Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen

Abstract

Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1–deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis.

High Preoperative Fibrinogen Level is Closely Associated with Receipt of Chemotherapy and Advanced Disease in Patients with Colorectal Cancer

“…The determination of the effect of these factors on colon cancer growth and spread is very striking finding. From these factors, the fibrinogen is now being considered a major determinant of colon cancer growth and dissemination (7). In all previous studies, the significance of preoperative fibrinogen is often studied mainly regarding a predictor of therapeutic response, prognostic value, and survival rate in patients with CRC (3,(18)(19)(20)(21).…”

“…The preoperative measurement of carcinoembryonic antigen (CEA) has been used for many years to predict the prognosis, survival rate, and recurrence, but is a normal range in more than half of CRC patients at the time of diagnosis and has been claimed more frequently not to be a perfect indicator in recent years (3)(4)(5). Despite these improvements concerning the host inflammatory response to tumor development and progression in recent years, there is still a lack of a simple, non-invasive and reliable method that accurately measured to disease stage and the need for chemotherapy (6,7). Consequently, a substantial number of new research has been launched to find a new blood-marker for CRC.…”

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

“…Proteases, cytokines, and bioactive lipids that are secreted into the extracellular space/milieu from cancer cells function in auto-or paracrine fashion to modify the tumor microenvironment so as to be amenable to invasion. There is substantial evidence that exogenous thrombin acts through its PAR-1 receptor to induce tumor growth and angiogenesis, as well as adhesion of tumor cells to platelets, ECs, fibronectin, and von Willebrand factor, with the cumulative result of promoting metastasis [reviewed in 3, [39][40][41][42]. However, the exact regulatory mechanism(s) by which endogenous thrombin is generated in the host during tumor growth and metastasis remains poorly defined.…”

“…Thrombin promotes cancer cell proliferation and tumor growth [reviewed in 3,19,27,28,41,61]. The latest findings revealed that thrombin-driven colonic adenocarcinoma growth depends on two targets of thrombin-mediated proteolysis: PAR-1, expressed by stromal cells, and the ECM protein, fibrinogen [41].…”

“…The latest findings revealed that thrombin-driven colonic adenocarcinoma growth depends on two targets of thrombin-mediated proteolysis: PAR-1, expressed by stromal cells, and the ECM protein, fibrinogen [41]. Tumor growth and proliferative indices were reduced in PAR-1-and fibrinogen-deficient mice.…”