The role of protein C signaling in inflammation-associated cancer in vivo

Activated protein C (APC) is an important physiologic anticoagulant that is generated from protein C by the action of the thrombin-thrombomodulin (TM) complex on endothelial cells. While it is an important regulator of coagulation, it also affects inflammation, apoptosis, proliferation, and angiogenesis. APC and its receptor, the Endothelial Protein C Receptor (EPCR), have also been linked to tumor malignancy. In this study, a murine model of colitis-associated colon adenoma formation was used to assess the role of PC in inflammation-associated colon cancer. Water containing 2% Dextran Sodium Sulphate (DSS) was administered for 1 week to APCMIN/+, APCMIN/+/PC+/-, and APCMIN/+/EPCRÌ_å«/Ì_å« mice. Increased size and multiplicity of tumors were observed in APCMIN/+/EPCRÌ_å«/Ì_å« mice at 2 wks post-treatment. Tumors displayed increased inflammatory cell infiltration, which may be attributed to enhanced adhesion molecule expression by tumor and stromal cells. Additionally, aPC affects the endothelial cell barrier integrity of vessels. In the absence of aPC-mediated signaling, inflammatory cells may migrate from the vessels into the tumor more readily. Further investigations into inflammatory cell invasion will facilitate an understanding of the relationships between inflammation and cancer.