title: DNA from dead cancer cells induces TLR9-mediated invasion and inflammation in living cancer cells.
abstract: TLR9 is a cellular DNA-receptor, which is widely expressed in breast and other cancers. Although synthetic TLR9-ligands induce cancer cell invasion in vitro, the role of TLR9 in cancer pathophysiology has remained unclear. We show here that living cancer cells uptake DNA from chemotherapy-killed cancer cells. We discovered that such DNA induces TLR9- and cathepsin-mediated invasion in living cancer cells. To study whether this phenomenon contributes to treatment responses, triple-negative, human MDA-MB-231 breast cancer cells stably expressing control, or TLR9 siRNA were inoculated orthotopically into nude mice. The mice were treated with vehicle or doxorubicin. The tumor groups exhibited equal decreases in size in response to doxorubicin. However, while the weights of vehicle-treated mice were similar, mice bearing control siRNA tumors became significantly more cachectic in response to doxorubicin, as compared with similarly treated mice bearing TLR9 siRNA tumors, suggesting a TLR9-mediated inflammation at the site of the tumor. In conclusion, our findings propose that DNA released from chemotherapy-killed cancer cells has significant influence on TLR9-mediated biological effects in living cancer cells. Through these mechanisms, tumor TLR9 expression may affect treatment responses to chemotherapy.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, SHEL 514, 1825 University Blvd, Birmingham, AL, 35294-3300, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Tuomela
authors.forename: Jouko
authors.initials: J
authors.lastname: Sandholm
authors.forename: Mika
authors.initials: M
authors.lastname: Kaakinen
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Joonas H
authors.initials: JH
authors.lastname: Kauppila
authors.forename: Joanna
authors.initials: J
authors.lastname: Ilvesaro
authors.forename: Dongquan
authors.initials: D
authors.lastname: Chen
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Harris
authors.forename: David
authors.initials: D
authors.lastname: Graves
authors.forename: Katri S
authors.initials: KS
authors.lastname: Selander
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden
chemical_list: D051217:Toll-Like Receptor 9; D004247:DNA