Alpha-1-Acid Glycoprotein (AGP) as a Potential Biomarker for Breast Cancer

Smith, Kevin D.; Behan, Jennifer; Matthews-Smith, Gerardine; Magliocco, Anthony M.

doi:10.5772/48177

Cited by 5 publications

(7 citation statements)

References 47 publications

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“…AAPs are particularly susceptible to glycosylation. Glycosyltransferases and glycosidases are responsible for building the precursors to glycans, a process highly vulnerable to changes in disease state (73). Oligosaccharyltransferases then transfer glycans to the polypeptide chain at asparagine (N-linked) or serine/threonine (O-linked) residues, the former of which exhibit a common pentasaccharide core.…”

Section: Structure and Genetics Of Human Aagmentioning

confidence: 99%

“…In most disease states, AAG is modified both quantitatively as described above, as well as qualitatively, a phenomenon described by Alminquist and Lausing (39) after comparing serum glycoproteins of cancer patients versus healthy donors. Relative to the associated polypeptide backbone, the heterogeneity in glycan composition and structure make it a good system for characterization and correlation with disease state (73). Some commonly exploited glycoproteins used in clinical cancer biomarker tests include carcinoembryonic antigen (CEA), cancer antigen 125 (CA-125), CA-19-9, and prostate-specific antigen (PSA), for the diagnosis of colorectal, ovarian, pancreatic and prostate cancers, respectively.…”

Section: Impact Of Disease State On Aag Properties and Utility As A Bmentioning

confidence: 99%

“…For example, testing serum levels of modified glycans associated with PSA enable the distinction between benign prostatic hypertrophy and cancerous prostate (41). In breast cancer, the serum glycosylation pattern not only distinguishes healthy from diseased tissue but also differentiates between malignant and non-malignant tumors and disease stage (73). In inflammatory diseases including rheumatoid arthritis and asthma, AAG glycans are more branched compared to healthy subjects (42).…”

Section: Impact Of Disease State On Aag Properties and Utility As A Bmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein

Smith¹,

Waters

2018

Pharm Res

111

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According to the free drug hypothesis only the unbound drug is available to act at physiological sites of action, and as such the importance of plasma protein binding primarily resides in its impact on pharmacokinetics and pharmacodynamics. Of the major plasma proteins, alpha-1-acid glycoprotein (AAG) represents an intriguing one primarily due to the high affinity, low capacity properties of this protein.In addition, there are marked species and age differences in protein expression, homology and drug binding affinity. As such, a thorough understanding of drug binding to AAG can help aid and improve the translation of pharmacokinetic/pharmacodynamic (PK/PD) relationships from preclinical species to human as well as adults to neonates. This review provides a comprehensive overview of our current understanding of the biochemistry of AAG; endogenous function, impact of disease, utility as a biomarker, and impact on PK/PD. Experimental considerations are discussed as well as recommendations for understanding the potential impact of AAG on PK through drug discovery and early development.

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Section: Structure and Genetics Of Human Aagmentioning

confidence: 99%

Section: Impact Of Disease State On Aag Properties and Utility As A Bmentioning

confidence: 99%

Section: Impact Of Disease State On Aag Properties and Utility As A Bmentioning

confidence: 99%

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Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein

Smith¹,

Waters

2018

Pharm Res

111

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“…The current method for early-stage diagnosis of BC is mammography. Nevertheless, in addition to its inaccurate diagnosis, many patients do not receive mammograms regularly due to lack of access to the facility, high cost, procedural discomfort, and perceived risks of radiation exposure [4]. Consequently, there has been an increasing interest in the development and validation of serum-based non-invasive biomarkers whose alteration in the serum precedes the appearance of a malignancy, of which there is currently none [5].…”

Section: Introductionmentioning

confidence: 99%

Exploring serum and immunoglobulin G N-glycome as diagnostic biomarkers for early detection of breast cancer in Ethiopian women

