Inflammatory CC chemokines have been associated with cancer, but unequivocal genetic evidence that they play a role in clinically relevant models of carcinogenesis is lacking. D6 is a promiscuous decoy receptor and scavenger for CC chemokines and plays a non-redundant role in taming of 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. In humans, D6 was mainly expressed by lymphatic vessels and leukocytes in the mucosa of individuals with IBD and colon cancer, as well as control individuals. Mice lacking expression of D6 were significantly more susceptible to experimental colitis than WT mice and upon repeated irritant administration failed to resolve colitis, and showed significantly higher levels of several pro-inflammatory chemokines. Using bone marrow chimeras the regulatory function of D6 on colitis was tracked to the stromal/lymphatic compartment, with no contribution of hemopoietic cells. Finally, D6-/- mice showed increased susceptibility to colitis-associated cancer in the distal segment of the colon compared with WT mice. The decoy receptor D6 expressed on lymphatic vessels plays a key role in the control of intestinal inflammation and in the development of inflammation-associated colon cancer. Our results unveil the lymphatic system as a new cellular compartment with an unexpected role in the pathogenesis of IBD and intestinal cancer, and candidate chemokines as novel players in tumor promotion and progression.
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