Colitis-associated cancer is dependent on the interplay between the hemostatic and inflammatory systems and supported by integrin alpha(M)beta(2) engagement of fibrinogen.
A link between colitis and colon cancer is well established, but the mechanisms regulating inflammation in this context are not fully defined. Given substantial evidence that hemostatic system components are powerful modulators of both inflammation and tumor progression, we used gene-targeted mice to directly test the hypothesis that the coagulation factor fibrinogen contributes to colitis-associated colon cancer in mice. This fundamental provisional matrix protein was found to be an important determinant of colon cancer. Fibrinogen deficiency resulted in a dramatic diminution in the number of colonic adenomas formed following azoxymethane/dextran sodium sulfate challenge. More detailed analyses in mice expressing a mutant form of fibrinogen that retains clotting function, but lacks the leukocyte integrin receptor alpha(M)beta(2) binding motif (Fibgamma(390-396A)), revealed that alpha(M)beta(2)-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., interleukin-6 elaboration) and epithelial alterations that contribute to adenoma formation. Consistent with these findings, the majority of Fibgamma(390-396A) mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibgamma(390-396A) mice were significantly smaller than those from control mice and less proliferative based on quantitative analyses of mitotic indices, suggesting an additional role for fibrin(ogen) in the growth of established adenomas. These studies show, for the first time, a unique link between fibrin(ogen) and the development of inflammation-driven malignancy. Given the importance of antecedent inflammation in the progression of numerous cancers, these studies suggest that therapies targeting fibrin(ogen)-alpha(M)beta(2) interactions may be useful in preventing and/or treating this important subset of malignancies.
Divisions of Gastroenterology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
Kris A
KA
Steinbrecher
Netanel A
NA
Horowitz
Elizabeth A
EA
Blevins
Kelley A
KA
Barney
Maureen A
MA
Shaw
Eleana
E
Harmel-Laws
Fred D
FD
Finkelman
Matthew J
MJ
Flick
Malinda D
MD
Pinkerton
Kathryn E
KE
Talmage
Keith W
KW
Kombrinck
David P
DP
Witte
Joseph S
JS
Palumbo
D000236:Adenoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001397:Azoxymethane; D002273:Carcinogens; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D018450:Disease Progression; D005353:Fibronectins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006487:Hemostasis / Q000502:physiology; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
D002273:Carcinogens; D016207:Cytokines; D005353:Fibronectins; D016177:Macrophage-1 Antigen; D016264:Dextran Sulfate; D001397:Azoxymethane