Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

Simple Summary In this review, we present a detailed discussion of how the plasminogen-activation system is utilized by tumor cells in their unrelenting attack on the tissues surrounding them. Plasmin is an enzyme which is responsible for digesting several proteins that hold the tissues surrounding solid tumors together. In this process tumor cells utilize the activity of plasmin to digest tissue barriers in order to leave the tumour site and spread to other parts of the body. We specifically focus on the role of plasminogen receptor-p11 which is an important regulatory protein that facilitates the conversion of plasminogen to plasmin and by this means promotes the attack by the tumour cells on their surrounding tissues. The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.