title: S100A8/A9 activate key genes and pathways in colon tumor progression.
abstract: The tumor microenvironment plays an important role in modulating tumor progression. Earlier, we showed that S100A8/A9 proteins secreted by myeloid-derived suppressor cells (MDSC) present within tumors and metastatic sites promote an autocrine pathway for accumulation of MDSC. In a mouse model of colitis-associated colon cancer, we also showed that S100A8/A9-positive cells accumulate in all regions of dysplasia and adenoma. Here we present evidence that S100A8/A9 interact with RAGE and carboxylated glycans on colon tumor cells and promote activation of MAPK and NF-κB signaling pathways. Comparison of gene expression profiles of S100A8/A9-activated colon tumor cells versus unactivated cells led us to identify a small cohort of genes upregulated in activated cells, including Cxcl1, Ccl5 and Ccl7, Slc39a10, Lcn2, Zc3h12a, Enpp2, and other genes, whose products promote leukocyte recruitment, angiogenesis, tumor migration, wound healing, and formation of premetastatic niches in distal metastatic organs. Consistent with this observation, in murine colon tumor models we found that chemokines were upregulated in tumors, and elevated in sera of tumor-bearing wild-type mice. Mice lacking S100A9 showed significantly reduced tumor incidence, growth and metastasis, reduced chemokine levels, and reduced infiltration of CD11b(+)Gr1(+) cells within tumors and premetastatic organs. Studies using bone marrow chimeric mice revealed that S100A8/A9 expression on myeloid cells is essential for development of colon tumors. Our results thus reveal a novel role for myeloid-derived S100A8/A9 in activating specific downstream genes associated with tumorigenesis and in promoting tumor growth and metastasis.
authors.affiliation: Sanford Children's Health Research Center, Sanford-Burnham Medical Research Institute, 10905 Road to the Cure, San Diego, CA 92121, USA.
authors.forename: Mie
authors.initials: M
authors.lastname: Ichikawa
authors.forename: Roy
authors.initials: R
authors.lastname: Williams
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: Geetha
authors.initials: G
authors.lastname: Srikrishna
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D040501:Calgranulin A / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D011134:Polysaccharides / Q000378:metabolism; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D040501:Calgranulin A; D040502:Calgranulin B; D018925:Chemokines; D016328:NF-kappa B; D011134:Polysaccharides; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D020928:Mitogen-Activated Protein Kinases