An antimicrobial peptide regulates tumor-associated macrophage trafficking via the chemokine receptor CCR2, a model for tumorigenesis

• Published in: PloS one Vol. 5; no. 6; p. e10993
• Main Authors: Jin, Ge, Kawsar, Hameem I, Hirsch, Stanley A, Zeng, Chun, Jia, Xun, Feng, Zhimin, Ghosh, Santosh K, Zheng, Qing Yin, Zhou, Aimin, McIntyre, Thomas M, Weinberg, Aaron
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 08.06.2010; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Anti-Infective Agents - pharmacology; Antimicrobial agents; Antimicrobial peptides; Biopsy; Breast cancer; Cancer; CC chemokine receptors; CCL18 protein; CCR2 protein; Cell adhesion & migration; Cell Biology/Gene Expression; Cell Line, Tumor; Cell migration; Cell Transformation, Neoplastic; Chemokine receptors; Chemokines; Chemotactic factors; Cytokines; Defensins; Dentistry; Desensitization; Immune system; Immunofluorescence; Immunology/Immune Response; Immunology/Innate Immunity; Infiltration; Inflammation; Inhibitors; Innate immunity; Interleukin; Interleukin 1; Interleukin 6; Interleukin 8; Lesions; Leukocyte migration; Macrophages; Macrophages - drug effects; Medical prognosis; Medicine; Metastases; Metastasis; Mice; Mice, Nude; Microscopy; Microscopy, Fluorescence; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Neoplasms, Experimental - pathology; Oncology; Oncology/Head and Neck Cancers; Oral cancer; Oral carcinoma; Patients; Peptides; Peptides - pharmacology; Peripheral blood; Pharmacology; Prognosis; Protein Transport; Receptors, CCR2 - metabolism; Recruitment; Rodents; Streptococcus infections; Studies; Trends; Tuberculosis; Tumor cells; Tumor necrosis factor-a; Tumor necrosis factor-α; Tumorigenesis; Tumors; Vascular endothelial growth factor; Cleveland Ohio; United States > US; Ohio
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0010993

Tumor-associated macrophages (TAMs) constitute a significant part of infiltrating inflammatory cells that are frequently correlated with progression and poor prognosis of a variety of cancers. Tumor cell-produced human beta-defensin-3 (hBD-3) has been associated with TAM trafficking in oral cancer; however, its involvement in tumor-related inflammatory processes remains largely unknown. The relationship between hBD-3, monocyte chemoattractant protein-1 (MCP-1), TAMs, and CCR2 was examined using immunofluorescence microscopy in normal and oral carcinoma in situ biopsy specimens. The ability of hBD-3 to chemoattract host macrophages in vivo using a nude mouse model and analysis of hBD-3 on monocytic cell migration in vitro, applying a cross-desensitization strategy of CCR2 and its pharmacological inhibitor (RS102895), respectively, was also carried out. MCP-1, the most frequently expressed tumor cell-associated chemokine, was not produced by tumor cells nor correlated with the recruitment of macrophages in oral carcinoma in situ lesions. However, hBD-3 was associated with macrophage recruitment in these lesions and hBD-3-expressing tumorigenic cells induced massive tumor infiltration of host macrophages in nude mice. HBD-3 stimulated the expression of tumor-promoting cytokines, including interleukin-1alpha (IL-1alpha), IL-6, IL-8, CCL18, and tumor necrosis factor-alpha (TNF-alpha) in macrophages derived from human peripheral blood monocytes. Monocytic cell migration in response to hBD-3 was inhibited by cross-desensitization with MCP-1 and the specific CCR2 inhibitor, RS102895, suggesting that CCR2 mediates monocyte/macrophage migration in response to hBD-3. Collectively, these results indicate that hBD-3 utilizes CCR2 to regulate monocyte/macrophage trafficking and may act as a tumor cell-produced chemoattractant to recruit TAMs. This novel mechanism is the first evidence of an hBD molecule orchestrating an in vivo outcome and demonstrates the importance of the innate immune system in the development of tumors.