PL-25 Mechanisms coupling thrombomodulin to tumor dissemination

Abstract

Thrombomodulin (TM) is a primarily endothelial associated high-affinity thrombin receptor crucial for thrombin-dependent protein C activation. The activated protein C/protein S complex proteolyzes coagulation factors V and VIII, rendering them nonfunctional [1]. The TM-thrombin complex also activates thrombin activatable fibrinolysis inhibitor (TAFI), which renders clot more resistant to lysis [2]. In addition to biological functions mediated through regulation of hemostatic function, TM has been shown to regulate multiple functions important in inflammation, including cytokine production, cell adhesion, and complement activation, through mechanisms involving the lectin-like domain [3]. A potential role for TM in tumor biology is suggested by studies showing that TM expression by tumor tissues correlates with a less advanced stage at diagnosis and a better prognosis for multiple cancers, including tumors of neural [4] and epithelial origin [5–8]. For example, studies by Ogawa and colleagues of tumor tissue from patients with squamous cell carcinoma (SCC) of the lung revealed decreased TM expression in tumor tissue from metastatic foci relative to primary tumors. Furthermore, patients with TM-negative tumors had a significantly poorer survival rate than those with TMpositive tumors [6]. Consistent with these observations, tumor cell lines subcloned from patients with malignant melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo [9]. This effect appeared to be thrombin and thrombin receptor independent, and possibly related to lectin like domain mediated signal transduction pathways. TM expression by tumor cells has also been implicated in limiting tumor cell invasive potential. For example, a human esophageal SCC cell line with high TM expression had significantly lower invasive potential than the same cell line with low TM expression [8].