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

Abstract

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.

The Urokinase Receptor (uPAR) as a “Trojan Horse” in Targeted Cancer Therapy: Challenges and Opportunities

“…In addition to consolidating the correlate of uPAR expression with tumor progression and aggressiveness, these observations also signify the important contribution of the uPAR-positive stromal compartment to the overall process. Indeed, stromal uPAR expression may support ECM proteolysis and malignant tumor invasion and concomitantly assist the well-known tumor-promoting functions of the stroma (e.g., angiogenesis) through the receptor-mediated signaling activities [ 11 , 12 , 15 , 52 , 146 , 147 ]. This observation further strengthens the now well-accepted idea of cancer progression as a complex process involving a dynamic molecular interplay between malignant and supporting stromal cells that concurrently remodel the tumor microenvironment (TME) to provide sustained pro-cancer signals.…”

“…Bidirectional paracrine signaling pathways intervene to regulate this complex cancer-stromal crosstalk. Soluble mediators released by cancer cells recruit and activate stromal cells such as macrophages to secrete further bioactive molecules (cytokines, growth factors, and proteolytic mediators, including uPA/uPAR), which create a permissive and supportive microenvironment for tumor growth and progression [ 146 , 147 , 148 ]. The negative prognostic value associated with uPAR stromal expression in multiple cancer types, including breast [ 135 ], colon [ 130 ], and pancreatic cancer [ 119 ], clearly emphasizes this concept and underscores the therapeutic potential of targeting the tumor stroma as a promising adjuvant anti-cancer treatment.…”

“…Given the intratumoral heterogeneity in uPAR expression, it is important to characterize this expression pattern when designing an optimal uPAR-targeted cytotoxic insult, as it would strongly impact its effectiveness. The remarkable stromal expression of uPAR also allows targeting this compartment, which offers multiple opportunities to enhance the therapeutic efficacy compared to exclusively targeting the tumor cells, especially in tumors expressing uPAR in both cell types, such as pancreatic cancer, or those lacking a tumor-specific molecular target [ 11 , 12 , 15 , 52 , 120 , 146 ]. Indeed, while having an indirect anti-cancer effect by attenuating the tumor-promoting effect of the stroma, cytotoxic targeting of this compartment may also increase drug-delivery efficiency by breaking down the dense stromal barrier, which severely hampers tumor perfusion by therapeutic agents, ultimately leading to drug resistance and disease recurrence [ 3 ].…”

PLAUR as a Potential Biomarker Associated with Immune Infiltration in Bladder Urothelial Carcinoma

“… 18 PLAUR was demonstrably elevated in a variety of malignant cancers and correlated with the prognosis of cancer patients. 19 , 20 However, the role of PLAUR in BLCA remains unclear.…”

Early Prediction of Objective Response of Fibrinogen in a Real-World Cohort of Hepatocellular Carcinoma Cases Treated by Programmed Cell Death Receptor-1 and Lenvatinib

“…The adhesion of tumor cells to platelets is facilitated by fibrinogen, causing platelet aggregation around the tumor cells, and immune attack may be prevented. 29 The metastasis, invasion and proliferation of tumor cells are regulated by fibrinogen via binding to growth factors, eg, PDGF (platelet-derived growth factor), FGF-2 (fibroblast growth factor-2), and VEGF (vascular endothelial growth factor). [30][31][32] Tumor progression is shown to be related to inflammatory response, that's, leukocyte infiltration in the tumor matrix, and fibrinogen is converted to fibrin, thereby promoting tumor angiogenesis.…”