Glycans and Galectins: Sweet New Approaches in Pancreatic Cancer Diagnosis and Treatment

Martínez-Bosch, Neus; Navarro, Pilar

doi:10.5772/28832

Cited by 4 publications

(6 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…By these interactions, it participates in different biological functions as cell cycle control, migration, invasion, angiogenesis and immune system response, both in physiological and pathological situations (5, 6). Gal1 is overexpressed in many tumors (7), including pancreatic cancer (8-14), where a positive correlation with tumor stage has been found (15). Of note, Gal1 overexpression in PDA was identified mostly in stromal cells.…”

Section: Introductionmentioning

confidence: 99%

Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation

Martínez-Bosch¹,

Fernández‐Barrena

Moreno³

et al. 2014

Cancer Research

Self Cite

102

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDA) is the most aggressive tumor, showing incidence and mortality values almost identical. Despite remarkable advances in PDA molecular characterization, this disease is still refractory to current treatments. Desmoplastic stroma, a constant hallmark of PDA, has recently emerged as the major responsible for PDA therapeutic resistance, therefore representing a promising target. Galectin-1 (Gal1), a glycan-binding protein, is highly expressed in PDA stroma but its role remains unknown. Here, we aim to understand in vivo Gal1 functions and the molecular pathways responsible for its oncogenic properties. Genetic ablation of Gal1 in Ela-myc mice dampens tumor progression through inhibition of proliferation, angiogenesis, desmoplasia and stimulation of tumor-associated immune response, resulting in a 20% increase on the animal life span. In vitro and in vivo studies unveil that these effects are mediated by modulation of the tumor microenvironment in a non-cell autonomous manner. Importantly, acinar-to-ductal metaplasia, a crucial step for PDA initiation, is also regulated by Gal1. Finally, high-throughput gene expression studies and molecular analysis aimed at identifying the underlying mechanism revealed that Gal1 promotes Hedgehog pathway both in PDA cells and stromal fibroblasts. In summary, our studies define a novel role of Gal1 in PDA tumor epithelium-stroma crosstalk and suggest this lectin as potential molecular target for therapy of neoplasms overexpressing Gal1.

show abstract

Section: Introductionmentioning

confidence: 99%

Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation

Martínez-Bosch¹,

Fernández‐Barrena

Moreno³

et al. 2014

Cancer Research

Self Cite

102

View full text Add to dashboard Cite

show abstract

“…6) seems to support the second with competitive or antagonistic binding for Mac-2BP by Gal-1 and E-selectin, forcing E-selectin to find a different form of Mac-2BP with higher carbohydrate moiety affinities or an entirely different ligand within the same relative location. This proposition is supported again through the clustering of ligands into specific domains, 14,21,23,28,30 where multiple forms of Mac-2BP can reside and bind to competitively between Gal-1 and E-selectin while maintaining apparent colocalization.…”

Section: Mac-2bp Antibody Blockade Significantly Reduces Low Shear Stmentioning

confidence: 95%

“…In either scenario, increased E-selectin adhesion efficacy induced by Gal-1 cell treatment may be able to overcome shear-disruptive effects of lower wall shear stresses, but the effect is lost at increasing wall shear stresses and during static adhesion assays. 21,23,28,30 In contrast there was significant decrease in breast cancer cell binding to E-selectin when the ZR-75-1 cell line was treated with Gal-1hFc and perfused over an Eselectin-coated plate (Fig. 7a).…”

Section: Mac-2bp Antibody Blockade Significantly Reduces Low Shear Stmentioning

confidence: 96%

“…One possible explanation for these results is that Gal-1 is able to bind with greater efficacy to multiple carbohydrate moieties rather than to a single lactosamine unit, 28 which dovetails with the phenomena of Gal-1 clustering E-selectin ligands together into specific domains. 14,21,23,28,30 However, this phenomena may not be seen in formaldehyde fixed samples due to decreased mobility of cellular components. In either scenario, increased E-selectin adhesion efficacy induced by Gal-1 cell treatment may be able to overcome shear-disruptive effects of lower wall shear stresses, but the effect is lost at increasing wall shear stresses and during static adhesion assays.…”

Section: Mac-2bp Antibody Blockade Significantly Reduces Low Shear Stmentioning

confidence: 99%

“…To the latter, multiple sources state that Gal-1 can both cluster ligands into specific domains, as well as increase ligand residence time on the cell surface. 19,21,28 This is especially relevant considering that Mac-2BP is a Gal-1 ligand that also acts as an E-selectin ligand. Having the ability to not only change the location of ligands that Gal-1 and E-selectin share but to maintain their presence as well would be a powerful mechanism to regulate cancer cell migration and adhesion.…”

Section: Mac-2bp Antibody Blockade Significantly Reduces Low Shear Stmentioning

confidence: 99%

See 2 more Smart Citations

Galectin-1 Influences Breast Cancer Cell Adhesion to E-selectin Via Ligand Intermediaries

et al. 2017

View full text Add to dashboard Cite

Introduction-Invasion of other tissues during bloodborne metastasis in part requires adhesion of cancer cells to vascular endothelium by specific fluid shear-dependent receptor-ligand interactions. This study investigates the hypothesis that the adhesion is mediated by ligands shared between endothelial E-selectin and Galectin-1 (Gal-1), both of which are upregulated during inflammation and cancer. Methods-Flow chamber adhesion and dynamic biochemical tissue analysis (DBTA) assays were used to evaluate whether Gal-1 modulates E-selectin adhesive interactions of breast cancer cells and tissues under dynamic flow conditions, while immunocytochemistry, immunohistochemistry, western blotting, and fluorescence anisotropy were used to study molecular interactions under static conditions. Results-Dynamic adhesion assays revealed a shear-dependent binding interaction between Gal-1hFc treated breast cancer cells and tissues and E-selectin-coated beads, caus-ing~300% binding increase of the beads compared to negative controls. Immunocyto-and immunohistochemical analyses showed that Gal-1 and E-selectin fluorescent signals colocalized on cells and tissues at~75% for each assay. Immunoprecipitation and Western blotting of Mac-2BP from breast cancer cell lysates revealed that Gal-1 and Eselectin share Mac-2BP as a ligand, while fluorescence anisotropy and circulating tumor cell model systems exhibited competitive or antagonistic binding between Gal-1 and E-selectin for shared ligands, including Mac-2BP. Furthermore, Mac-2BP functional blockade inhibited the effects of Gal-1 on E-selectin binding. Conclusions-In summary, this investigation reveals a sheardependent interaction between E-selectin and Gal-1 that may be due to intermediation by a similar or shared ligand(s), including Mac-2BP, which may provide a rational basis for development of novel diagnostics or therapeutics for breast cancer.

show abstract

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Orozco

Martínez-Bosch

Guerrero

et al. 2018

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

Self Cite

116

123

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a -driven mouse model of PDA ( ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities.

show abstract

Glycans and Galectins: Sweet New Approaches in Pancreatic Cancer Diagnosis and Treatment

Cited by 4 publications

References 91 publications

Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation

Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation

Galectin-1 Influences Breast Cancer Cell Adhesion to E-selectin Via Ligand Intermediaries

Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor–stroma crosstalk

Contact Info

Product

Resources

About