Fibrinolytic System and Cancer: Diagnostic and Therapeutic Applications

Abstract

Fibrinolysis is a crucial physiological process that helps to maintain a hemostatic balance by counteracting excessive thrombosis. The components of the fibrinolytic system are well established and are associated with a wide array of physiological and pathophysiological processes. The aberrant expression of several components, especially urokinase-type plasminogen activator (uPA), its cognate receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), has shown a direct correlation with increased tumor growth, invasiveness, and metastasis. As a result, targeting the fibrinolytic system has been of great interest in the field of cancer biology. Even though there is a plethora of encouraging preclinical evidence on the potential therapeutic benefits of targeting the key oncogenic components of the fibrinolytic system, none of them made it from “bench to bedside” due to a limited number of clinical trials on them. This review summarizes our existing understanding of the various diagnostic and therapeutic strategies targeting the fibrinolytic system during cancer.

A Clinical Prognostic Model Based on Preoperative Hematological and Clinical Parameters Predicts the Progression of Primary WHO Grade II Meningioma

“…An increasing number of studies have indicated that tumorigenesis is closely associated with abnormalities in the coagulation cascade response in the early stage of tumor. The coagulation system is an integral component of the unique vascular microenvironment for tumor proliferation and progress ( 28 , 29 ). FIB and DD, as important factors in the coagulation cascade and fibrinolysis processes, respectively, have been shown to be involved in the invasive process of a variety of malignancies ( 8 , 19 , 30 ).…”

Experimental and Clinical Evidence Supports the Use of Urokinase Plasminogen Activation System Components as Clinically Relevant Biomarkers in Gastroesophageal Adenocarcinoma

“…It is clear that in many carcinoma types, including GOC, the uPAS is a driver of tumour aggressiveness. Not surprisingly, several experimental anti-cancer and imaging approaches targeting various components of the uPAS have been pursued (reviewed in detail by Lin et al [131], Mahmood and Rabbani [15] and Yuan et al [132]). Briefly, anti-uPAS therapeutic approaches include antagonists of uPAR and various uPAR ligand (e.g., uPA, vitronectin, integrins, etc) interactions, small molecule and antibody inhibitors directed against uPA protease activity, PAI-1 inhibitors and uPA-therapeutic drug conjugates [15,131,132].…”

“…Not surprisingly, several experimental anti-cancer and imaging approaches targeting various components of the uPAS have been pursued (reviewed in detail by Lin et al [131], Mahmood and Rabbani [15] and Yuan et al [132]). Briefly, anti-uPAS therapeutic approaches include antagonists of uPAR and various uPAR ligand (e.g., uPA, vitronectin, integrins, etc) interactions, small molecule and antibody inhibitors directed against uPA protease activity, PAI-1 inhibitors and uPA-therapeutic drug conjugates [15,131,132]. Our group has previously described the use of PAI-2 conjugated cytotoxins and therapeutic radioisotopes, which were effective in mouse models of human breast and colon cancer [133][134][135][136][137].…”

“…Nevertheless, this highlights the promise of perhaps more selective uPAS drugs for the treatment of advanced disease. Small molecule uPAR binding peptides and antibodies targeting uPAR and uPA conjugated to imaging radioisotopes are also being developed that have been shown to successfully detect primary tumours and metastases (which overexpress uPA/uPAR) with ongoing clinical trials aiming to determine the utility of these approaches for prognostication and/or response to therapy (reviewed in Mahmood and Rabbani [15]). To the best of our knowledge, none of these trials yet includes patients with GOC.…”

“…As a broad-spectrum serine protease, plasmin then directly and indirectly (via the activation of pro-metalloproteinases) degrades a wide range of proteins in the ECM and BMs. This process enables tumour cell dissemination around the body, a key step required for the seeding of tumour cells at distant sites to form metastases [6,7,[11][12][13][14][15]. Tissue plasminogen activator (tPA) is the intra-vascular counterpart to uPA, involved in fibrin degradation to prevent blood clot formation [13].…”