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.