A novel multiplexed immunoassay identifies CEA, IL-8 and prolactin as prospective markers for Dukes’ stages A-D colorectal cancers

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Abstract

Background

Current methods widely deployed for colorectal cancers (CRC) screening lack the necessary sensitivity and specificity required for population-based early disease detection. Cancer-specific protein biomarkers are thought to be produced either by the tumor itself or other tissues in response to the presence of cancers or associated conditions. Equally, known examples of cancer protein biomarkers (e.g., PSA, CA125, CA19-9, CEA, AFP) are frequently found in plasma at very low concentration (pg/mL-ng/mL). New sensitive and specific assays are therefore urgently required to detect the disease at an early stage when prognosis is good following surgical resection. This study was designed to meet the longstanding unmet clinical need for earlier CRC detection by measuring plasma candidate biomarkers of cancer onset and progression in a clinical stage-specific manner. EDTA plasma samples (1 μL) obtained from 75 patients with Dukes’ staged CRC or unaffected controls (age and sex matched with stringent inclusion/exclusion criteria) were assayed for expression of 92 human proteins employing the Proseek® Multiplex Oncology I proximity extension assay. An identical set of plasma samples were analyzed utilizing the Bio-Plex Pro™ human cytokine 27-plex immunoassay.

Results

Similar quantitative expression patterns for 13 plasma antigens common to both platforms endorsed the potential efficacy of Proseek as an immune-based multiplex assay for proteomic biomarker research. Proseek found that expression of Carcinoembryonic Antigen (CEA), IL-8 and prolactin are significantly correlated with CRC stage.

Conclusions

CEA, IL-8 and prolactin expression were found to identify between control (unaffected), non-malignant (Dukes’ A + B) and malignant (Dukes’ C + D) stages.

Electronic supplementary material

The online version of this article (doi:10.1186/s12014-015-9081-x) contains supplementary material, which is available to authorized users.

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Most cited references 53

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IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells.

Romaine I. Fernando, Marianne D. Castillo, Mary Litzinger … (2011)

The switch of tumor cells from an epithelial to a mesenchymal-like phenotype [designated as epithelial-to-mesenchymal transition (EMT)] is known to induce tumor cell motility and invasiveness, therefore promoting metastasis of solid carcinomas. Although multiple studies have focused on elucidating the signaling events that initiate this phenotypic switch, there has been so far no characterization of the pattern of soluble mediators released by tumor cells undergoing EMT, and the potential impact that this phenotypic switch could have on the remodeling of the tumor microenvironment. Here we show that induction of EMT in human carcinoma cells via overexpression of the transcription factor Brachyury is associated with enhanced secretion of multiple cytokines, chemokines, and angiogenic factors and, in particular, with the induction of the IL-8/IL-8R axis. Our results also indicate the essential role of interleukin 8 (IL-8) signaling for the acquisition and/or maintenance of the mesenchymal and invasive features of Brachyury-overexpressing tumor cells and show that IL-8 secreted by tumor cells undergoing EMT could potentiate tumor progression by inducing adjacent epithelial tumor cells into EMT. Altogether, our results emphasize the potential role of EMT in the modulation of the tumor microenvironment via secretion of multiple soluble mediators and suggest that IL-8 signaling blockade may provide a means of targeting mesenchymal-like, invasive tumor cells.

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IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma.

Jiankun Liu, Yuzhong Duan, Xiaoming Cheng … (2011)

IL-17, which exerts strong pro-inflammatory effects, has emerged as an important mediator in inflammation-associated cancer. However, the characteristics of IL-17-producing cells, the relevance of IL-17 to clinical parameters and its function in the development and progression of colorectal carcinoma still remain to be explored. In the present study, we first found the levels of IL-17 producing cells were significantly increased in the tumor regions of samples from colorectal carcinoma patients compared with non-tumor regions. Confocal microscopic analysis showed co-staining of IL-17 with CD4 and CD68, indicating IL-17 in colorectal carcinoma was expressed by macrophage and Th17. High expression of IL-17 was associated with high microvessel density. Univariate and multivariate analysis revealed that IL-17 was an independent prognostic factor for overall survival. To explore the underlying mechanisms of IL-17 in angiogenesis, we used PCR-array to find pro-angiogenic factor in cancer cells specifically induced by IL-17, then validated VEGF as one of factors in IL-17-mediated angiogenesis with the use of quantitative RT-PCR, ELISA and VEGF immunohistochemistry. Our results propose IL-17 as a novel indicator of prognosis in the patients with colorectal carcinoma and could serve as a novel therapeutic target for colorectal carcinoma, furthermore our results indicate that IL-17 producing cells may facilitate development of colorectal carcinoma by fostering angiogenesis via promote VEGF production from cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved.

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Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55.

