The urokinase plasminogen activator system is a serine protease family, including urokinase-type plasminogen activator (uPA), plasminogen activator inhibitors (PAIs), tissue-type plasminogen activator, and the uPA receptor (uPAR). The urokinase plasminogen activator system is associated with metastasis, poor prognosis, and high mortality. The plasminogen activator inhibitors, PAI-1 and PAI-2, inhibit uPA and tissue-type plasminogen activator; PAI-1 is the major inhibitor of the uPA/uPAR system, binding the active uPA–uPAR complex and degrading it.
Due to its inhibiting role toward uPA, PAI-1 is expected to negatively regulate cancer cells, limiting their proliferation and growth. While in some cases this is true, increasing evidence shows that PAI-1 positively influences tumor invasion and angiogenesis, and it is correlated with a poor prognosis. The loss of PAI-1 instead reduces tumor growth, invasion, and metastasis [1].
PAI-1 and its role in tumors
PAI-1 is a glycoprotein of 45 kDa and 379–381 residues with nine α helices and three β sheets. A sequence of 26 (Ser 343-Arg 368) amino acids in the C-terminus composes the reactive center loop, which contains the proteolytic cleavage for uPA. Depending on the state of the reactive center loop, PAI-1 can be classified into three forms: active, latent, and cleaved. Numerous studies indicate that PAI-1 is overexpressed in most human cancer cell lines and in most human neoplasms. PAI-1 plays a role in sustaining tumor proliferative signals, resisting tumor cell death, tumor angiogenesis, tumor invasion and metastasis, and tumor inflammation [2]. PAI-1 also plays a role in cancer-associated thrombosis, and recent studies focused on the role of PAI-1 in pancreatic cancer, one of the deadliest cancers worldwide.
Pancreatic cancer
Pancreatic cancer is the seventh leading cause of global cancer deaths, accounting for 4.7% of all cancer deaths [3]. It can induce a hypercoagulable state associated with clinically significant thrombosis. The principal risk factors for venous and arterial thrombosis in cancer patients are surgery, immobility, tumor histology and stage, chemotherapy, and some targeted therapies. In addition, the risk factors can be grouped by patient-, tumor- and treatment-related factors. Patients with pancreatic cancer experience one of the highest rates of thrombosis, with venous thromboembolism (VTE) prevalence of 12–36% and with an estimated arterial thromboembolism incidence of 2–5%. Furthermore, patients with metastatic disease at the time of diagnosis have a 3.3-fold increased risk of VTE than patients with localized disease.
In pancreatic cancer patients, the mechanisms leading to hypercoagulability have not been fully elucidated. Whereas some of these mechanisms may be common to other types of cancers, pancreatic cancer also possesses unique mechanisms that contribute to thrombosis development [4].
One of the key players for thrombosis in pancreatic cancer is tissue factor (TF), a transmembrane receptor that initiates the coagulation extrinsic pathway. TF is expressed in exocrine pancreatic cells upon malignant transformation and on inflammatory and stromal cells within the tumor microenvironment. The vascular endothelial cell disruption leads to exposure of subendothelial TF to blood, which binds and activates factor VII (FVII) and leads to prothrombin, thrombin release, and fibrin clot formation.
Tumors can inhibit fibrinolysis, the process that leads to blood clots breakdown. Human pancreatic tumors and cell lines highly express activated PAI-1, which is a key inhibitor of fibrinolysis, leading to an increased risk of VTE.
Malignant pancreatic cells secrete inflammatory cytokines (IL-1, TNF-α, and VEGF), which increase TF production, PAI-1 synthesis, and heterocellular adhesion molecule expression, which contribute to hypercoagulability.
Finally, pancreatic tumor cells induce platelet aggregation, which is another key contributor to the prothrombotic state. Platelets are involved in cancer-associated thrombosis in several ways. Activated platelets expose negatively charged phospholipids that create a procoagulant surface, which induces thrombin generation and fibrin formation. Activated platelets also release PAI-1 that inhibits fibrinolysis, creating a local hypofibrinolytic state at the site of the clot [4].
The study
A recent study investigated the role of PAI-1 in VTE in pancreatic cancer using samples from patients and mice bearing human pancreatic tumors. The levels of active PAI-1 were measured in patients prospectively observed during the disease for VTE occurrence. The study found that doubling of PAI-1 plasma levels resulted in a 40% increase of VTE, confirming an association between active PAI-1 plasma levels and VTE in patients with pancreatic cancer. Importantly, the study measured the levels of active PAI-1 in patients’ plasma because active PAI-1 and not total PAI-1 seems to be a potential marker for VTE.
The study also established a new mouse model to investigate VTE in mice bearing human pancreatic tumors (PANC-1 cell lines) expressing PAI-1. PANC-1 tumors grown in mice pancreas release human PAI-1 into the circulation causing impaired thrombus resolution 8 days after inferior vena cava ligation. In other words, human PAI-1 derived from the PANC-1 tumors can inhibit the fibrinolytic system in mice. In addition, PANC-1 tumors increase the levels of mouse PAI-1 in the plasma, even if the source of mouse PAI-1 in tumor-bearing mice is still unknown.
In summary, the study confirmed an association between active PAI-1 levels and VTE in pancreatic cancer. Mice bearing human pancreatic tumors have increased levels of tumor-derived human PAI-1 and host-derived mouse PAI-1 associated with impaired thrombus resolution. These results mean that PAI-1, in particular activated PAI-1, is a risk marker of VTE in pancreatic cancer.
One limitation of the study is the use of platelet-poor plasma. As previously said, platelets are one of the major sources of PAI-1; for this reason, the measured levels of PAI-1 in this study could be affected [5].
Keep reading the ASH series:
MicroRNA and role in cancer-associated thrombosis
Interplay between the hematologic system and solid tumor progression
Modeling predictors and outcomes in myeloproliferative neoplasms and thrombosis
References
- Dass K, Ahmad A, Azmi AS, Sarkar SH, Sarkar FH. Evolving role of uPA/uPAR system in human cancers. Cancer Treat Rev. 2008;34(2):122-136. doi:10.1016/j.ctrv.2007.10.005
- Kubala MH, DeClerck YA. The plasminogen activator inhibitor-1 paradox in cancer: a mechanistic understanding. Cancer Metastasis Rev. 2019;38(3):483-492. doi:10.1007/s10555-019-09806-4
- Global Cancer Observatory, WHO, available at https://gco.iarc.fr/
- Campello E, Ilich A, Simioni P, et al. The relationship between pancreatic cancer and hypercoagulability: a comprehensive review on epidemiological and biological issues. Br J Cancer 2019;121:359–371. https://doi.org/10.1038/s41416-019-0510-x
- Hisada Y, Garratt KB, Maqsood A, et al. Plasminogen activator inhibitor 1 and venous thrombosis in pancreatic cancer. Blood Adv 2021;5(2):487–495. doi: https://doi.org/10.1182/bloodadvances.2020003149