PMID- 20544025
OWN - NLM
STAT- MEDLINE
DCOM- 20100901
LR  - 20240214
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 6
DP  - 2010 Jun 8
TI  - An antimicrobial peptide regulates tumor-associated macrophage trafficking via 
      the chemokine receptor CCR2, a model for tumorigenesis.
PG  - e10993
LID - 10.1371/journal.pone.0010993 [doi]
LID - e10993
AB  - 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 
      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. 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-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.
FAU - Jin, Ge
AU  - Jin G
AD  - Department of Biological Sciences, Case Western Reserve University School of 
      Dental Medicine, Cleveland, Ohio, USA. ge.jin@case.edu
FAU - Kawsar, Hameem I
AU  - Kawsar HI
FAU - Hirsch, Stanley A
AU  - Hirsch SA
FAU - Zeng, Chun
AU  - Zeng C
FAU - Jia, Xun
AU  - Jia X
FAU - Feng, Zhimin
AU  - Feng Z
FAU - Ghosh, Santosh K
AU  - Ghosh SK
FAU - Zheng, Qing Yin
AU  - Zheng QY
FAU - Zhou, Aimin
AU  - Zhou A
FAU - McIntyre, Thomas M
AU  - McIntyre TM
FAU - Weinberg, Aaron
AU  - Weinberg A
LA  - eng
GR  - R01DC009246/DC/NIDCD NIH HHS/United States
GR  - R01 DC009246/DC/NIDCD NIH HHS/United States
GR  - P01DE019759/DE/NIDCR NIH HHS/United States
GR  - P01 DE019089/DE/NIDCR NIH HHS/United States
GR  - P01 DE019759/DE/NIDCR NIH HHS/United States
GR  - R01 DC007392/DC/NIDCD NIH HHS/United States
GR  - R01DC007392/DC/NIDCD NIH HHS/United States
GR  - P01DE019089/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20100608
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Anti-Infective Agents)
RN  - 0 (Ccr2 protein, mouse)
RN  - 0 (Peptides)
RN  - 0 (Receptors, CCR2)
SB  - IM
CIN - Biomark Med. 2010 Oct;4(5):752. PMID: 20964089
MH  - Animals
MH  - Anti-Infective Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - *Cell Transformation, Neoplastic
MH  - Macrophages/*drug effects
MH  - Mice
MH  - Mice, Nude
MH  - Microscopy, Fluorescence
MH  - Neoplasms, Experimental/*pathology
MH  - Peptides/*pharmacology
MH  - Protein Transport
MH  - Receptors, CCR2/*metabolism
PMC - PMC2882331
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/06/15 06:00
MHDA- 2010/09/02 06:00
PMCR- 2010/06/08
CRDT- 2010/06/15 06:00
PHST- 2009/12/08 00:00 [received]
PHST- 2010/05/17 00:00 [accepted]
PHST- 2010/06/15 06:00 [entrez]
PHST- 2010/06/15 06:00 [pubmed]
PHST- 2010/09/02 06:00 [medline]
PHST- 2010/06/08 00:00 [pmc-release]
AID - 09-PONE-RA-14798R1 [pii]
AID - 10.1371/journal.pone.0010993 [doi]
PST - epublish
SO  - PLoS One. 2010 Jun 8;5(6):e10993. doi: 10.1371/journal.pone.0010993.