The lymphatic system controls intestinal inflammation and inflammation-associated Colon Cancer through the chemokine decoy receptor D6.
OBJECTIVE
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.
Division of Gastroenterology, Istituto Clinico Humanitas IRCCS, Milan, Italy.
Stefania
S
Vetrano
Elena M
EM
Borroni
Adelaida
A
Sarukhan
Benedetta
B
Savino
Raffaella
R
Bonecchi
Carmen
C
Correale
Vincenzo
V
Arena
Massimo
M
Fantini
Massimo
M
Roncalli
Alberto
A
Malesci
Alberto
A
Mantovani
Massimo
M
Locati
Silvio
S
Danese
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D018925:Chemokines / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003106:Colon / Q000378:metabolism; D003110:Colonic Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D003113:Colonoscopy / Q000379:methods; D018450:Disease Progression; D004198:Disease Susceptibility; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism; D007962:Leukocytes / Q000473:pathology; D042601:Lymphatic Vessels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D054447:Receptors, CCR10 / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D000097628:Chemokine Receptor D6
D018925:Chemokines; D018836:Inflammation Mediators; D054447:Receptors, CCR10; D000097628:Chemokine Receptor D6