S100A8/A9: A Janus-faced molecule in cancer therapy and tumorgenesis

doi:10.1016/j.ejphar.2009.08.044

European Journal of Pharmacology

Volume 625, Issues 1–3, 25 December 2009, Pages 73-83

https://doi.org/10.1016/j.ejphar.2009.08.044 Get rights and content

Abstract

Correlations exist between the abundance of S100 proteins and disease pathologies. Indeed, this is evidenced by the heterodimeric S100 protein complex S100A8/A9 which has been shown to be involved in inflammatory and neoplastic disorders. However, S100A8/A9 appears as a Janus-faced molecule in this context. On the one hand, it is a powerful apoptotic agent produced by immune cells, making it a very fascinating tool in the battle against cancer. It spears the risk to induce auto-immune response and may serve as a lead compound for cancer-selective therapeutics. In contrast, S100A8/A9 expression in cancer cells has also been associated with tumor development, cancer invasion or metastasis. Clearly, there is a dichotomy and future investigations into the role of S100A8/A9 in cancer biology need to consider both sides of the same coin.

Introduction

S100 proteins are a group of multigenic, non-ubiquitous cytoplasmic Ca²⁺-binding proteins that are differentially expressed in a wide variety of cell types. S100A8 and S100A9 were originally discovered as immunogenic proteins expressed and specifically released from phagocytes. High S100A8/A9 plasma levels are measured in a number of inflammatory disorders, such as chronic bronchitis, cystic fibrosis, and rheumatoid arthritis (Nacken et al., 2003). Interestingly, there are high correlations between S100A8/A9 plasma concentrations and clinical and laboratory markers of inflammation, as well as the rapid normalization following clinical improvement, suggesting that these proteins track disease activity.

Although a number of distinct functions have been attributed to the S100 proteins, their biological functions still remain unclear. Intra- as well as extracellular roles have been proposed (Table 1). For example, intracellular S100A8/A9 promotes NADPH oxidase and NF-κB activation. The secreted form has chemotactic and chemorepulsive properties; exerts apoptosis-inducing activity on cancer cells and, remarkably, cancer cells utilize these S100 proteins as guidance for the adhesion and invasion of disseminating malignant cells. In the extracellular milieu, S100A8/A9 can also bind cell surface receptor(s) such as the receptor for adavanced glycation end products (RAGE) and induces the expression of cytokine(s).

The promiscuity of S100A8/A9 has direct implications on a wide range of potential effects on human health and is the basis of this review. Clearly, S100A8/A9 has gained interest in many fields of medicine due to its deregulated epidermal expression as a response to stress and in association with neoplastic disorders. Although several excellent general articles on S100 proteins have been published recently (Donato, 2007, Heizmann et al., 2007, Schaub and Heizmann, 2008), in this review we will only include details on the cell growth-modulating and apoptosis-inducing activity of S100A8/A9.

Section snippets

S100A8 and S100A9 are members of the S100 protein family

The members of the S100 protein family compose a multigenic family of non-ubiquitous cytoplasmic Ca²⁺-binding proteins of EF-hand type. They are small acidic proteins (10–12 kDa) that are found exclusively in vertebrates (Schafer and Heizmann, 1996) and are differentially expressed in a wide variety of cell types. They have been implicated in the regulation of many diverse processes such as signal transduction, cell growth and motility, cell-cycle regulation, transcription, differentiation and

Extracellular S100A8/A9 induces apoptosis in target cells

The extracellular S100A8/A9 protein complex has been shown to exert apoptotic/cytotoxic effects against various tumor cells. S100A8/A9 exhibits growth-inhibitory activity against mouse embryonic fibroblasts and human dermal fibroblasts (Yui et al., 1997), and many tumor cells with broad specificity such as L-929 mouse fibrosarcoma (Yui et al., 1995) MH-134 mouse hepatoma, B16 mouse melanoma, J774.1 mouse macrophage-like cells, Ros17/2.8, rat osteosarcoma, and MCF-7 human mammary adenocarcinoma (

Stress response-induced S100 expression

In normal epidermis S100A8 and S100A9 are expressed at only minimal levels. However, their expression is induced in response to stress at specific conditions. For example, they are significantly up-regulated in differentiating suprabasal wound keratinocytes (Thorey et al., 2001), especially in the first 12 to 24 h after injury, with a gradual return to baseline expression over a 2-week period (Soo et al., 2002). Similarly, they are transiently induced in keratinocytes after UVB irradiation (

Conclusions and future perspectives

S100A8/A9 appears as a Janus-faced molecule. It is a powerful apoptotic agent produced by immune cells, making it a very fascinating tool in the battle against cancer. In fact, S100A8/A9 promotes apoptosis in a number of cancer cells. S100A8/A9-positive phagocytes accumulate at the edge of malignant tissue, and after their release S100A8/A9 may be involved in the immune response against tumor by inducing apoptosis and regression of tumor cells.

