Modulation of Malignant Growth by the Coagulation Mechanism and Anticoagulants

This issue of Seminars in Thrombosis and Hemostasis reviews the impact of the clotting and fibrinolytic systems as well as anticoagulants on the modulation of malignant growth. The interrelationship between hemostasis and cancer is as yet not widely appreciated, although the propensity for thromboembolic complications in cancer patients appears to be widely accepted. The interrelationship, however, goes beyond thrombosis. Hemostasis is deeply involved in tumor growth, angiogenesis, and metastasis and modulation of these pathways may yield interesting and promising future treatment modalities.

In the first article, Zacharski provides an overview on how hemostasis and malignancies interrelate. The best-known and most widely studied relationship is that of cancer and thromboembolic diseases. Besides nonspecific causes, such as immobilization, surgeries, chemotherapy, and others, certain tumors release procoagulants, and others may activate the fibrinolytic system. Venous thromboembolism is the most frequently encountered clinical manifestation of cancer patients, but some may experience a more systemic activation of the clotting system, leading to disseminated intravascular coagulation (DIC), usually the compensated form. Less appreciated is the relationship among coagulation, anticoagulants, and control of tumor growth. Components of the coagulation system have been linked to cancer cells, and use of anticoagulants can, in certain forms of cancer, change the course of the disease. A third and very provocative concept appears to suggest that the coagulation system is involved in the early phases of tumor development. This would imply future new treatment modalities for cancer patients. The author strongly suggests that greater attention needs to be given by oncologists to the interrelationship between coagulation and malignancies.

In the next contribution, Deitscher reviews the clinical importance and management of deep venous thrombosis (DVT) in cancer patients. DVT and pulmonary embolism (PE) appear to be underdiagnosed in cancer patients, resulting in considerable morbidity and mortality. Standard treatment options with unfractionated heparin and oral anticoagulants can be problematic; heparin resistance and recurrence of DVT while on anticoagulants are just two issues. In addition, increased bleeding during anticoagulant treatment is often encountered. The use of low-molecular-weight heparins (LMWH) is extensively reviewed, not only for prophylaxis and treatment of thrombotic events but also for their potential benefits in metastasis prevention and prolongation of survival and their impact on angiogenesis. This comprehensive article is a valuable resource for health-care providers who care for cancer patients.

Splichal and coworkers discuss the multifunctional aspects of statins, especially from the viewpoint of their antithrombotic and antineoplastic properties. Although the statins were originally developed as cholesterol-lowering agents, it was quickly realized that they exert additional beneficial properties. The antithrombotic features have been demonstrated in experimental models and in humans, and numerous mechanisms have been identified that operate independently of the cholesterol-lowering properties. Statins appear to lower Rho activity that results in inhibition of coagulation and in blocking processes that lead to vascular damage. Because Rho proteins are also involved in abnormal cell growth and in tumor progression, the statins' potential of being antineoplastic has been suggested. In vitro studies have confirmed the anticancer activities of statins, and in vivo data seem to strongly suggest the same. Statins appear to be growth inhibitory rather than cytotoxic. Although they alone are probably not very useful in treating certain forms of cancer, they likely have an additional benefit when combined with other treatment modalities, especially cytotoxic agents. Final outcome awaits large clinical trials.

The defects in the coagulation system of multiple myeloma patients are described by Zangari and associates. Although some patients with this malignant disease have an increased bleeding tendency, most have thromboembolic events. There are several possible explanations for this: interference by immunoglobulins with the polymerization of fibrin leading to structures that are not readily dissolved by plasmin, autoantibody formation with procoagulant properties, effects of inflammatory cytokines on endothelium, and the development of resistance to activated protein C (APC). Injury of endothelium by tumor cells and injury by chemotherapy may be additional reasons for the observed hypercoagulability. All of these potential mechanisms are expertly discussed.

