A circulating ligand for galectin-3 is a haptoglobin-related glycoprotein elevated in individuals with colon cancer1 1Investigators of the Great Lakes-New England Clinical and Epidemiology Center of the Early Detection Research Network are Dean Brenner, Daniel Normalle, and Kim Turgeon (University of Michigan), Sapna Syngal (Dana Farber Cancer Institute), Robert S. Bresalier (University of Texas M.D. Anderson Cancer Center), John Barron (Dartmouth/Hitchcock Medical Center), and Norman Marcon (University of

Bresalier, Robert S.; Byrd, James C.; Tessler, David A.; Lebel, Joseph; Koomen, John M.; Hawke, David H.; Half, Elizabeth E.; Liu, Kai Feng; Mazurek, Nachman

doi:10.1053/j.gastro.2004.06.016

Cited by 44 publications

(10 citation statements)

References 19 publications

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“…One study found strongly increased binding of galectin-3 to a haptoglobin like protein on western blots of sera from cancer patients, but only after desialylation [51]. Other earlier studies have found variable correlation between cancer and serum levels (low µg/ml) of the Mac-2-binding protein, named based on its affinity for galectin-3 [61].…”

Section: Discussionmentioning

confidence: 98%

“…1C), the galectin-1 binding glycan accounts for only 10% or less of these, and therefore other N-glycans, not binding galectin-1, are carried along in the galectin-1 bound fraction. These other glycans may also be part of a cancer related glycan profile, if, for example, the haptoglobin comes from cancer cells, as proposed [51], or liver cells indirectly affected by the presence of cancer elsewhere in the body. Therefore, previous studies and the present study may have detected overlapping sets of cancer related haptoglobin glycoforms.…”

Section: Discussionmentioning

confidence: 99%

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Galectin-1-Binding Glycoforms of Haptoglobin with Altered Intracellular Trafficking, and Increase in Metastatic Breast Cancer Patients

et al. 2011

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Sera from 25 metastatic breast cancer patients and 25 healthy controls were subjected to affinity chromatography using immobilized galectin-1. Serum from the healthy subjects contained on average 1.2 mg per ml (range 0.7–2.2) galectin-1 binding glycoproteins, whereas serum from the breast cancer patients contained on average 2.2 mg/ml (range 0.8–3.9), with a higher average for large primary tumours. The major bound glycoproteins were α-2-macroglobulin, IgM and haptoglobin. Both the IgM and haptoglobin concentrations were similar in cancer compared to control sera, but the percentage bound to galectin-1 was lower for IgM and higher for haptoglobin: about 50% (range 20–80) in cancer sera and about 30% (range 25–50) in healthy sera. Galectin-1 binding and non-binding fractions were separated by affinity chromatography from pooled haptoglobin from healthy sera. The N-glycans of each fraction were analyzed by mass spectrometry, and the structural differences and galectin-1 mutants were used to identify possible galectin-1 binding sites. Galectin-1 binding and non-binding fractions were also analyzed regarding their haptoglobin function. Both were similar in forming complex with haemoglobin and mediate its uptake into alternatively activated macrophages. However, after uptake there was a dramatic difference in intracellular targeting, with the galectin-1 non-binding fraction going to a LAMP-2 positive compartment (lysosomes), while the galectin-1 binding fraction went to larger galectin-1 positive granules. In conclusion, galectin-1 detects a new type of functional biomarker for cancer: a specific type of glycoform of haptoglobin, and possibly other serum glycoproteins, with a different function after uptake into tissue cells.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Galectin-1-Binding Glycoforms of Haptoglobin with Altered Intracellular Trafficking, and Increase in Metastatic Breast Cancer Patients

et al. 2011

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“…A systemic analysis of the galectin-binding proteins in human serum has shown that galectin-3 and -8 both recognised a broad range of serum proteins, whereas galectin-2 and -4 showed binding to only trace or no serum ligands (Cederfur et al , 2008). For example, IgGA1 is shown to bind strongly to galectin-1 (Sangeetha and Appukuttan, 2005), whereas a haptoglobin-related serum glycoprotein (Bresalier et al , 2004) and the Mac-2-binding protein (Iacovazzi et al , 2010) are serum ligands of galectin-3. Our own study has shown that, although circulating galectin-2, -3, -4 and -8 levels were all elevated in the circulation of cancer patients and all were shown to induce cancer cell adhesion by interaction with the TF disaccharide on the cancer-associated MUC1 in vitro , only serum galectin-2 level was found to be directly associated with a significantly increased mortality in patients with colorectal cancer (Barrow et al , 2011a).…”

Section: Discussionmentioning

confidence: 99%

Circulating galectins -2, -4 and -8 in cancer patients make important contributions to the increased circulation of several cytokines and chemokines that promote angiogenesis and metastasis

