An Antimicrobial Peptide Regulates Tumor-Associated Macrophage Trafficking via the Chemokine Receptor CCR2, a Model for Tumorigenesis

PLoS One

Hameem I. Kawsar¹  Thomas M. McIntyre¹  Zhimin Feng²  Ge Jin²  Stanley A. Hirsch²  Qing Yin Zheng²  Santosh K. Ghosh²  Aaron Weinberg³  Xun Jia³  Chun Zeng⁴  Aimin Zhou⁵ 

[1] Case Comprehensive Cancer Center, Cleveland, Ohio, United States of America;Department of Biological Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio, United States of America;Department of Chemistry, Cleveland State University, Cleveland, Ohio, United States of America;Department of Oral Pathology, Case Western Reserve University School of Dental Medicine, Cleveland, Ohio, United States of America;Department of Otolaryngology-Head and Neck Surgery, University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America

关键词: Macrophages;    Cell migration;    Chemokines;    Mouse models;    Biopsy;    Cytokines;    Inflammation;    Monocytes;   

DOI  :  10.1371/journal.pone.0010993

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

Background 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 β-defensin-3 (hBD-3) has been associated with TAM trafficking in oral cancer; however, its involvement in tumor-related inflammatory processes remains largely unknown.Methodology 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.Conclusions/Findings 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-1α (IL-1α), IL-6, IL-8, CCL18, and tumor necrosis factor-α (TNF-α) 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.

【 授权许可】

CC BY