title: S100A9 interaction with TLR4 promotes tumor growth.
abstract: By breeding TRAMP mice with S100A9 knock-out (S100A9(-/-)) animals and scoring the appearance of palpable tumors we observed a delayed tumor growth in animals devoid of S100A9 expression. CD11b(+) S100A9 expressing cells were not observed in normal prostate tissue from control C57BL/6 mice but were readily detected in TRAMP prostate tumors. Also, S100A9 expression was observed in association with CD68(+) macrophages in biopsies from human prostate tumors. Delayed growth of TRAMP tumors was also observed in mice lacking the S100A9 ligand TLR4. In the EL-4 lymphoma model tumor growth inhibition was observed in S100A9(-/-) and TLR4(-/-), but not in RAGE(-/-) animals lacking an alternative S100A9 receptor. When expression of immune-regulating genes was analyzed using RT-PCR the only common change observed in mice lacking S100A9 and TLR4 was a down-regulation of TGFβ expression in splenic CD11b(+) cells. Lastly, treatment of mice with a small molecule (ABR-215050) that inhibits S100A9 binding to TLR4 inhibited EL4 tumor growth. Thus, S100A9 and TLR4 appear to be involved in promoting tumor growth in two different tumor models and pharmacological inhibition of S100A9-TLR4 interactions is a novel and promising target for anti-tumor therapies.
authors.affiliation: Immunology Group, Lund University, Lund, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Källberg
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogl
authors.forename: David
authors.initials: D
authors.lastname: Liberg
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.forename: Per
authors.initials: P
authors.lastname: Björk
authors.forename: Pernilla
authors.initials: P
authors.lastname: Wikström
authors.forename: Anders
authors.initials: A
authors.lastname: Bergh
authors.forename: Johannes
authors.initials: J
authors.lastname: Roth
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ivars
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D040502:Calgranulin B / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D015363:Quinolones; D013154:Spleen / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000097:blood; D000097382:CD68 Molecule
chemical_list: D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D039481:CD11b Antigen; D040502:Calgranulin B; D020928:Mitogen-Activated Protein Kinases; D011804:Quinolines; D015363:Quinolones; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C493487:Tlr4 protein, mouse; C516109:tasquinimod; C498977:Mok protein, mouse