Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity

Vogl, Thomas; Eisenblätter, Michel; Völler, Tom; Zenker, Stefanie; Hermann, Sven; Lent, P. van; Faust, Andreas; Geyer, Christiane; Petersen, Beatrix; Roebrock, Kirsten; Schäfers, Michael; Bremer, Christoph; Roth, Johannes

doi:10.1038/ncomms5593

Cited by 155 publications

(124 citation statements)

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“…For investigation of the effects of S100A8/A9 on gene expression, including ESR1 and GATA3, 1x10 6 MCF-7 cells were seeded in a 6-well plate (Corning Life Sciences, Lowell, MA, USA) and treated with 10 ng/ml human recombinant S100A8/A9 (R&D Systems, Inc., Minneapolis, MN, USA) for 24 h. S100A8/A9 expression was additionally investigated in breast tumor tissue samples. Breast tumor tissue was obtained from a 53-year-old patient, who underwent a modified radical mastectomy at the Second Hospital of Jiaxing (Jiaxing, China) following a diagnosis of stage I invasive ductal carcinoma of the left breast.…”

Section: Methodsmentioning

confidence: 99%

“…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). S100A8/A9 is proposed to be a sensitive biomarker for monitoring inflammatory activities (6). Circulating levels of S100A8/A9 have additionally been identified to be elevated in several tumors, including lung, colon, gastric and breast cancer (BC), and may contribute to cancer cell survival and metastasis (7).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Bao

Wang

2016

Oncology Letters

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“…Moreover, lysates from resected tumors, tumor cells from tissue culture, and tissue culture supernatant were analyzed for S100A8/A9 using a specific, in-house-established enzyme-linked immunosorbent assay (ELISA) (14,23).…”

Section: Validation Experimentsmentioning

confidence: 99%

“…A polyclonal antibody against murine S100A9, harvested and purified from immunized rabbits in house, was labeled with Cy5.5 (aS100A9-Cy5.5, l excitation [l ex ] 5 673 nm; l emission [l em ] 5 692 nm; GE Healthcare Bio-Sciences Corp.) as described earlier (14). As control for unspecific tracer distribution, rabbit-derived IgG of irrelevant specificity was labeled with Cy5.5 or Cy7 (rabIgG-Cy5.5/Cy7, l ex 5 747 nm; l em 5 774 nm; GE Healthcare Bio-Sciences Corp.) for parallel injection experiments.…”

Section: Tracer Synthesismentioning

confidence: 99%

“…In a recent publication, the principles of S100A9 imaging were successfully established in various models of inflammation, confirming sensitivity and specificity of the antibody-based tracer aS100A9-Cy5.5 for local changes of monocyte activity (14). On the basis of this experience, we aimed to prove the feasibility to visualize tumor-associated inflammation and assess this approach for estimation of the activity of tumor-educated immune cells in the tumor microenvironment.…”

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confidence: 99%

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Optical In Vivo Imaging of the Alarmin S100A9 in Tumor Lesions Allows for Estimation of the Individual Malignant Potential by Evaluation of Tumor–Host Cell Interaction

et al. 2015

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Tumors recruit and reprogram immune cells to support tumor development and spread, the most prominent among them being of monocytic origin such as tumor-associated macrophages (TAM) or myeloid-derived suppressor cells (MDSC). The alarmin S100A8/ A9 has been implicated in the induction of TAM and MDSC. We assessed S100A9 as a molecular imaging marker for the activity of tumor-associated immune cells in a syngeneic murine breast cancer model. S100A9 could serve as a surrogate marker for tumor immune crosstalk as a function of malignancy, providing a tool with the potential for both basic research in tumor immunology and clinical stratification of patients. Methods: BALB/c mice were inoculated with murine breast cancer cells of common origin but different metastatic capability. At different times during tumor development, optical imaging was performed using a S100A9-specific probe to visualize activated monocytes. To further explore the impact of tumor-educated monocytes, splenic myeloid cells were isolated from either healthy or tumor-bearing animals and injected into tumor-bearing mice. We analyzed the effect of the cell transfer on immune cell activity and tumor development. Results: We could prove S100A9-driven imaging to sensitively and specifically reflect monocyte activity in primary tumor lesions. The imaging results were corroborated by histology and fluorescence-activated cell sorting analyses. In a prospective experiment, S100A9 imaging proved indicative of the individual tumor growth, with excellent correlation. Moreover, we could show that the monocyte activity as depicted by S100A9 activity in the primary tumor lesion mirrored the tumor's metastatic behavior. Treatment with tumor-primed splenic monocytes induced increased tumor growth, accompanied by an augmented infiltration of activated myeloid cells (MDSC and TAM) into the tumor. The consecutive S100A9 expression as depicted by in vivo imaging was significantly increased. Conclusion: S100A9 proved to be a sensitive and specific marker for the activity of tumor-associated immune cells. To our knowledge, S100A9 imaging represents a first in vivo imaging approach for the estimation of recruitment and activity of tumorassociated myeloid immune cells. We demonstrated the potential value of this imaging approach for prediction of local and systemic tumor development.

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Damage-associated Molecular Patterns

Cavaillon

2017

Inflammation - From Molecular and Cellular Mechanisms to the Clinic

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Alarmin S100A8/S100A9 as a biomarker for molecular imaging of local inflammatory activity

Cited by 155 publications

References 44 publications

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

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

Optical In Vivo Imaging of the Alarmin S100A9 in Tumor Lesions Allows for Estimation of the Individual Malignant Potential by Evaluation of Tumor–Host Cell Interaction

Damage-associated Molecular Patterns

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