In the next article, Kwaan and coworkers address the pathogenesis of the increased risk for thrombosis in cancer patients. Two major contributors are tissue factor (TF) released from many cells, especially cancer cells, and cancer procoagulant (CP). TF is the prime initiator of clotting physiologically, but it is also released when cells undergo apoptosis. This could explain the high incidence of thrombosis in cancer patients under treatment. CP is expressed in many malignant cells and tissues. Both contribute to increased thrombin generation, and thrombin appears to be mitogenic. In addition, in many cancer patients, the fibrinolytic system is downregulated. Clearly, multiple factors increase the risk of thrombosis. Also, the impact of various cancer treatment modalities on thrombogenesis is examined. This article makes the long-observed association between thrombosis and malignancies plausible.

In their first article, Wojtukiewicz and associates describe the interactions between gastric cancer and the coagulation system in situ. Patients with gastric malignancies have a high incidence of thromboembolic complications. Although considerable data exist that suggest that this type of cancer is involved in the activation of the clotting system, little is known about the presence of coagulation-related proteins within the gastric tumor tissue. Using immunohistochemical techniques, the authors identified fibrin and related molecules as well as TF, prothrombin, and certain other coagulation-related factors in the tumor stroma, some on vessels within the tumor. Interestingly, no tissue factor pathway inhibitor (TFPI) was found, and other regulators of the clotting system were less expressed than procoagulant factors were. In addition, proteins of the fibrinolytic system were only found in small quantities. The authors suggest that TF-mediated extravascular coagulation occurs in the gastric cancer but that there are insufficient counterbalancing forces and insufficient fibrinolytic activity to regulate this phenomenon.

Next, Kohli and coworkers review the role of the clotting and fibrinolytic systems in patients with prostate cancer. These patients display, paradoxically, bleedings and thromboembolic episodes, most notably DIC. Patients with prostate cancer display a wide spectrum of thromboembolic complications, some related to therapies, especially estrogens. Patients have elevated levels of in vivo markers of hypercoagulability, and histologically tumor tissues contain fibrin and several other procoagulant factors. It is likely that TF plays a key role in hypercoagulability related to prostate cancer. Increased fibrinolysis may be linked to the bleeding tendency. There appears to be an overexpression of urokinase (u-PA) in prostate cancer leading to hyperfibrinolysis. In addition, angiogenesis, mediated by the coagulation system, especially thrombin, plays a major role. Vascular endothelial growth factors, induced by thrombin and by platelet activation, greatly influence angiogenesis in prostate cancer.

Abu-Hajir et al address the issue of assessing angiogenesis by noninvasive means. Angiogenesis is an integral part of tumor growth and development. If this could be measured accurately and reliably, important prognostic information could be gained. Measurements of microvessel density (MVD) have been successfully employed, but this technique requires histological sampling of tumor tissue and is thus invasive. Magnetic resonance imaging (MRI) is commonly used as a noninvasive procedure, but this technique has drawbacks, in particular unreliable information on tumor growth. Dynamic contrast agent-enhanced MRI methods have been developed that provide greater specificity about tumor vascularity, especially in brain tumors. This method allows for measurement of relative cerebral blood volume in both tumor and brain. The authors describe their experience with this procedure and give specific technical information as well as clinical applications.

In their second article, Wojtukiewicz and coworkers describe the in situ presence of components of the fibrinolytic system in laryngeal cancer tissues. Previously, they reported on the presence of TF, factors VII and X in tumor cells of laryngeal cancer tissue, and the presence of fibrinogen and factor XIIIa in tumor connective tissue. TFPI was found in tissues surrounding the tumor but not in tumor cells. In this study, they demonstrate the presence of plasminogen and tissue-type plasminogen activator (t-PA) in laryngeal tumor cells, especially in differentiated tumors. In undifferentiated tumor cells, u-PA was found, especially the low-molecular-weight form; high-molecular-weight u-PA was expressed to a lesser degree. Relatively low concentrations of plasminogen activator inhibitors (PAI) 1, 2, and 3 were identified in laryngeal carcinoma tumor cells. The data suggest that profibrinolytic forces dominate in laryngeal cancer cells. These could be involved in the promotion of tumor growth and dissemination. Based on these observations, new therapeutic options are discussed.

All contributors of this interesting and informative issue deserve great thanks and appreciation; special thanks go to Professor Zacharski for assembling and guest-editing this issue.