H Tilg, E Trehu, M Atkins … (1994)

The aim of this study was to investigate whether interleukin (IL)-6 induces the production of IL-1 and tumor necrosis factor (TNF) antagonists. Serial plasma samples were obtained from cancer patients participating in phase I and II trials of recombinant IL-6 administered as a 120-hour continuous intravenous (IV) infusion. Plasma IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor p55 (TNFsRp55) levels were measured by specific radioimmunoassays (RIAs). IL-1Ra levels increased rapidly, reaching peak values (9.6 +/- 1.7 ng/mL) within 2 to 4 hours of beginning treatment. Thereafter, levels promptly declined, reaching near baseline within 24 hours despite continuation of IL-6. TNFsRp55 plasma levels increased within 4 to 8 hours after initiating treatment and increased progressively throughout the duration of therapy. IL-1 beta and TNF-alpha plasma levels were below the detection limit in all samples tested. Peripheral blood mononuclear cells (PBMC) exposed to IL-6 produced only small amounts (1.56 +/- 0.3 ng/mL) of IL-1Ra, even in the presence of exogenous soluble IL-6 receptor (gp80). TNFsRp55 levels measured in the supernatants of IL-6-stimulated PBMC were below the detection limit of the assay. Macrophages generated by culturing monocytes in granulocyte-macrophage colony-stimulating factor (GM-CSF) were much more responsive to IL-6 than freshly isolated unfractionated or adherent PBMC and synthesized almost as much IL-1Ra when stimulated with IL-6 as with endotoxin. These results suggest that the antinflammatory properties of IL-6 may be due; in part, to the induction of IL-1Ra synthesis and the release of soluble TNF receptors. Our findings also suggest that tissue macrophages may be an important source of IL-6-induced IL-1Ra.

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Author and article information

Contributors

Sadia Mahboob: sadia.mahboob@students.mq.edu.au

Seong Beom Ahn: charlie.ahn@mq.edu.au

Harish R Cheruku: harish.cheruku@mq.edu.au

David Cantor: david.cantor@mq.edu.au

Emma Rennel: Emma.Rennel@olink.com

Simon Fredriksson: simon.fredriksson@olink.com

Gabriella Edfeldt: Gabriella.Edfeldt@olink.com

Edmond J Breen: EBreen@proteome.org.au

Alamgir Khan: AKhan@proteome.org.au

Abidali Mohamedali: abidali.mohamedali@mq.edu.au

Md Golam Muktadir: get2muktadir@hotmail.com

Shoba Ranganathan: shoba.ranganathan@mq.edu.au

Sock-Hwee Tan: tshwee@yahoo.com.au

Edouard Nice: ed.nice@monash.edu

Mark S Baker: mark.baker@mq.edu.au

Journal

Journal ID (nlm-ta): Clin Proteomics

Journal ID (iso-abbrev): Clin Proteomics

Title: Clinical Proteomics

Publisher: BioMed Central (London )

ISSN (Print): 1542-6416

ISSN (Electronic): 1559-0275

Publication date (Electronic): 8 April 2015

Publication date PMC-release: 8 April 2015

Publication date Collection: 2015

Volume: 12

Issue: 1

Electronic Location Identifier: 10

Affiliations

[ ]Australian School of Advanced Medicine, Faculty of Medicine and Human Sciences, Macquarie University, Rm1, Level 1, 75 Talavera Road, Sydney, NSW 2109 Australia

[ ]Department of Chemistry and Biomolecular Sciences, Faculty of Science, Macquarie University, Sydney, NSW 2109 Australia

[ ]Olink Bioscience, Dag Hammarskjölds Väg, 54A, 75183 Uppsala, Sweden

[ ]Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109 Australia

[ ]School of Science and Health, University of Western Sydney, NSW, Australia

[ ]Department of Biochemistry and Molecular Biology, Monash University, Clayton Campus, Melbourne, VIC 3800 Australia

Article

Publisher ID: 9081

DOI: 10.1186/s12014-015-9081-x

PMC ID: 4435647

PubMed ID: 25987887

SO-VID: 72aef900-3cd4-4ffd-bf55-65ead876cb0b

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 29 October 2014

Date accepted : 4 March 2015

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ScienceOpen disciplines: Molecular medicine

Keywords: multiplex immunoassay,plasma biomarker,colorectal cancer

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ScienceOpen disciplines: Molecular medicine

Keywords: multiplex immunoassay, plasma biomarker, colorectal cancer

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A novel multiplexed immunoassay identifies CEA, IL-8 and prolactin as prospective markers for Dukes’ stages A-D colorectal cancers

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Karger: Oncology

Most cited references 53

IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells.

IL-17 is associated with poor prognosis and promotes angiogenesis via stimulating VEGF production of cancer cells in colorectal carcinoma.

Interleukin-6 (IL-6) as an anti-inflammatory cytokine: induction of circulating IL-1 receptor antagonist and soluble tumor necrosis factor receptor p55.

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