PLG

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Introduction

The plasminogen activation (PA) system plays an important role in various pathophysiological processes, including remodeling of blood vessels and tissues, and tumor formation and development, etc.Some molecular components of the PA system have received a lot of attention in the field of cancer, because their overall expression is related to the progression of certain types of cancer and patient prognosis, or because they have a rate-limiting role in plasmin production. Therefore, a lot of research in the past 20 years has focused on plasminogen activators (tPA and uPA), their inhibitors (PAI-1 and PAI-2), the uPA receptors (uPAR) and various plasminogen receptors. The research on the actual cleavage-executing enzyme plasmin seems to have been abandoned to some extent. In addition, as an effective proteolytic enzyme, plasmin has been proven by a large amount of evidence that it can cleave and degrade a variety of proteins in vitro. However, these early discoveries may hinder subsequent studies of precise plasmin targets and functions in a living animal, especially in the context of the tumor microenvironment, where the list of non-fibrin proteins proven to be actual in vivo plasmin substrates is rather limited.

Figure 1. Components of the plasminogen-plasmin system (McMahon, B.J.; Kwaan, H.C. 2015)

Specific Functions ofIn Vivo Generated Plasmin in the Tumor Microenvironment

The mechanism of uPA-mediated plasmin production plays an important role in the tumor environment. Therefore, the expression level of uPA in tumor cells is closely related to its migration, invasion, colonization and metastasis, and processes that are enhanced at least in part by tumor uPA-generated plasmin. On the other hand, compared with implants of wild-type recipients, primary tumors originating from uPA-competent tumor cells implanted into uPA-deficient mice have retarded development and reduced vascular distribution. In addition, the activity of host uPA can also regulate inflammatory cell influx into the primary tumors. Comparative studies of plasminogen null mice and their plasminogen-expressing littermates can more directly determine the specific role of plasmin in normal physiology and cancer progression. Studies have shown that the function of plasminogen is complex, and its performance in cancer depends on the site of tumor development. The physiological process of inflammatory cell recruitment also requires the participation of plasminogen, although the result of such influx is dependent on the model system. Therefore, impaired accumulation of macrophages in the peritoneal cavity was observed in plasminogen knockout mice. In contrast, plasminogen inhibits the influx of tumor-infiltrating macrophages into fibrosarcoma tumors and inhibits tumor progression and angiogenesis.

Plasmin-Mediated Cleavage of Cell Surface Molecules as a Target for Cancer Therapy

Plasmin-mediated proteolytic modification of cell surface molecules leads to its functional activation, indicating that some functions of plasmin are ignored or underestimated by mainstream cancer research. Plasmin-mediated fibrinolysis is inhibited by the widespread use of anti-plasmin inhibitors and increases the formation of microthrombi, thereby inadvertently promoting the thrombi-dependent survival of tumor cells. Consistent with this situation, when melanoma cells were inoculated into aprotinin-treated mice, the size of thrombus and the level of lung colonization in the experimental metastasis model increased significantly. A large amount of experimental data and clinical reports on the termination of aprotinin trials for patients with lung, esophageal or breast cancer caution against indiscriminate targeting plasmin-like serine proteases for cancer treatment.

For a long time, compared with directly inhibiting plasmin-mediated proteolysis, targeting those components of the PA system which activate plasminogen or pro-uPA or inhibit uPA activity has been considered a more promising anti-cancer treatment strategy. In several independent models, it was proved that using a specific activation-preventing mAb (mAb-112) to target the cleavage-activating step of cell surface-bound pro-uPA can effectively reduce the metastasis of prostate cancer cells. Finally, the plasmin cleavage portions of the transmembrane molecule can also be used as an important biomarker in the pathological process. Therefore, just as the biochemical detection of the plasmin-cleaved amino-terminal domain of the NMDA receptor can indicate damage to the central nervous system, the detection of the 65 kDa plasmin-cleaved fragment of CDCP1 may indicate the ongoing dissemination of cancer cells.

Figure 2. Known steps in the activity of the plasminogen-plasmin system on the cell surface (McMahon, B.J.; Kwaan, H.C. 2015)