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The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors
Robert J.B. Nibbs, … , Keith D. Hunter, Gerard J. Graham
Robert J.B. Nibbs, … , Keith D. Hunter, Gerard J. Graham
Published July 2, 2007
Citation Information: J Clin Invest. 2007;117(7):1884-1892. https://doi.org/10.1172/JCI30068.
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Research Article

The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors

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Abstract

A subset of CC chemokines, acting through CC chemokine receptors (CCRs) 1 to 5, is instrumental in shaping inflammatory responses. Recently, we and others have demonstrated that the atypical chemokine receptor D6 actively sequesters and destroys many of these proinflammatory CC chemokines. This is critical for effective resolution of inflammation in vivo. Inflammation can be protumorigenic, and proinflammatory CC chemokines have been linked with various aspects of cancer biology, yet there is scant evidence supporting a critical role for these molecules in de novo tumor formation. Here, we show that D6-deficient mice have increased susceptibility to cutaneous tumor development in response to chemical carcinogenesis protocols and, remarkably, that D6 deletion is sufficient to make resistant mouse strains susceptible to invasive squamous cell carcinoma. Conversely, transgenic D6 expression in keratinocytes dampens cutaneous inflammation and can confer considerable protection from tumor formation in susceptible backgrounds. Tumor susceptibility consistently correlated with the level of recruitment of T cells and mast cells, cell types known to support the development of skin tumors in mice. These data demonstrate the importance of proinflammatory CC chemokines in de novo tumorigenesis and reveal chemokine sequestration by D6 to be a novel and effective method of tumor suppression.

Authors

Robert J.B. Nibbs, Derek S. Gilchrist, Vicky King, Antonio Ferra, Steve Forrow, Keith D. Hunter, Gerard J. Graham

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Figure 2

Deletion of D6 increases tumor burden in DMBA/TPA-treated FVB/N mice.

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Deletion of D6 increases tumor burden in DMBA/TPA-treated FVB/N mice.
  ...
(A–D) D6-deficient or WT FVB/N mice were treated on 3 consecutive days with TPA, and skin was harvested 2 or 4 days later. Skin was also prepared from shaved carrier mice 2 days after receiving carrier (acetone) only. After staining, sections were scored for skin thickness (dermis plus epidermis) (A), Ki67+ keratinocytes (basal and suprabasal layers) (B), epidermal CD3+ T cells (C), and MCs (D). (A, C, and D) 25–40 data points were collected from stained sections from 5 TPA-treated mice or 4–5 carrier controls of each genotype per time point. (B) The number of Ki67+ keratinocytes/mm was determined by counting 5 randomly selected 400-μm regions of epidermis from stained sections from 5 TPA-treated mice or 4–5 carrier controls of each genotype per time point. Data were analyzed using a 2-tailed unpaired Student’s t test. Two repeat experiments generated similar data. (E) Fifteen DMBA-treated D6-deficient or WT mice received TPA twice a week for 20 weeks. Total papillomas and papillomas greater than 5 mm in diameter were counted once a week. Fraction of papilloma-free mice (left) and mean tumor burden per mouse (right) are shown. Log-rank tests were used to analyze data in the left panels. See Results for results of statistical tests on tumor burden data. *P < 0.001; †P < 0.01.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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