eritoran and Carcinoma--Lewis-Lung

S100A8/A9 is a major component of the acute phase of inflammation, and appears to regulate cell proliferation, redox regulation and chemotaxis. We previously reported that S100A8/S100A9 are upregulated in the premetastatic lung. However, the detailed mechanisms by which S100A8 contributes to tumor progression have not been elucidated. In this study, we investigated the TLR4/MD-2 dependency by S100A8 on tumor progression. We found that S100A8 (2-89) peptide stimulated cell migration in a manner dependent on TLR4, MD-2 and MyD88. The S100A8 (2-89) peptide also activated p38 and NF-κB in TLR4-dependent manner. The peptide induced the upregulation of both IL-6 and Ccl2 in peritoneal macrophages obtained from wild-type mice, but not TLR4-deficient mice. We then investigated the responsible region of S100A8 for TLR4/MD-2 binding by a binding assay, and found that C-terminal region of S100A8 binds to TLR4/MD-2 complex. To further evaluate the TLR4 dependency on tumor microenvironment, Lewis lung carcinoma-bearing mice were treated with Eritoran, an antagonist of TLR4/MD-2 complex. We found that both tumor volume and pulmonary recruitment of myeloid-derived suppressor cells were reduced with the treatment of Eritoran for five consecutive days. Eritoran reduced the development of tumor vasculature, and increased tumor-infiltration of CD8(+) T-cells. Taken together, S100A8 appears to play a crucial role in the activation of the TLR4/MD-2 pathway and the promotion of a tumor growth-enhancing immune microenvironment.

Topics: Animals; Binding Sites; Calgranulin A; Calgranulin B; Carcinoma, Lewis Lung; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemokine CCL2; Disaccharides; Enzyme Activation; Humans; Interleukin-6; Lymphocyte Antigen 96; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; NF-kappa B; Oxidation-Reduction; p38 Mitogen-Activated Protein Kinases; Protein Binding; Sugar Phosphates; Toll-Like Receptor 4; Tumor Microenvironment