Colitis-Associated Cancer Is Dependent on the Interplay between the Hemostatic and Inflammatory Systems and Supported by Integrin αMβ2 Engagement of Fibrinogen

Abstract

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 employed 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 αMβ2 binding motif (Fibγ390-396A) revealed αMβ2-mediated engagement of fibrin(ogen) is mechanistically coupled to local inflammatory processes (e.g., IL-6 elaboration) and epithelial alterations which contribute to adenoma formation. Consistent with these findings, the majority of Fibγ390-396A mice developed no discernable adenomas, whereas penetrance was 100% in controls. Furthermore, the adenomas harvested from Fibγ390-396A 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 demonstrate, 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)-αMβ2 interactions may be useful in preventing and/or treating this important subset of malignancies.

Plasminogen Deficiency Delays the Onset and Protects from Demyelination and Paralysis in Autoimmune Neuroinflammatory Disease

“…Fibrin-rich matrices are an important local cue for leukocyte activation, mediated via interaction with the integrin receptor ␣ M ␤ 2 . Elimination of the ␣ M ␤ 2 binding motif on fibrinogen, while retaining clotting function, significantly protects mice in the settings of inflammatory joint disease, colitis, Duchene's muscular dystrophy, and, most notably, EAE (Adams et al, 2007;Flick et al, 2007;Steinbrecher et al, 2010;Vidal et al, 2012). In this latter context, fibrin matrices appear to drive microglial/macrophage migration and local activation events, leading to demyelination and loss of motor function in EAE (Adams et al, 2007;Davalos et al, 2012;Ryu et al, 2015).…”

Oncogenes and the coagulation system – forces that modulate dormant and aggressive states in cancer

“…Of note in this context are well controlled and elegantly executed studies of Palumbo and colleagues who demonstrated that in a mouse model were colon cancer originates on the background of inflammatory bowel disease, coagulation factors, such as fibrinogen are an essential part of the disease pathogenesis. In this setting the leukocyte binding domain of fibrinogen (Fibγ390-396A) was required for tumor formation, a finding that suggests a link between coagulation and inflammation [109]. This is also important because in this model cancer cells are not introduced externally, but are formed endogenously in mice subjected to the proinflammatory protocol of azoxymethane and dextran sodium sulfate exposure, and thereby the related processes likely induce (transform) colonic epithelium to form a full blown adenoma [25,109].…”

“…In this setting the leukocyte binding domain of fibrinogen (Fibγ390-396A) was required for tumor formation, a finding that suggests a link between coagulation and inflammation [109]. This is also important because in this model cancer cells are not introduced externally, but are formed endogenously in mice subjected to the proinflammatory protocol of azoxymethane and dextran sodium sulfate exposure, and thereby the related processes likely induce (transform) colonic epithelium to form a full blown adenoma [25,109]. It remains unclear whether the nexus of inflammatory and coagulant events is mainly a part of the supportive niche for CSCs transformed by another mechanism (mutagenesis), or whether host responses are responsible for the transformation process.…”

Factor XIII activity mediates red blood cell retention in venous thrombi

“…However, Fibγ 390-396A mice have defective clearance of Staphylococcus aureus (4) and are protected against autoinflammatory disorders (5)(6)(7)(8)(9). These effects are thought to stem from the lack of fibrin-driven leukocyte responses during inflammation.…”