Newly Identified Metabolites Connect Colon Cancer to Thrombosis

Patients with cancer are at 4-to-7-fold higher risk of venous thromboembolism (VTE). The risk of cancer-associated VTE varies with the type of cancer, underscoring the presence of cancer type-specific drivers and a need for appropriate animal models, both of which have been understudied. Here, we generated a colon cancer-specific mouse model and probed for the development of VTE and factors that might induce it. To this end, a group of athymic animals injected with human colon adenocarcinoma cell line (HT-29) underwent inferior vena cava (IVC) ligation, a validated model of venous thrombosis. Compared to corresponding controls (age- and gender-matched), mice on regular chow diet with xenografts exhibited significantly higher IVC clot weights. Plasma analysis of metabolites led us to identify the tryptophan metabolites, Kynurenine and Indoxyl Sulfate, which are known activator of the Aryl Hydrocarbon Receptor (AHR), as significantly elevated in the cancer model (2-3 fold; p<0.05). Plasma from these animals activated the AHR pathway and augmented both tissue factor (TF) and Plasminogen Activator Inhibitor 1 (PAI-1) levels in venous endothelial cells. PAI-1 is a known target of AHR pathway in other cells. Using an AHR inhibitor, we showed that the above effects of the plasma depended on AHR activation. Consistent with these findings, immunostaining of the endothelial layer of IVC in animals with xenografts revealed predominantly nuclear AHR (sign of activation) and clear increases in TF and PAI-1 expression- telltale signs of an activated AHR-TF/PAI-1 axis. As TF augments thrombogenesis and PAI-1 inhibits thrombolysis, these results may explain the enhanced thrombogenicity in this model. While this model represents a novel tool to mechanistically probe mediators of cancer-associated VTE, it links for the first-time cancer-associated VTE to a set of metabolites. Our data raise a possibility of AHR-TF/PAI-1 axis as a mediator of VTE in other tumors, worthy of exploration given its potential as a biomarker and a therapeutic target.