Fibrin and Extracellular Matrix: Scaffolds and Network for Malignant Cells

Abstract

Malignant cells build up a protective shield in form of a fibrin meshwork surrounding the tumor which helps it to escape the body’s immune system. In addition, tumor and stromal cells provide with an abundant extracellular matrix (ECM) consisting of proteoglycans, collagens, glycoproteins and glucosaminoglycans an additional scaffold with the capacity to bind large quantities of immunsuppressive substances. Many investigations found that heparin has a wide variety of positive effects counteracting these shielding and immunosuppressive properties of the ECM. Heparin can bind and neutralize many protective substances produced by the tumor cells. It inhibits cross-linking of collagen by deamination, and reduces the expression of FAK, LOX, glucosamines and proteoglycans. By these actions it prevents the development of a stiff and rigid ECM which presents additionally an effective scaffold for the tumor cells and also reduce the efficiency of therapeutic methods. In an ambulant trial with exogenously-added heparin in high dosages the survival probability over three years was significantly higher than without (p<0.001). Therefore, a combined therapy with a fibrinolyticum and heparin should be considered. This auxiliary treatment has the potential to support established therapy and improve anti-tumor response by the immune system.

Different strategies in treatment of malignant cells

“…This is obviously caused by the fibrin network surrounding the malignant cell and the glycoproteins and glycoprotein glycans predominantly paxillin and fibronectin in ECM. (8,9,10,21). Some investigations and publications found out that inflammatory mediators that contribute to neoplasia include prostaglandins, inflammatory cytokines i. e. IL -1ß, TNF-alpha, IL-6 and IL-15 and chemokines i.e.…”

“…These substances mainly induced by FAK and LOX form by tight connection with fibrin an effective scaffold. (7,10,31). However, heparins have a wide variety of positive effects counteracting these shielding and immunosuppressive properties of ECM properties.…”

“…The connection between chronic inflammation and malignancy or cancer is also wellrecognized (3 ,4 ,5). Moreover, the association between coagulation, changed ECM and malignant cells has been observed for centuries (6,7,8,9,10). In former publications it was demonstrated by monoclonal antibodies that malignant cells are surrounded directly by a net of fibrin as a scaffold against the immune surveillance whereas normal cells and tissues showed no deposits of fibrin (10).…”

“…Moreover, the association between coagulation, changed ECM and malignant cells has been observed for centuries (6,7,8,9,10). In former publications it was demonstrated by monoclonal antibodies that malignant cells are surrounded directly by a net of fibrin as a scaffold against the immune surveillance whereas normal cells and tissues showed no deposits of fibrin (10). This was especially marked and shown with malignant hemopoetic and cancer stem cells in blood and lymphatic vessels because there is an abundance of fibrinogen.…”

“…Moreover, they are able to survive stress and DNA damage better than benign cells (14,15). Further, the pathogenesis of haemostatic disorders caused by malignant tumors is complex and reflects the interaction of an increased coagulation system combined with fibrinogen production and activated platelets and fibroblasts (10,16). Additionally, tumor and malignant cells provide with an abundant extracellular matrix (ECM) consisting of proteoglycans, collagens, glycoproteins and glycosaminoglycans a further scaffold.…”