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Angiogenesis, Metastasis, and the Cellular Microenvironment

Toll-Like Receptor 9 Agonists Promote Cellular Invasion by Increasing Matrix Metalloproteinase Activity

¹ Division of Hematology-Oncology, Department of Medicine, ² Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, and ³ Biostatistics and Bioinformatics Unit, Comprehensive Cancer Center, University of Alabama at Birmingham; ⁴ Birmingham Veterans Administration Medical Center, Birmingham, Alabama; and ⁵ Department of Oral and Maxillofacial Diseases, Institute of Dentistry, University of Helsinki, Helsinki, Finland

Requests for reprints: Katri S. Selander, Division of Hematology-Oncology, Department of Medicine, University of Alabama at Birmingham, WTI T558, 1824 6th Avenue South, Birmingham, AL 35294-3300. Phone: 205-975-5973; Fax: 205-934-9511. E-mail: Katri.Selander{at}ccc.uab.edu

Toll-like receptor 9 (TLR9) recognizes microbial DNA. We show here that TLR9 protein is expressed in human breast cancer cells and clinical breast cancer samples. Stimulation of TLR9-expressing breast cancer cells with the TLR9 agonistic CpG oligonucleotides (1-10 µmol/L) dramatically increased their in vitro invasion in both Matrigel assays and three-dimensional collagen cultures. Similar effects on invasion were seen in TLR9-expressing astrocytoma and glioblastoma cells and in the immortalized human breast epithelial cell line MCF-10A. This effect was not, however, dependent on the CpG content of the TLR9 ligands because the non-CpG oligonucleotides induced invasion of TLR9-expressing cells. CpG or non-CpG oligonucleotide-induced invasion in MDA-MB-231 cells was blunted by chloroquine and they did not induce invasion of TLR9^– breast cancer cells. Treatment of MDA-MB-231 cells with CpG or non-CpG oligonucleotides induced the formation of 50-kDa gelatinolytic band in zymograms. This band and the increased invasion were abolished by a matrix metalloproteinase (MMP) inhibitor GM6001 but not by a serine proteinase inhibitor aprotinin. Furthermore, CpG oligonucleotide treatment decreased tissue inhibitor of metalloproteinase-3 expression and increased levels of active MMP-13 in TLR9-expressing but not TLR9^– breast cancer cells without affecting MMP-8. Neutralizing anti-MMP-13 antibodies inhibited the CpG oligonucleotide-induced invasion. These findings suggest that infections may promote cancer progression through a novel TLR9-mediated mechanism. They also propose a new molecular target for cancer therapy, because TLR9 has not been associated with cancer invasiveness previously. (Mol Cancer Res 2006;4(7):437–47)

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