Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection

Rubinstein, Natalia; Alvarez, Mariano J.; Zwirner, Norberto Walter; Toscano, Marta A.; Ilarregui, Juan M.; Bravo, Alicia; Mordoh, José; Fainboim, Leonardo; Podhajcer, Osvaldo L.; Rabinovich, Gabriel A.

doi:10.1016/s1535-6108(04)00024-8

Cited by 476 publications

(505 citation statements)

References 55 publications

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“…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). This study now reports a critical role in angiogenesis, a third important pillar in tumor growth.…”

Section: Discussionmentioning

confidence: 75%

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.

422

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: 75%

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.

422

406

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“…In turn, IL-6 stimulated the mobilization and expansion of MDSCs and the tumor infiltration of gdT cells that secreted galectin-1. 105 Further analysis showed similar results in a murine model of ovarian cancer, whereas TLR5 loss of function accelerated tumor growth in a model of IL-6 unresponsive breast cancer cells via an increase in systemic IL-17 mediated also by the commensal microbiota. 104 Therefore, TLR5 signaling regulates systemic inflammation and immune responses resulting in cancer suppression or progression.…”

Section: Inflammation and Metastasismentioning

confidence: 69%

Inflammation and skeletal metastasis

Roca

McCauley

2015

BoneKEy Reports

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On the road to metastasis a cancer cell has to overcome two major obstacles: the physical escape from the primary tumor to a distant tissue and the adaptation to the new microenvironment via colonization and the formation of a secondary tumor. Accumulated scientific findings support the hypothesis that inflammation is a critical component of the tumor microenvironment and develops as a result of tumor-induced recruitment of inflammatory cells and their reciprocal interaction with other cells from the tumor network. These interactions modulate immune responses to suppress antitumor immunity and activate feedback amplification signaling loops that link nearly all the cells in the cancer inflammatory milieu. The coordinated regulation of cytokines/chemokines, receptors and other inflammatory mediators enables the different steps of the metastatic cascade. As a target organ for colonization, the bone is rich in inflammatory mediators that are critical for successful cancer growth. In this review, we focus on the inflammatory cells, molecules and mechanisms that facilitate the expansion of cancer cells from the primary tumor to their new 'home' in the skeleton.

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“…B16 has well-document Ag escape mechanisms, including down-regulation of class I molecule expression and Ag-processing machinery (66), Growing B16 tumors have been shown to induce CD4 ϩ CD25 ϩ regulatory cells that facilitate immune escape (67)(68)(69). In addition, B16 cells produce vesicular endothelial growth factor, which inhibits DC function and T cell immunity, and galectin-1, which is a negative regulator of T cell activation and survival (70). Taken together, these observations suggest that the B16 tumor possesses many of the tumor escape mechanisms used by human tumors and is a formidable model tumor for the evaluation of immunotherapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity

He¹,

Zhang²,

Zhang

et al. 2005

The Journal of Immunology

141

152

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Dendritic cell (DC) therapies are currently being evaluated for the treatment of cancer. The majority of ongoing clinical trials use DCs loaded with defined antigenic peptides or proteins, or tumor-derived products, such as lysates or apoptotic cells, as sources of Ag. Although several theoretical considerations suggest that DCs expressing transgenic protein Ags may be more effective immunogens than protein-loaded cells, methods for efficiently transfecting DCs are only now being developed. In this study we directly compare the immunogenicity of peptide/protein-pulsed DCs with lentiviral vector-transduced DCs, and their comparative efficacy in tumor immunotherapy. Maturing, bone marrow-derived DCs can be efficiently transduced with lentiviral vectors, and transduction does not affect DC maturation, plasticity, or Ag presentation function. Transduced DCs efficiently process and present both MHC class I- and II-restricted epitopes from the expressed transgenic Ag OVA. Compared with peptide- or protein-pulsed DCs, lentiviral vector-transduced DCs elicit stronger and longer-lasting T cell responses in vivo, as measured by both in vivo killing assays and intracellular production of IFN-γ by Ag-specific T cells. In the B16-OVA tumor therapy model, the growth of established tumors was significantly inhibited by a single immunization using lentiviral vector-transduced DCs, resulting in significantly longer survival of immunized animals. These results suggest that compared with Ag-pulsed DCs, vaccination with lentiviral vector-transduced DCs may achieve more potent antitumor immunity. These data support the further development of lentiviral vectors to transduce DCs with genes encoding Ags or immunomodulatory adjuvants to generate and control systemic immune responses.

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Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection

Cited by 476 publications

References 55 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

Inflammation and skeletal metastasis

Immunization with Lentiviral Vector-Transduced Dendritic Cells Induces Strong and Long-Lasting T Cell Responses and Therapeutic Immunity

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