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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.
AuthorsJohanna Tuomela, Jouko Sandholm, Mika Kaakinen, Ankita Patel, Joonas H Kauppila, Joanna Ilvesaro, Dongquan Chen, Kevin W Harris, David Graves, Katri S Selander
JournalBreast cancer research and treatment (Breast Cancer Res Treat) Vol. 142 Issue 3 Pg. 477-87 (Dec 2013) ISSN: 1573-7217 [Electronic] Netherlands
PMID24212717 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Toll-Like Receptor 9
  • DNA
Topics
  • Animals
  • Breast Neoplasms (genetics, immunology, metabolism, pathology)
  • Cell Line, Tumor
  • DNA (metabolism)
  • Disease Models, Animal
  • Female
  • Heterografts
  • Humans
  • Inflammation (genetics, immunology, metabolism)
  • Mice
  • Models, Biological
  • Neoplasm Invasiveness
  • RNA Interference
  • Toll-Like Receptor 9 (genetics, metabolism)
  • Tumor Burden

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