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Listeria monocytogenes Promotes Tumor Growth via Tumor Cell Toll-Like Receptor 2 Signaling

Departments of ¹ Biochemistry and Molecular Biology, ² Gynecology and Obstetrics, and ³ Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, The People's Republic of China; ⁴ Immunobiology Center, Mount Sinai School of Medicine; and ⁵ Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York

Requests for reprints: Zuo-Hua Feng, Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, The People's Republic of China. Phone: 86-27-83650754; Fax: 86-27-83650754; E-mail: fengzhg{at}public.wh.hb.cn or Huabao Xiong, Immunobiology Center, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029-6574. Phone: 212-659-9413; Fax: 212-849-2525; E-mail: Huabao.Xiong{at}mssm.edu.

The contribution of bacterial infection to tumorigenesis is usually ascribed to infection-associated inflammation. An alternate view is that direct interaction of bacteria with tumor cells promotes tumor progression. Here, we show that the microenvironment of large tumors favors bacterial survival, which in turn directly accelerates tumor growth by activating tumor cell Toll-like receptors (TLR). Listeria monocytogenes (Lm) survives in the microenvironment of large but not small tumors, resulting in the promotion of tumor growth. Lm did not affect the percentage of regulatory T cells or myeloid suppressor cells in the tumor. Through TLR2 signaling, Lm activated mitogen-activated protein kinases and nuclear factor-B in tumor cells, resulting in the increased production of nitric oxide and interleukin-6 and increased proliferation of tumor cells. All of these effects were abrogated by silencing expression of TLR2, but not TLR4. The interaction of Helicobacter pylori with tumor cells from gastric carcinoma patients resulted in similar effects. These findings provide a new insight into infection-associated tumorigenesis and illustrate the importance of antibiotic therapy to treat tumors with bacterial infiltration. [Cancer Res 2007;67(9):4346–52]

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