IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients

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Abstract

Macrophage-associated cytokines play an important role in cancer metastasis; however, the functions of interleukins (IL) 6 and 10 in breast cancer (BC) progression and metastasis are not clear. In this study the roles of IL-6/IL-10 in regulating vascular invasion and their prognostic significance in BC are investigated. MDA-MB-231 and MCF-7 migration (± IL-6 or IL-10) was assessed by scratch wound assay. Cancer cell adhesion to IL-6/IL-10 stimulated blood and lymphatic endothelial cells (EC) was investigated. Expression of IL-6 /IL-10 was assessed using immunohistochemistry in an annotated cohort of early stage BC ( n = 1380) and associations with clinicopathological variables and clinical outcome evaluated. IL-6 did not alter BC cell migration however a dose-dependent inhibition in MDA-MB-231 migration with IL-10 treatment was observed ( P = 0.03). BC cells were more adhesive to blood vs lymphatic EC, however, IL-6/IL-10 had no effect on adhesion patterns. High expression of IL-6/IL-10 was associated with clinicopathological criteria (e.g. hormone receptor status, all P < 0.05), improved disease-free survival (DFS; P < 0.05) and improved BC-specific survival (BCSS; only IL-6, P = 0.017). However, neither IL-6 nor IL-10 expression were independent prognostic factors from multivariate analysis. In BC subgroups, IL-6 and IL-10 were good prognosticators in terms of DFS in non-basal, non-triple-negative (non-TN), ER-positive, PgR-positive (only IL-10), and Her-2-negative (only IL-6) BC (all P < 0.05). IL-6 was associated with improved BCSS in non-basal, ER-positive and non-TN BC (all P < 0.05).

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Most cited references 36

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REporting recommendations for tumour MARKer prognostic studies (REMARK)

L M McShane, D Altman, W Sauerbrei … (2005)

Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.

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Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes.

Sébastien Brunet, R W Blamey, Ian Ellis … (2009)

Triple-negative (TN; estrogen receptor, progesterone receptor, and HER-2 negative) cancer and basal-like breast cancer (BLBC) are associated with poor outcome and lack the benefit of targeted therapy. It is widely perceived that BLBC and TN tumors are synonymous and BLBC can be defined using a TN definition without the need for the expression of basal markers. We have used two well-defined cohorts of breast cancers with a large panel of biomarkers, BRCA1 mutation status, and follow-up data to compare the clinicopathologic and immunohistochemical features of TN tumors expressing one or more of the specific basal markers (CK5/6, CK17, CK14, and epidermal growth factor receptor; BLBC) with those TN tumors that express none of these markers (TN3BKE-). Here, we show that although the morphologic features of BLBC are not significantly different from that of TN3BKE- tumors, BLBC showed distinct clinical and immunophenotypic differences. BLBC showed a statistically significant association with the expression of the hypoxia-associated factor (CA9), neuroendocrine markers, and other markers of poor prognosis such as p53. A difference in the expression of cell cycle-associated proteins and biomarkers involved in the immunologic portrait of tumors was seen. Compared with TN3BKE- tumors, BLBC was positively associated with BRCA1 mutation status and showed a unique pattern of distant metastasis, better response to chemotherapy, and shorter survival. TN breast cancers encompass a remarkably heterogeneous group of tumors. Expression of basal markers identifies a biologically and clinically distinct subgroup of TN tumors, justifying the use of basal markers (in TN tumors) to define BLBC.

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Oestrogen receptor negative breast cancers exhibit high cytokine content

Carine Chavey, Frédéric Bibeau, Sophie Gourgou-Bourgade … (2007)

Introduction An emerging hypothesis suggests that cytokines could play an important role in cancer as potential modulators of angiogenesis and leucocyte infiltration. Methods A novel multiplexed flow cytometry technology was used to measure the expression of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, granulocyte colony-stimulating factor [CSF], granulocyte-macrophage CSF, IFN-γ, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1β, tumour necrosis factor [TNF]-α) at the protein level in 105 breast carcinoma. B lymphocyte, T lymphocyte and macrophage levels were determined by immunohistochemistry. Results Fourteen of the 17 cytokines were expressed in breast carcinoma, whereas only nine cytokines could be detected in normal breast. Most cytokines were more abundant in breast carcinoma than in normal breast, with IL-6, IL-8, granulocyte CSF, IFN-γ, MCP-1 and MIP-1β being very abundant. IL-2, IL-6, IL-8, IL-10, IFN-γ, MCP-1, MIP-1β and TNF-α, and to a lesser extent IL-1β and IL-13 exhibited levels of expression that were inversely correlated to oestrogen receptor and progesterone receptor status. Most cytokines were not correlated with age at cancer diagnosis, tumour size, histological type, or lymph node status. However, IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 and MIP-1β were more abundant in high-grade tumours than in low-grade tumours. In addition, IL-8 and MIP-1β were expressed to a greater degree in HER2-positive than in HER2-negative patients. The expression of most of the studied cytokines was correlated to levels of activator protein-1, which is known to regulate numerous cytokines. Overexpression of MCP-1 and MIP-1β were linked to B lymphocyte, T lymphocyte and macrophage infiltration, whereas high levels of IL-8 were correlated with high macrophage content in tumour. Moreover, IL-8 positive tumours exhibited increased vascularization. Conclusion We found that multiple cytokines were overexpressed in oestrogen receptor negative breast carcinoma, and that the three major cytokines – MCP-1, MIP-1β and IL-8 – were correlated with inflammatory cell component, which could account for the aggressiveness of these tumours.

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Author and article information

Contributors

Stewart G. Martin: +44 (0)115 823 1846 , stewart.martin@nottingham.ac.uk

Journal

Journal ID (nlm-ta): Cancer Immunol Immunother

Journal ID (iso-abbrev): Cancer Immunol. Immunother

Title: Cancer Immunology, Immunotherapy

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0340-7004

ISSN (Electronic): 1432-0851

Publication date (Electronic): 18 December 2017

Publication date PMC-release: 18 December 2017

Publication date (Print): 2018

Volume: 67

Issue: 4

Pages: 537-549

Affiliations

[1 ]Division of Cancer and Stem Cells, Academic Clinical Oncology, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB UK

[2 ]Division of Cancer and Stem Cells, Histopathology, School of Medicine, University of Nottingham, Nottingham University Hospitals NHS Trust, City Hospital Campus, Hucknall Road, Nottingham, NG5 1PB UK

Article

Publisher ID: 2106

DOI: 10.1007/s00262-017-2106-8

PMC ID: 5860102

PubMed ID: 29256156

SO-VID: aec41be5-052b-4382-832f-08c00f70adab

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 10 March 2017

Date accepted : 12 December 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009794, Breast Cancer Now;

Award ID: 2011NovSP025

Award ID: 2011MayPr3

Award Recipient : Sarah J. Storr Stewart G. Martin

Funded by: The People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007-2013)

Award ID: PCOFUND-GA-2012-600181

Award Recipient : Aula Ammar

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer,il-6,il-10,macrophage-associated cytokines,metastasis

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: breast cancer, il-6, il-10, macrophage-associated cytokines, metastasis

IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients

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Most cited references 36

REporting recommendations for tumour MARKer prognostic studies (REMARK)

Triple-negative breast cancer: distinguishing between basal and nonbasal subtypes.

Oestrogen receptor negative breast cancers exhibit high cytokine content

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