et al. 2019

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Background Alterations in protein glycosylation patterns have potentially been targeted for biomarker discovery in a wide range of diseases including cancer. Although there have been improvements in patient diagnosis and survival for breast cancer (BC), there is no clinically validated serum biomarker for its early diagnosis. Here, we profiled whole serum and purified Immunoglobulin G (IgG) fraction N -glycome towards identification of non-invasive glycan markers of BC. Methods We employed a comprehensive glycomics approach by integrating glycoblotting-based glycan purification with MALDI-TOF/MS based quantitative analysis. Sera of BC patients belonging to stages I-IV and normal controls (NC) were collected from Ethiopian women during 2015–2016. IgG was purified by affinity chromatography using protein G spin plate and further subjected to glycoblotting for glycan release. Mass spectral data were further processed and evaluated rigorously, using various bioinformatics and statistical tools. Results Out of 35 N -glycans that were significantly up-regulated in the sera of all BC patients compared to the NC, 17 complex type N -glycans showed profound expression abundance and diagnostic potential (AUC = 0.8–1) for the early stage (I and II) BC patients. Most of these glycans were core-fucosylated, multiply branched and sialylated structures, whose abundance has been strongly associated with greater invasive and metastatic potential of cancer. N -glycans quantified form IgG confirmed their abundance in BC patients, of which two core-fucosylated and agalactosylated glycans ( m/z 1591, 1794) could specifically distinguish (AUC = 0.944 and 0.921, p ≤ 0.001) stage II patients from NC. Abundance of such structural features in IgG is associated with a decrease in its immunosuppressive potential towards tumor cells, which in part may correlate with the aggressive nature of BC commonly noticed in black population. Conclusions Our comprehensive study has addressed for the first time both whole serum and IgG N -glycosylation signatures of native black women suffering from BC and revealed novel glyco-biomarkers with marked overexpression and distinguishing ability at early stage patients. Further studies on direct identification of the intact glycoproteins using a glycoprteomics approach will provide a deeper understanding of specific biomarkers towards their clinical utility. Graphical abstract Electronic supplementary material The online version of this article (10.1186/s12885-019-5817-8) contains supplementary material, which is available to authorized users.

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“…The hyperbranched and hypersialylated glycans most of which have shown ethnic-based differences in the present study are possibly originated from Alpha-1-acid glycoprotein (AGP). It is one of the heavily N -glycosylated serum proteins carrying mainly high molecular weight glycans [53] among of which our group has recently succeeded in developing a focused glycoproteomics strategy to directly quantify serum level of AGP carrying a tri-antennary glycoform in multiple cancer types [54].…”

Section: Discussionmentioning

confidence: 99%

Healthy human serum N-glycan profiling reveals the influence of ethnic variation on the identified cancer-relevant glycan biomarkers

et al. 2018

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BackgroundMost glycomics studies have focused on understanding disease mechanisms and proposing serum markers for various diseases, yet the influence of ethnic variation on the identified glyco-biomarker remains poorly addressed. This study aimed to investigate the inter-ethnic serum N-glycan variation among US origin control, Japanese, Indian, and Ethiopian healthy volunteers.MethodsHuman serum from 54 healthy subjects of various ethnicity and 11 Japanese hepatocellular carcinoma (HCC) patients were included in the study. We employed a comprehensive glycoblotting-assisted MALDI-TOF/MS-based quantitative analysis of serum N-glycome and fluorescence HPLC-based quantification of sialic acid species. Data representing serum N-glycan or sialic acid levels were compared among the ethnic groups using SPSS software.ResultsTotal of 51 N-glycans released from whole serum glycoproteins could be reproducibly quantified within which 33 glycoforms were detected in all ethnicities. The remaining N-glycans were detected weakly but exclusively either in the Ethiopians (13 glycans) or in all the other ethnic groups (5 glycans). Highest abundance (p < 0.001) of high mannose, core-fucosylated, hyperbranched/hypersialylated N-glycans was demonstrated in Ethiopians. In contrast, only one glycan (m/z 2118) significantly differed among all ethnicities being highest in Indians and lowest in Ethiopians. Glycan abundance trend in Ethiopians was generally close to that of Japanese HCC patients. Glycotyping analysis further revealed ethnic-based disparities mainly in the branched and sialylated structures. Surprisingly, some of the glycoforms greatly elevated in the Ethiopian subjects have been identified as serum biomarkers of various cancers. Sialic acid level was significantly increased primarily in Ethiopians, compared to the other ethnicities.ConclusionThe study revealed ethnic-specific differences in healthy human serum N-glycome with highest abundance of most glycoforms in the Ethiopian ethnicity. The results strongly emphasized the need to consider ethnicity matching for accurate glyco-biomarker identification. Further large-scale study employing various ethnic compositions is needed to verify the current result.

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Alpha-1-Acid Glycoprotein (AGP) as a Potential Biomarker for Breast Cancer

Cited by 5 publications

References 47 publications

Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein

Pharmacokinetic and Pharmacodynamic Considerations for Drugs Binding to Alpha-1-Acid Glycoprotein

Exploring serum and immunoglobulin G N-glycome as diagnostic biomarkers for early detection of breast cancer in Ethiopian women

Healthy human serum N-glycan profiling reveals the influence of ethnic variation on the identified cancer-relevant glycan biomarkers

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