In epithelial cells S100A8/A9 is expressed in

Acknowledgements

This work was in part funded by a CLA/GSK/CIHR postdoctoral fellowship (S.G. and S.C.) and a CIHR National Training Program in Allergy and Asthma fellowship (to S.G.), by NIH RO1 GM62112 (to W.J.C.), and by the “Deutsche Forschungsgemeinschaft (DFG)”, project KE 820/2-4 and project KE 820/6-1 (both to C.K.). S.G. is currently a Parker B. Francis Fellow in Pulmonary Disease. A.J.H. is supported by the Canada Research Chairs Program.

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Purpose: As a promotor of tumor invasion and tumor microenvironment (TME) formation, the protein complex S100A8/S100A9 is associated with poor prognosis. Our aim was to further evaluate its origin and regulatory effects, and to establish an imaging biomarker for TME activity. Methods: S100A9^−/−cells (ko) were created from syngeneic murine breast cancer 4T1 (high malignancy) and 67NR (low malignancy) wildtype (wt) cell lines and implanted into either female BALB/c wildtype or S100A9^−/⁻ mice (n = 10 each). Anti-S100A9-Cy5.5-targeted fluorescence reflectance imaging was performed at 0 h and 24 h after injection. Potential early changes of S100A9-presence under immune checkpoint inhibition (anti-PD-L1, n = 7 vs. rat IgG2b as isotype control, n = 3) were evaluated. Results: In S100A9^−/−mice contrast-to-noise-ratios were significantly reduced for wt and S100A9^−/−tumors. No significant differences were detected for 4T1 ko and 67NR ko cells as compared to wildtype cells. Under anti-PD-L1 treatment S100A9 presence significantly decreased compared with the control group. Conclusion: Our results confirm a secretion of S100A8/S100A9 by the TME, while tumor cells do not apparently release the protein. Under immune checkpoint inhibition S100A9-imaging reports an early decrease of TME activity. Therefore, S100A9-specific imaging may serve as an imaging biomarker for TME formation and activity.
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Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPβ. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.
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ReviewS100A8/A9: A Janus-faced molecule in cancer therapy and tumorgenesis

Abstract

Introduction

Section snippets

S100A8 and S100A9 are members of the S100 protein family

Extracellular S100A8/A9 induces apoptosis in target cells

Stress response-induced S100 expression

Conclusions and future perspectives

Acknowledgements

Eur. J. Cancer

Lancet

Eur. J. Cancer

J. Invest. Dermatol.

J. Biol. Chem.

Cell Calcium

Cell Calcium

Int. J. Biochem. Cell Biol.

J. Invest. Dermatol.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

FEBS Lett.

J. Invest. Dermatol.

Eur. J. Pharmacol.

Cell

J. Biol. Chem.

Pathol. Res. Pract.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

J. Mol. Biol.

J. Biol. Chem.

BMC Cancer

Cancer Cell

J. Invest. Dermatol.

J. Invest. Dermatol.

J. Biol. Chem.

FEBS Lett.

Cell Calcium

Genomics

J. Biol. Chem.

J. Biol. Chem.

Immunohistochemical investigation of S100A9 expression in pulmonary adenocarcinoma: S100A9 expression is associated with tumor differentiation

Oncol. Rep.

Gene-expression profiles predict survival of patients with lung adenocarcinoma

Nat. Med.

The calcium-binding proteins MRP8 and MRP14 form a membrane-associated heterodimer in a subset of monocytes/macrophages present in acute but absent in chronic inflammatory lesions

Eur. J. Immunol.

Structure of the Ca2+/S100B/NDR kinase peptide complex: insights into S100 target specificity and activation of the kinase

Biochemistry

Distribution of a formalin-resistant myelomonocytic antigen (L1) in human tissues. II. Normal and aberrant occurrence in various epithelia

Am. J. Clin. Pathol.

S100 protein subcellular localization during epidermal differentiation and psoriasis

J. Histochem. Cytochem.

Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development

Int. J. Oncol.

Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein

J. Exp. Med.

Calprotectin-mediated zinc chelation as a biostatic mechanism in host defence

Scand. J. Immunol.

Metal chelation and inhibition of bacterial growth in tissue abscesses

Science

Expression of S100 proteins in normal human tissues and common cancers using tissue microarrays: S100A6, S100A8, S100A9 and S100A11 are all overexpressed in common cancers

Histopathology

Genome-wide comparison of human keratinocyte and squamous cell carcinoma responses to UVB irradiation: implications for skin and epithelial cancer

Oncogene

The 23-kilodalton protein, a substrate of protein kinase C, in bovine neutrophil cytosol is a member of the S100 family

Biochemistry

S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer

Cancer Res.

Intracellular and extracellular roles of S100 proteins

Microsc. Res. Tech.

RAGE: a single receptor for several ligands and different cellular responses: the case of certain S100 proteins

Curr. Mol. Med.

Kinetic study of the activation of the neutrophil NADPH oxidase by arachidonic acid. Antagonistic effects of arachidonic acid and phenylarsine oxide

Biochemistry

Review
S100A8/A9: A Janus-faced molecule in cancer therapy and tumorgenesis

Structure of the Ca²⁺/S100B/NDR kinase peptide complex: insights into S100 target specificity and activation of the kinase