Thrombin Drives Tumorigenesis in Colitis-Associated Colon Cancer

Abstract

The established association between inflammatory bowel disease and colorectal cancer underscores the importance of inflammation in colon cancer development. Based on evidence that hemostatic proteases are powerful modifiers of both inflammatory pathologies and tumor biology, gene-targeted mice carrying low levels of prothrombin were used to directly test the hypothesis that prothrombin contributes to tumor development in colitis-associated colon cancer (CAC). Remarkably, imposing a modest 50% reduction in circulating prothrombin in fII+/− mice, a level that carries no significant bleeding risk, dramatically decreased adenoma formation following an azoxymethane/dextran sodium sulfate challenge. Similar results were obtained with pharmacological inhibition of prothrombin expression or inhibition of thrombin proteolytic activity. Detailed longitudinal analyses showed that the role of thrombin in tumor development in CAC was temporally associated with the antecedent inflammatory colitis. However, direct studies of the antecedent colitis showed that mice carrying half-normal prothrombin levels were comparable to control mice in mucosal damage, inflammatory cell infiltration and associated local cytokine levels. These results suggest that thrombin supports early events coupled to inflammation-mediated tumorigenesis in CAC that are distinct from overall inflammation-induced tissue damage and inflammatory cell trafficking. That prothrombin is linked to early events in CAC was strongly inferred by the observation that prothrombin deficiency dramatically reduced the formation of very early, pre-cancerous aberrant crypt foci. Given the importance of inflammation in the development of colon cancer, these studies suggest that therapeutic interventions at the level of hemostatic factors may be an effective means to prevent and/or impede colitis-associated colon cancer progression.

Genetic diminution of circulating prothrombin ameliorates multiorgan pathologies in sickle cell disease mice

“…Cohorts of Berkeley sickle mice were injected with either a murine FII-specific or a control ASO gapmer starting at 3 weeks of age for up to 15 weeks of age (supplemental Figure 3A). The FII-specific ASO gapmer is complementary to the 39 noncoding portion of the F2 messenger RNA (mRNA, a sequence found to be unique in the mouse genome), 52,55 and specifically reduces hepatic F2 mRNA (thereby reducing circulating FII levels) without any impact on other coagulation system components (supplemental Figure 2). The FII-specific ASO dose used reduced circulating FII levels to ;10% of normal ( Figure 1A), a level of FII found here ( Figure 1B) and previously 55,56 to prolong PTs mildly without causing spontaneous bleeding.…”

Thrombin inhibition and cyclophosphamide synergistically block tumor progression and metastasis

“…62 Thrombin has been demonstrated to drive inflammatory responses in many pathologies including cancer. 63 In addition to proinflammatory cytokines such as IL-1b, IL-6, and PGE 2 , other tumor-derived cytokines such as TGF-b and VEGF are also involved in MDSC expansion. 61 Thrombin is a potent inducer of TGF-b, both by activating platelets to cause the release of TGF-b from the a-granules of platelets and via the release of latent TGF-b from extracellular matrix stores (Fig.…”

Thrombin—unique coagulation system protein with multifaceted impacts on cancer and metastasis

“…As an example, thrombin-driven adenoma formation in colon and colitisassociated cancers is associated with fibrin(ogen)-mediated engagement of the leukocyte integrin receptor αMβ2 [96,98]. Moreover, fibrinogen is thought to contribute to tumor angiogenesis in colonic adenocarcinoma [41] by binding VEGF [99] and other proteins capable of shaping the tumor microenvironment (e.g., FGF-2, tPA, plasminogen, PAI-2, TGF-β1 (see below)) [41,100,101].…”