Elsevier

Biochemical Pharmacology

Volume 72, Issue 11, 30 November 2006, Pages 1622-1631
Biochemical Pharmacology

S100A8 and S100A9 in inflammation and cancer

https://doi.org/10.1016/j.bcp.2006.05.017Get rights and content

Abstract

Calprotectin (S100A8/A9), a heterodimer of the two calcium-binding proteins S100A8 and S100A9, was originally discovered as immunogenic protein expressed and secreted by neutrophils. Subsequently, it has emerged as important pro-inflammatory mediator in acute and chronic inflammation. More recently, increased S100A8 and S100A9 levels were also detected in various human cancers, presenting abundant expression in neoplastic tumor cells as well as infiltrating immune cells. Although, many possible functions have been proposed for S100A8/A9, its biological role still remains to be defined. Altogether, its expression and potential cytokine-like function in inflammation and in cancer suggests that S100A8/A9 may play a key role in inflammation-associated cancer.

Introduction

During the past decade, cancer research has generated a complex picture of dynamic genetic and epigenetic changes within the genome of transformed cells influencing the expression and function of numerous proto-oncogenes and tumor suppressor genes implicated in regulatory circuits governing cell proliferation, differentiation, and homeostasis. Emerging evidence indicates that tumorigenesis is a multistage process bearing analogy to classical evolution and leading to progressive conversion of normal cells into cancer cells. Hanahan and Weinberg suggested that the vast majority of cancer cell genotypes is the consequence of six essential alterations in cell physiology that result in malignant growth including self-sufficiency in growth signals, insensitivity to growth-inhibitory signals, evasion of programmed cell death, unlimited replication potential, sustained angiogenesis, and tissue invasion/metastasis [1]. In addition, solid cancers are not only autonomous masses of transformed tumor cells, but also consist of multiple cell types including adjacent fibroblasts and epithelial cells, innate and adaptive immune cells, as well as cells from the blood and lymphatic vasculature, which create a tumor-specific microenvironment. Recent studies on mouse tumor models and numerous clinical observations have provided new insights in the molecular mechanisms of communication between tumor and stromal cells and in the role of soluble factors and direct cell–cell adhesion during each stage of cancer development [2], [3], [4], [5], [6], [7].

Chemically induced skin carcinogenesis represents one of the best-established in vivo models to study the multistage nature of tumor development and to design novel therapeutic concepts for human epithelial neoplasia [8], [9]. This tumor model is generated first by single application with the mutagen 7,12-dimethylbenz(a)anthracene (DMBA), which leads to frequent HA-Ras mutations of initiated keratinocytes. Tumor promotion is achieved by repeated subsequent treatment with phorbolesters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA) resulting in benign papillomas, some of which spontaneously progress into malignant squamous cell carcinomas (SCC). Compelling experimental evidence argues for an important contribution of gene regulatory networks controlled by the transcription factor AP-1 in neoplastic transformation of keratinocytes and skin cancer development. AP-1 is mainly composed of Jun and Fos protein dimers and mediates gene transcription in response to many physiological and pathological stimuli, including cytokines, growth factors, stress signals, bacterial and viral infections, as well as oncogenic stimuli [10], [11]. Studies in genetically modified mice and in cell culture models have highlighted a crucial role for AP-1 in numerous cellular events, such as proliferation, differentiation, and survival, which are involved in normal development and neoplastic transformation [12]. The requirement of AP-1-mediated gene transcription that leads to tumor promotion in response to TPA has been extensively studied in the mouse epidermal JB6 model [13], [14]. Moreover, detailed analysis of genetically modified mice with impaired JNK/AP-1 function revealed that changes in the gene regulatory network depending on JNK signaling and AP-1 activity are key features of multistage skin carcinogenesis in vivo[15], [16], [17], [18]. NF-κB is another important transcription factor that has been identified as an essential player in neoplastic transformation of keratinocytes [13], [14]. NF-κB collectively describes a family of dimeric transcription factors consisting of at least five Rel/NF-κB family members, p50/p105 (NF-κB1), p52/p100 (NF-κB2), c-Rel, p65 (RelA), and RelB, which form homo- and heterodimers [19], [20]. Initially described and intensively studied in the context of inflammatory and innate immune responses [21], recent studies demonstrated that NF-κB regulates cell proliferation, survival, and cell migration, and is constitutively active in different types of cancer [22]. The precise role of NF-κB in tumorigenesis is still unclear as opposing effects depending on the tumor model system and its function in the development of epithelial malignancy is still under debate [23], [24].

