Expression of galectins on microvessel endothelial cells and their involvement in tumour cell adhesion

Lotan, Reuben; Belloni, Paula; Tressler, Robert; Lotan, Dafna; Xu, Xiao Chun; Nicolson, Garth L.

doi:10.1007/bf00731282

Cited by 122 publications

(85 citation statements)

References 42 publications

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“…Interfering with gal-1 function could (i) prevent metastasis formation through inhibition of gal-1-facilitated tumor cell-EC interactions (22,23), (ii) abrogate tumor escape from immunity through blockade of gal-1-induced apoptosis in activated T lymphocytes (14,20), and (iii) prevent the execution of tumor angiogenesis (this work). This multifunctionality makes gal-1 an excellent target for cancer therapy.…”

Section: Discussionmentioning

confidence: 91%

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

Thijssen¹,

Postel

Brandwijk³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

433

406

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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...

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Section: Discussionmentioning

confidence: 91%

“…Previous studies have shown that gal-1 is key in two mainstays of cancer. First, gal-1 supports metastasis formation, because it facilitates interactions between tumor cells and EC (22,23). Second, it protects the tumor against immunity, because it can induce apoptosis in tumor-infiltrating cytotoxic leukocytes (14,20).…”

Section: Discussionmentioning

confidence: 99%

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

Thijssen¹,

Postel

Brandwijk³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

433

406

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“…In the case of galectin-9, our data suggest that galectin-9 acts as a L. major-specific tagging protein or an adhesion molecule so that macrophages can recognize L. major more efficiently. It has been known that some galectins, which can cross-link different cells expressing their oligosaccharide ligands (28,34,35), act as adhesion molecules even though galectins are soluble proteins (32,63,64). Galectin-9 contains two CRDs linked by a peptide linker and is thus intrinsically divalent (33,46,65).…”

Section: Discussionmentioning

confidence: 99%

Specific Recognition of Leishmania major Poly-β-galactosyl Epitopes by Galectin-9

Pelletier

Hashidate

Urashima

et al. 2003

Journal of Biological Chemistry

102

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Leishmania parasites are the causative agents of leishmaniasis, manifesting itself in a species-specific manner. The glycan epitopes on the parasite are suggested to be involved in the Leishmania pathogenesis. One of such established species-unique glycan structures is the poly-␤-galactosyl epitope (Gal␤1-3) n found on L. major, which can develop cutaneous infections with strong inflammatory responses. Interestingly, the polygalactosyl epitope is also suggested to be involved in the development of the parasites in its host vector, sand fly. Thus, the recognition of the galactosyl epitope by lectins expressed in host or sand fly should be implicated in the species-specific manifestations of leishmaniasis and in the parasite life cycle, respectively. We recently reported that one host ␤-galactoside-binding protein, galectin-3, can distinguish L. major from the other species through its binding to the poly-␤-galactosyl epitope, proposing a role for galectin-3 as an immunomodulator that could influence the L. major-specific immune responses in leishmaniasis. Here we report that galectin-9 can also recognize L. major by binding to the L. major-specific polygalactosyl epitope. Frontal affinity analysis with different lengths of poly-␤-galactosyllactose revealed that the galectin-9 affinity for polygalactose was enhanced in proportion to the number of Gal␤1-3 units present. Even though both galectins have comparable affinities toward the polygalactosyl epitopes, only galectin-9 can promote the interaction between L. major and macrophages, suggesting distinctive roles for the galectins in the L. major-specific development of leishmaniasis in the host.

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“…Galectin-1 is a beta-galactoside binding protein that is produced by endothelial cells and induces apoptosis in bound activated T cell (Perillo et al 1995;Rabinovich et al 1998;Lotan et al 1994).…”

Section: Deletion Of Activated T Cells By the Livermentioning

confidence: 99%

Immune Functioning in Non lymphoid Organs: The Liver

Parker

Picut

2011

Toxicol Pathol

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The liver is the primary hematopoietic organ of the mammalian body during the fetal stage. The postnatal liver retains immunologically important functions and contains a substantial population of immunologically active cells, including T and B lymphocytes, Kupffer cells, liver-adapted natural killer (NK) cells (pit cells), natural killer cells expressing T cell receptor (NKT cells), stellate cells, and dendritic cells. The liver is the major site of production of the acute phase proteins that are associated with acute inflammatory reactions. Kupffer cells have an important role in the nonspecific phagocytosis that comprises a major component of the barrier to invasion of pathogenic organisms from the intestine. Hepatic NK and NKT cells are important in the nonspecific cell killing that is important in resistance to tumor cell invasion. The liver has a major role in deletion of activated T cells and induction of tolerance to ingested and self-antigens. Disposal of waste molecules generated through inflammatory, immunologic, or general homeostatic processes is accomplished via the action of specific endocytic receptors on sinusoidal endothelial cells of the liver. Age-related changes in sinusoids (pseudocapillarization), autophagy, and functions of various hepatic cell populations result in substantial alterations in many of these immunologically important functions.

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Expression of galectins on microvessel endothelial cells and their involvement in tumour cell adhesion

Cited by 122 publications

References 42 publications

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

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

Specific Recognition of Leishmania major Poly-β-galactosyl Epitopes by Galectin-9

Immune Functioning in Non lymphoid Organs: The Liver

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