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.