The lymphatic system controls intestinal inflammation and inflammation-associated colon cancer through the chemokine decoy receptor D6
- Stefania Vetrano1,
- Elena M Borroni2,
- Adelaida Sarukhan2,
- Benedetta Savino2,
- Raffaella Bonecchi2,
- Carmen Correale1,
- Vincenzo Arena3,
- Massimo Fantini4,
- Massimo Roncalli2,
- Alberto Malesci1,2,
- Alberto Mantovani2,
- Massimo Locati2,
- Silvio Danese1
- 1Division of Gastroenterology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
- 2Department of Translational Medicine, University of Milan, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
- 3Institute of Pathology, Catholic University of Rome, Italy
- 4Division of Gastroenterology, University of Tor Vergata, Rome, Italy
- Correspondence to Silvio Danese, Istituto Clinico Humanitas IRCCS, Viale Manzoni 56, Rozzano, Milan, Italy;
- Revised 5 August 2009
- Accepted 14 August 2009
- Published Online First 20 October 2009
Background and aims Inflammatory CC chemokines have long been associated with cancer, but unequivocal evidence of a role in clinically relevant models of carcinogenesis is lacking. D6, a promiscuous decoy receptor that scavenges inflammatory CC chemokines, plays a non-redundant role in reducing the inflammatory response in various organs. As inflammation is a key player in the development of inflammatory bowel disease (IBD) and IBD-associated colorectal cancer, we investigated D6 expression in human colitis and colon cancer, and its role in experimental colitis and inflammation-associated colon cancer.
Results In humans, D6 was mainly expressed by lymphatic vessels and leukocytes in the mucosa of individuals with IBD and colon cancer, as well as the mucosa of control individuals. Mice lacking expression of D6 were significantly more susceptible to experimental colitis than wild-type mice and failed to resolve colitis, with significantly higher levels of several pro-inflammatory chemokines. In bone marrow chimeric mice, the ability of D6 to regulate colitis was tracked to the stromal/lymphatic compartment, with no contribution of haemopoietic cells. Finally, after administration of the carcinogen azoxymethane, D6−/− mice showed increased susceptibility to colitis-associated cancer in the distal segment of the colon compared with wild-type mice.
Conclusions D6 expressed on lymphatic vessels plays a key role in the control of intestinal inflammation and the development of inflammation-associated colon cancer. Our results reveal a new unexpected role for the lymphatic system in the pathogenesis of IBD and intestinal cancer, and candidate chemokines as novel players in tumour promotion and progression.
- Chemokine decoy receptor D6
- inflammatory bowel disease (IBD)
- dextran sulfate sodium (DSS)
- colon cancer
- inflammation and cancer
AM, ML and SD contributed equally to this paper.
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Funding This study was supported by grants from the Broad Medical Research Program, the European Crohn's and Colitis Organization (ECCO), the Italian Ministry of Health (Ricerca Finalizzata 2006, n.72 and Bando Giovani Ricercatori 2007), Fondazione Cariplo and My First AIRC Award (to SD) and from the European Community (INNOCHEM project 518167), the Ministero dell'Istruzione dell'Università e della Ricerca (Rome, Italy; PRIN project 2002061255; FIRB project RBIN04EKCX) and Fondazione Cariplo (Milan, Italy; NOBEL project) (to AM and ML). This work was conducted with the support of the Fondazione Humanitas per la Ricerca (Rozzano, Italy). The generous contribution of the Italian Association for Cancer Research (AIRC; Milan, Italy) is gratefully acknowledged. BME is a recipient of a fellowship from the Italian Foundation for Cancer Research (FIRC; Milan, Italy).
Competing interests None.
Ethics approval This study was with the approval of the ethics committee of the Istituto Clinico Humanitas.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.