The analysis of gene expression profiles using microarray technology in cancer research is extensively used to measure the expression of a large set of genes during tumorigenesis and to identify potential biomarkers for tumor diagnosis and novel molecular targets for anticancer therapy. Recently, we and others have performed global gene expression analysis to define characteristic alterations of the gene regulatory network that occur within different stages of chemically induced skin carcinogenesis. These studies have revealed a comprehensive list of differentially expressed genes some of which represent novel AP-1 target genes [25], [26], [27], [28], [29], [30], [31], [32].

Section snippets

S100A8 and S100A9 expression in cancer

Two differentially expressed genes, which exhibited a strong up-regulation in advanced stages of skin cancer in mouse and human, encode the S100 family members S100A8 and S100A9 (Fig. 1; [29], [30], [32]). In addition, significant alterations in the expression of other S100 members, such as S100A3, S100A6, and S100A7, were found in skin tumors suggesting a functional role of S100 proteins during promotion and/or malignant progression of epidermal skin cancer [30], [33], [34]. S100 proteins

Regulation of S100A8 and S100A9 transcription: the role of AP-1 and others

S100A8 and S100A9 are often co-expressed suggesting a common mechanism of transcriptional regulation [29]. In vitro studies with myeloid and endothelial cells revealed strong induction of transcription by numerous pro-inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) [68], [69]. Detailed analysis of proximal promoter regions of human S100A8 and S100A9 revealed common binding sites for distinct transcription factors, such as AP-1, NF-κB, and C/EBP, and

Molecular functions of S100A8 and S100A9

What is the consequence of S100A8 and S100A9 protein over-expression on epithelial cells with regard to human cancer development? Although, recent experimental studies have described the functional role of distinct S100 proteins (e.g. S100A4 and S100A7), and the biochemical pathways they target during carcinogenesis [74], [75], the molecular functions of S100A8 and S100A9 on epithelial cells are currently elusive. Data from our laboratory unraveled an increase in AP-1 and NF-κB-mediated gene

S100A8/A9 and its functions as a pro-inflammatory cytokine

Originally, S100A8/A9 was discovered as an immunogenic protein expressed by neutrophils with potent anti-microbial properties referred to by its former name calprotectin [84], [85]. Meanwhile, there is accumulating evidence that high S100A8/A9 levels are characteristic for inflammatory conditions and that it acts as a chemotactic molecule constitutively expressed by neutrophils, activated monocytes, and macrophages [78], [86], [87]. Altogether, S100A8 and S100A9 proteins contribute to

The receptor RAGE: S100 receptor in inflammation and cancer?

S100A8 and S100A9 proteins fulfill various distinct intracellular functions and are also involved in myeloid cytoskeletal rearrangements, cell migration, in the arachidonic acid metabolism, and in the regulation of neutrophilic NADPH-oxidase [82], [95], [108], [109], [110], [111]. However, most biological functions relevant to inflammation seem to require the release of the S100A8/A9 heterodimer to the extracellular space [39], [78], [112]. S100A8/A9 is released from activated neutrophils as

Conclusion and outlook

Recent evidence suggests that S100A8/A9 and its potential receptor RAGE are not exclusively involved in the acute and the chronic state of inflammation. The expression pattern of S100A8/A9 in epithelial tumor cells and in the stromal compartment, its up-regulation in various types of tumors as well as its regulation via a putative tumor-promoting feed-forward loop indicate a functional role of S100–RAGE interaction in inflammation-associated cancer. Further studies are needed to elucidate the

Acknowledgements

We gratefully acknowledge Marina Schorpp-Kistner, Bettina Hartenstein, Astrid Riehl, Britta Klucky, Gerhard Fürstenberger, Delphine Goux and Angelika Bierhaus for critical discussion and reading of the manuscript. This work was supported by the German Ministry for Education and Research (National Genome Research Network, NGFN-1, 01GR0101, and NGFN-2, 01GS0460/01GR0418), by the Research Training Network (RTN, HPRN-CT2002-00256), by the DKFZ-MOST German Israeli Cooperation Program in Cancer

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