The GAG-specific branched peptide NT4 reduces angiogenesis and invasiveness of tumor cells.

Luisa Bracci,Lorenzo Depau,Lucia Terzuoli,Alessandro Pini,Silvia Scali,Elisabetta Mandarini,Jlenia Brunetti,Chiara Falciani

doi:10.1371/journal.pone.0194744

Abstract

Heparan sulfate proteoglycans, HSPGs, modulate major transformations of cancer cells, leading to tumor growth, invasion and metastasis. HSPGs also regulate neo-angiogenesis which prompts cancer progression and metastatic spread. A different aspect of heparin and analogs is their prominent role in the coagulation of blood. The interplay between coagulation and metastasis is being actively studied: anticoagulants such as heparin-derivatives have anticancer activity and procoagulants, such as thrombin, positively modulate proliferation, migration and invasion. The branched peptide NT4 binds to HSPGs and targets selectively cancer cells and tissues. For this, it had been extensively investigated in the last years and it proved to be efficient as chemotherapeutic and tumor tracer in in vivo models of cancer. We investigated the effects of the branched peptide in terms of modulation of angiogenesis and invasiveness of cancer cells. NT4 proved to have a major impact on endothelial cell proliferation, migration and tube formation, particularly when induced by FGF2 and thrombin. In addition, NT4 had important effects on aggressive tumor cells migration and invasion and it also had an anticoagulant profile.The peptide showed very interesting evidence of interference with tumor invasion pathways, offering a cue for its development as a tumor-targeting drug, and also for its use in the study of links between coagulation and tumor progression involving HSPGs.

Highlights

The first indication that proteoglycans are involved in cancer biology dates back to 1960 when it was observed that certain carcinomas induced abnormal expression of proteoglycans in the host stroma and in the connective tissue surrounding cancer cells [1]
heparan sulfate proteoglycans (HSPGs) interact with growth factors, such as fibroblast growth factors (FGFs), heparin-binding epidermal growth factor-like growth factor (HBEFG), platelet-derived growth factor (PDGF) [7] and many others
Since NT4 binds HSPGs with sub-nanomolar affinity [24], we investigated the effects of the nude peptide, in terms of modulation of invasiveness and angiogenesis, on fibroblast growth factor 2 (FGF2) and thrombin-stimulated endothelial and tumor cells

Summary

Introduction

The first indication that proteoglycans are involved in cancer biology dates back to 1960 when it was observed that certain carcinomas induced abnormal expression of proteoglycans in the host stroma and in the connective tissue surrounding cancer cells [1]. Heparan sulfate proteoglycans (HSPGs) regulate cancer progression by promoting major transformations in cell phenotype, leading to tumor growth, invasion and metastasis [2]. HSPGs overexpression leads to enhanced proliferation of many types of tumor cells [6]. The huge structural diversity of HSPGs allows them to interact with a variety of proteins, such as extracellular matrix (ECM) macromolecules, growth factors, chemokines, morphogens and enzymes. Most of the proteins that engage with HSPGs have an heparin binding site that interacts with sulfated GAG chains [4]. Cell-associated HSPGs and those in the extracellular matrix (ECM) enhance angiogenesis by acting as growth factor co-receptors, whereas heparin and the shed soluble forms of HSPGs neutralize growth factors far from their receptors and inhibit angiogenesis [10,11]

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