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

Nibbs, R. J.B. , Gilchrist, D. S., King, V., Ferra, A., Forrow, S., Hunter, K. D. and Graham, G. J. (2007) The atypical chemokine receptor D6 suppresses the development of chemically induced skin tumors. Journal of Clinical Investigation, 117(7), pp. 1884-1892. (doi: 10.1172/JCI30068)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nibbs, Professor Rob and Gilchrist, Dr Derek and Ferra, Mr Antonio and King, Dr Vicky and Graham, Professor Gerard
• Authors: Nibbs, R. J.B., Gilchrist, D. S., King, V., Ferra, A., Forrow, S., Hunter, K. D., and Graham, G. J.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing > Dental School; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Journal of Clinical Investigation
• Publisher: Americal Society for Clinical Investigation
• ISSN: 0021-9738
• ISSN (Online): 1558-8238