Galectin-1 is essential in tumor angiogenesis and is a target for antiangiogenesis therapy

Abstract

We describe that galectin-1 (gal-1) is a receptor for the angiogenesis inhibitor anginex, and that the protein is crucial for tumor angiogenesis. gal-1 is overexpressed in endothelial cells of different human tumors. Expression knockdown in cultured endothelial cells inhibits cell proliferation and migration. The importance of gal-1 in angiogenesis is illustrated in the zebrafish model, where expression knockdown results in impaired vascular guidance and growth of dysfunctional vessels. The role of gal-1 in tumor angiogenesis is demonstrated in gal-1-null mice, in which tumor growth is markedly impaired because of insufficient tumor angiogenesis. Furthermore, tumor growth in gal-1-null mice no longer responds to antiangiogenesis treatment by anginex. Thus, gal-1 regulates tumor angiogenesis and is a target for angiostatic cancer therapy.angiostatic therapy ͉ endothelial cell ͉ galectin ͉ tumor models ͉ anginex A n adequate vasculature is a prerequisite for tumors to grow, and the need for neovessel formation (or angiogenesis) provides a target for treatment of cancer (1). Endothelial cells (EC) that line the tumor vasculature are particularly suitable target cells for therapeutic approaches, because they are easily accessible to agents delivered by the blood (2). However, to affect only tumor vasculature, specific targets on angiogenically active EC are essential. To date, only a few targets of tumor vasculature have been identified (3).We recently developed the specific angiostatic peptide anginex, which inhibits tumor growth through specific inhibition of angiogenesis (4-6). Although a broad profile of activities of anginex is known, such as prevention of EC adhesion and induction of apoptosis, the molecular target on tumor EC was never identified. In a receptor-finding study using a yeast twohybrid screening approach, we identified galectin-1 (gal-1) as a target protein of anginex.gal-1 belongs to a family of carbohydrate-binding proteins that share a conserved carbohydrate recognition domain of Ϸ130 aa (7-9). Over a dozen mammalian galectins have been described (10, 11), and members of this family are expressed in a wide range of species, suggesting an important role for galectins in basic cellular mechanisms. Galectins can be secreted and, depending on the cell type or state of differentiation, they have been found in the nucleus, cytoplasm, or extracellular matrix. It has been proposed that gal-1 mediates cell adhesion and migration (12) and is involved in several processes, including proliferation (13), apoptosis (14), and even mRNA splicing (15). The role of gal-1 in EC function or vascular biology has not been extensively studied.Here, we describe the function of gal-1 in angiogenesis. We provide direct functional evidence that gal-1 is required for tumor angiogenesis and outgrowth of tumors. Furthermore, we show that gal-1 is the target for the potent angiogenesis inhibitor anginex, thus establishing gal-1 as an important target for anticancer therapy.Results gal-1 Binds the Angiostatic Peptide Anginex...

Intra-articular lentivirus-mediated delivery of galectin-3 shRNA and galectin-1 gene ameliorates collagen-induced arthritis

“…36 Similarly, galectin-1 is crucial for tumor angiogenesis. In the galectin-1-null mouse, tumor growth is markedly impaired because of insufficient 37 Synovial angiogenesis also has an important role in the inflamed joints of patient with RA. In this study, the Lt.shGal3-treated rats with CIA had reduced microvessel density within the synovial tissues, thus supporting the angiogenic role for galectin-3.…”

Galectin-1 is a major effector of TrkB-mediated neuroblastoma aggressiveness

“…This clearly stresses the importance of our findings in the in vitro model and suggests a functional link between Trk and Gal-1 expressions also in the primary tumors. This is important, because the inhibition of Gal-1 functions by siRNA has been shown to inhibit tumor angiogenesis, which can be accomplished by siRNA (Mathieu et al, 2007) or by a Gal-1-specific peptide (Thijssen et al, 2006). Gal-1 expression has also been correlated with tumor aggressiveness (Jung et al, 2007;Chiang et al, 2008).…”

“…Gal-1 function has been found to be intricately linked to essential biological processes in tumor cells. It regulates complex signaling pathways involved in tumor-host interaction (Juszczynski et al, 2007;Rodig et al, 2008) and angiogenesis (Thijssen et al, 2006). By forcing activated T cells to undergo apoptosis (He and Baum, 2004), Gal-1 expression has been hypothesized to contribute to the tumor-immune escape.…”

The AP1-dependent secretion of galectin-1 by Reed–Sternberg cells fosters immune privilege in classical Hodgkin lymphoma

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