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The effect of Eosinophil cationic protein (ECP) on Hodgkin lymphoma cell lines
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemial structure and function.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
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2011 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 8, 850-858 p.Article in journal (Refereed) Published
Abstract [en]

Background In classical Hodgkin lymphoma (HL), many eosinophils in tumour tissue indicate poor prognosis, probably caused by stimulation of the tumour cells, the Hodgkin Reed Sternberg (HRS) cells. However, eosinophils are primarily known for their role in innate immunity, where one function is to secrete the toxic substances eosinophil cationic protein (ECP), and eosinophil protein X (EPX). The aim of this study was to investigate the effects of ECP on HRS cells in vitro.

Method The fluorometric microculture cytotoxicity-assay (FMCA) measured survival index (SI) of cells from the HL cell lines HDLM-2, KMH2, and L428 after incubation with ECP or EPX. The gene products of a coding ECP polymorphism, ECP97arg and ECP97thr, and ECPs, with different levels of glycosylation were investigated. Flow cytometry was used to monitor the effects of ECP on markers of cell death.

Results A concentration dependent reduction of SI was seen after ECP treatment. For the B-cell derived cell lines, KMH2 and L428, ECP was cytotoxic with a dose response relationship similar to a previously investigated small-cell lung cancer cell-line. In contrast, for HDLM-2, which is a cell line of T-cell origin, the cytotoxicity was even more pronounced at the lowest concentrations tested, and then reached a plateau at about 0.018µM. At a concentration of 0.14µM of ECP, an SI of 71%±1.9 was recorded for HDLM-2, which did not accentuate despite higher concentrations of ECP. ECP97arg and ECP97thr displayed similar cytotoxicity, and the level of glycosylation did not affect cytotoxicity for HDLM-2, in contrast to the small-cell lung cancer cell-line. For EPX, no or very limited reduction in SI was seen, compared to ECP (p<0.001). The majority of cells that died from ECP (the HDLM-2 cell line) were PI positive, and only a few were annexin V positive.

Conclusions ECP is cytotoxic for HRS cells, but heterogeneity between cell lines was seen. The two cell lines of B-cell origin, KMH2 and L428, were sensitive to high ECP concentrations, but for HDLM-2, of T-cell origin, the cytotoxicity reached a plateau at higher concentrations. Thus, even at presumably high concentrations, ECP can be present around HRS cells without eradicating all cells.

Place, publisher, year, edition, pages
2011. Vol. 39, no 8, 850-858 p.
Keyword [en]
Hodgkin lymphoma, Eosinophil cationic protein, cytotoxicity, HDLM-2, eosinophils
National Category
Hematology Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-100590DOI: 10.1016/j.exphem.2011.05.006ISI: 000293801600005PubMedID: 21679745OAI: oai:DiVA.org:uu-100590DiVA: diva2:210605
Note

First two authors contributed equally.

Available from: 2009-04-02 Created: 2009-04-02 Last updated: 2014-08-15Bibliographically approved
In thesis
1. Hodgkin Lymphoma – an Interplay Between Tumour Cell and Microenvironment
Open this publication in new window or tab >>Hodgkin Lymphoma – an Interplay Between Tumour Cell and Microenvironment
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hodgkin lymphoma (HL) is a malignant disorder characterised by few tumour cells surrounded by a massive infiltrate of inflammatory cells, fibrosis, and microvessels. Therefore, it is a good model in which to study the interplay between tumour cells and the microenvironment.

In a population-based series, stage IIB had poor prognosis, equivalent to the most advanced stage (stage IV). The most prominent negative prognostic factor was tumour bulk in the mediastinum (often large fibrotic tumours).

The tumour cells expressed interleukin-9 (IL-9) in their cytoplasm in half of the cases. These cases had an over representation of nodular sclerosis histology (characterised by fibrotic bands) and infiltration of eosinophils and mast cells in the tumours. Despite this, IL-9 expression was not a negative prognostic factor.

A role of inflammatory cells is to contribute to angiogenesis. Yet, a correlation between high microvessel count and high mast cell number in HL tumours was not identified, in contrast to other lymphomas. However, a correlation to poor prognosis was seen for cases with high microvessel count.

Eosinophils contain eosinophil cationic protein (ECP). ECP was cytotoxic to cells from two HL cell lines of B-cell origin and one HL line of T-cell origin. At high concentrations, the cytotoxic effect was not as pronounced for the line of T-cell origin. If the in vitro cell lines are representative of HL in vivo, eosinophils may have different roles in different HL tumours.

In addition to the effect from tumour cells, host-related factors contribute to the inflammatory infiltrate in HL. A history of asthma and hives, and carrying the ECP434GG genotype were associated with elevated numbers of eosinophils, whereas, history of tobacco smoking was associated with lower numbers.

HL is a complex tumour consisting of recruited and subverted normal cells, fibrosis and angiogenesis: these constitute the microenvironment, which likely supports tumour cell growth, and differs between patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 449
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-100593 (URN)978-91-554-7494-2 (ISBN)
Public defence
2009-05-16, Auditorium Minus Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
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Available from: 2009-04-24 Created: 2009-04-02 Last updated: 2009-04-27Bibliographically approved

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Glimelius, IngridRubin, JennyMolin, DanielAmini, Rose-MarieVenge, PerEnblad, Gunilla

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