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

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 3

Transgenic expression of D6 in the epidermis of FVB/N mice dampens cutaneous inflammation and suppresses papilloma formation.

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Transgenic expression of D6 in the epidermis of FVB/N mice dampens cutan...
(A) RNA from epidermal sheets from dorsal skin of WT and K14-D6 mice was subjected to RT-PCR (with or without reverse transcriptase [RT]) for mouse D6 or actin. Products were electrophoresed on an agarose gel and visualized with ethidium bromide under UV light. (B) Keratinocytes (2.5 × 105) from neonatal K14-D6 or WT mice were cultured in 1 ml of medium containing 10 nM BioCCL3, and remaining BioCCL3 was detected by western blotting at the times indicated. Data are representative of 3 repeated experiments. (C–E) WT and K14-D6 mice (n = 5 per group) received TPA on 3 consecutive days, and dorsal skin was harvested 4 days later. Untreated mice of each genotype (n = 5/group) were shaved and dorsal skin immediately harvested. Processed sections were scored for skin thickness (dermis plus epidermis) (C), epidermal CD3+ T cells (D), and MCs (E). A total of 25–40 data points were collected for each parameter from sections from 5 mice of each genotype. Data were analyzed using a 2-tailed unpaired Student’s t test. A repeat experiment generated similar data. (F) Fifteen K14-D6 mice and 17 WT counterparts received DMBA, and then TPA on days 1, 5, and 10 every 2 weeks for 20 weeks. Papillomas greater than 5 mm in diameter were counted once a week. The fraction of papilloma-free mice (left) and the mean tumor burden per mouse (right) are shown. Log-rank tests were applied to the data in the left panel. See Results for results of statistical tests on tumor burden data. *P < 0.001.