Chen

Duckworth

et al. 2014

Br J Cancer

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Background:Circulating concentrations of the cytokines interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) and chemokines monocyte chemotatic protein 1 (MCP-1)/CCL2 and growth-regulator oncogene α (GROα)/chemokine C-X-C motif ligand 1 are commonly increased in cancer patients and they are increasingly recognised as important promoters, via divergent mechanisms, of cancer progression and metastasis.Methods:The effect of galectins-2, -4 and -8, whose circulating levels are highly increased in cancer patients, on endothelial secretion of cytokines was assessed in vitro by cytokine array and in mice. The relationship between serum levels of galectins and cytokines was analysed in colon and breast cancer patients.Results:Galectins-2, -4 and -8 at pathological concentrations induce secretion of G-CSF, IL-6, MCP-1 and GROα from the blood vascular endothelial cells in vitro and in mice. Multiple regression analysis indicates that increased circulation of these galectins accounts for 41∼83% of the variance of these cytokines in the sera of colon and breast cancer patients. The galectin-induced secretion of these cytokines/chemokines is shown to enhance the expression of endothelial cell surface adhesion molecules, causing increased cancer-endothelial adhesion and increased endothelial tubule formation.Conclusion:The increased circulation of galectins -2, -4 and -8 in cancer patients contributes substantially to the increased circulation of G-CSF, IL-6 and MCP-1 by interaction with the blood vascular endothelium. These cytokines and chemokines in turn enhance endothelial cell activities in angiogenesis and metastasis.

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“…This approach achieves the efficient and reproducible separation of APPs glyco-isoforms to be further analyzed for quantitative and qualitative differences even starting from a small amount of biological fluid. As an additional advantage, separated glycoprotein can be detected by direct binding of other specific carbohydrate-binding species like galectins [29,30], in immunoblotting. We applied this approach to our 2-Dbased experimental procedure showing specific Gal-3 binding to Hpt isoforms and their correlation to MS so that we can conclude that (i) complex and/or hybrid-type structures are asymmetrically present on Hpt spots; (ii) they are responsible for spot 47 and 18-fold change emerged with ECL; (iii) the above-mentioned differences could not be directly detected in non-purified samples; and (iv) the purification step prior to 2-DE does not alter these PTMs.…”

Section: Discussionmentioning

confidence: 99%

“…One of them, galectin-3 (Gal-3), having a strong affinity for galactose, in particular when it is bound to N-acetyl-D-glucosamine with a b1-4 bond (same specificity of erythrina cristagalli lectin (ECL); Supporting Information Fig. S3) [30] recognizes a b-haptoglobin (Hpt) subunit in the serum of individuals with colon cancer. Moreover, other investigations begin to evaluate the role of the above-mentioned molecules in immune-surveillance modulation in vitro [31,32], in case of transplantation [33,34], and in axonal guidance [35,36].…”

Section: Introductionmentioning

confidence: 99%

Acute‐phase proteins investigation based on lectins affinity capture prior to 2‐DE separation: Application to serum from multiple sclerosis patients

Robotti

Natale²,

Albo³

et al. 2010

Electrophoresis

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Plasma acute-phase proteins (APPs) glyco-isoforms are important biomarkers of inflammatory processes such as those occurring in multiple sclerosis (MS). Specific analysis of these proteins is often hampered by sample biochemical complexity. The aim of our study was to set up a method to accurately visualize, identify and quantify APPs glyco-isoforms in human serum. An enrichment strategy based on affinity chromatography using the carbohydrate-binding proteins concanavalin A (ConA) and erythrina cristagalli lectin (ECL) was applied to pooled serum samples from 15 patients and 9 healthy individuals. Image analysis of 2-DE detected 30 spots with a fold change higher than 1.5. A total of 14 were statistically significant (p value<0.05): 7 up-regulated and 7 down-regulated in MS samples. ESI LC-Nanospray IT mass spectrometry analysis confirmed that all of them were APPs isoforms supporting the idea that the accurate analysis of differential glycosylation profiles in these biomarkers is instrumental to distinguish between MS patients and healthy subjects. Additionally, overlaps in ConA/ECL maps protein patterns suggest how the used lectins are able to bind sugars harbored by the same oligosaccharide structure. Among identified proteins, the presence of complex and/or hybrid type N-linked sugar structures is well known. Performing galectin-3 binding and Western blotting, we were able to demonstrate a correlation between hybrid type glyco-isoforms of β-haptoglobin and MS. In conclusion, although the patho-physiological role of the identified species still remains unclear and further validations are needed, these findings may have a relevant impact on disease-specific marker identification approaches.

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Cited by 44 publications

References 19 publications

Galectin-1-Binding Glycoforms of Haptoglobin with Altered Intracellular Trafficking, and Increase in Metastatic Breast Cancer Patients

Galectin-1-Binding Glycoforms of Haptoglobin with Altered Intracellular Trafficking, and Increase in Metastatic Breast Cancer Patients

Circulating galectins -2, -4 and -8 in cancer patients make important contributions to the increased circulation of several cytokines and chemokines that promote angiogenesis and metastasis

Acute‐phase proteins investigation based on lectins affinity capture prior to 2‐DE separation: Application to serum from multiple sclerosis patients

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