Effect of sulfated glycosaminoglycans on tumor invasion and metastasis

Abstract

Metastasis is the most devastating aspect of the tumor, being the main cause of morbidity and mortality in cancer patients. The events that lead to tumor invasion and metastasis depend fundamentally on the initial aquisition of a mesenchymal phenotype by the primary carcinoma, which provides the necessary machinary for invasion, intravasation, vascular transport, extravasation and tumor colonization. These events are orquestrated by different growth factors, proteoglycans and adhesion molecules, acting at the surface of cells. The anticoagulant heparin binds several of these molecules and can regulate the interactions that occur during tumor invasion and metastasis. For example, heparin modulates the binding of FGF-2 to its tyrosine kinase receptor during tumor proliferation, and the binding of growth factors involved in epithelial to mesenchymal transition during tumor invasion. It also binds P-selectin on activated platelets, preventing tumor cell-platelet interaction during hematogeneous metastasis. In this review, we discuss the role of sulfated glycosaminoglycans during tumor invasion and metastasis, and the possible therapeutic use of heparin analogs on cancer treatment.

Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases

“…Moreover, HA and sGAG affect various intracellular signaling pathways that can promote tumor cell proliferation, motility, and invasiveness as well as angiogenesis and stromal cell recruitment (50–53). In a recent study, Ropponen et al .…”

Overexpression of α2,3sialyl T-antigen in breast cancer determined by miniaturized glycosyltransferase assays and confirmed using tissue microarray immunohistochemical analysis

“…Such abnormal glycans mediate the interaction of cancer cells with the endothelium leading to angiogenesis [4] and metastasis [5]. They also facilitate tumor cell-platelet interaction during hematogeneous metastasis [6,7], and enhance tumorigenic potential through signaling pathways [8–10]. In addition to these functional roles, glycans and glycosylated proteins serve as cancer biomarkers, examples being CA-125 (ovarian cancer), CA 15-3 (breast cancer), CA 19-9 (pancreatic cancer) and carcinoembryonic antigen (CEA, colon cancer).…”

Glycosaminoglycans analogs from marine invertebrates: structure, biological effects, and potential as new therapeutics

“…P-selectin-mediated platelet-tumor cell and tumor-cell endothelium interactions facilitate the initial steps of hematogeneous metastasis (Borsig et al, 2001, 2002). The dermatan sulfates from S. plicata and P. nigra , that contain the same disaccharide core structure [α-L-IdoA(2SO 4 )-1→3β-D-GalNAc] n , but sulfated at carbon 4 or 6 of the GalNAc residues, respectively, and opposed HCII activities are potent inhibitors of P-selectin (Kozlowski and Pavao, 2011; Kozlowski et al, 2011). Both ascidian dermatan sulfates regardless of the position of sulfation on the N-acetylgalactosamine drastically attenuate metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells, and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model (Kozlowski and Pavao, 2011; Kozlowski et al, 2011).…”

“…The dermatan sulfates from S. plicata and P. nigra , that contain the same disaccharide core structure [α-L-IdoA(2SO 4 )-1→3β-D-GalNAc] n , but sulfated at carbon 4 or 6 of the GalNAc residues, respectively, and opposed HCII activities are potent inhibitors of P-selectin (Kozlowski and Pavao, 2011; Kozlowski et al, 2011). Both ascidian dermatan sulfates regardless of the position of sulfation on the N-acetylgalactosamine drastically attenuate metastasis of both MC-38 colon carcinoma and B16-BL6 melanoma cells, and the infiltration of inflammatory cells in a thioglycollate peritonitis mouse model (Kozlowski and Pavao, 2011; Kozlowski et al, 2011). Additionally, both ascidians glycosaminoglycans reduced thrombus size in a FeCl 3 -induced arterial thrombosis model, irrespective of their HCII activities.…”

“…Additionally, both ascidians glycosaminoglycans reduced thrombus size in a FeCl 3 -induced arterial thrombosis model, irrespective of their HCII activities. Interestingly, the arterial thrombi demonstrated a markedly reduced platelet deposition after dermatan sulfate treatment (Kozlowski and Pavao, 2011; Kozlowski et al, 2011), suggesting that the ascidians glycosaminoglycan inhibited P-selectin and thereby the binding of activated platelets during thrombus formation. These results provide evidence that inhibition of P-selectin is a potential therapeutic target in thrombosis, inflammation and metastasis, and ascidian dermatan sulfates may serve as anti-selectin agents.…”