology Letters

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Abstract. S100A8 and S100A9 are calcium-binding proteins that are secreted primarily by granulocytes and monocytes, and are upregulated during the inflammatory response. S100A8 and S100A9 have been identified to be expressed by epithelial cells involved in malignancy. In the present study, the transcriptional levels of S100A8 and S100A9 were investigated in various subtypes of breast cancer (BC), and the correlation with estrogen receptor 1 (ESR1) and GATA binding protein 3 (GATA3) gene expression was evaluated using microarray datasets. The expression of S100A8 and S100A9 in BC cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR). The regulation of ESR1 and GATA3 by administration of recombinant S100A8/A9 was examined in the BC MCF-7 cell line using quantitative (q)PCR. The association between S100A8 and S100A9 and overall survival (OS) was investigated in GeneChip ® data of BC. The expression levels of S100A8 and S100A9 were higher in human epidermal growth factor receptor 2 (Her2)-amplified and basal-like BC. The messenger (m)RNA levels of S100A8 and S100A9 were inversely correlated with ESR1 and GATA3 expression. S100A8/A9 induced a 10-fold decrease in the mRNA levels of ESR1 in MCF-7 cells. Poor OS was associated with high expression levels of S100A9, but not with high expression levels of S100A8 in BC. In conclusion, strong expression and secretion of S100A8/A9 may be associated with the loss of estrogen receptor in BC, and may be involved in the poor prognosis of Her2 + /basal-like subtypes of BC.

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S100A8 and S100A9: New Insights into Their Roles in Malignancy

Cited by 216 publications

References 115 publications

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia

S100A8/A9 is associated with estrogen receptor loss in breast cancer

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