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Redox-signaling transmitted in trans to neighboring cells by melanoma-derived TNF-containing exosomes
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Biomedicine and Surgery. Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-3927-4394
Department of Laboratory Medicine, Division of Pathology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
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2007 (English)In: Free Radical Biology and Medicine, ISSN 0891-5849, Vol. 43, no 1, 90-99 p.Article in journal (Refereed) Published
Abstract [en]

Hydrogen peroxide is known to be involved in redox signaling pathways that regulate normal processes and disease progression, including cytokine signaling, oxidative stress, and cancer. In studies on immune surveillance against cancer, hydrogen peroxide was found to disrupt cytotoxic T-cell function, thus contributing to tumor escape. In this study, secretion of TNF-containing vesicles of rab9+ endosomal origin, termed exosomes, was investigated using GFP-TNF constructs. We observed a polarized intracellular trafficking and apical secretion of TNF-positive nanovesicles. Cell-to-cell transfer of TNF was observed in exosomes in real-time microscopy, occurring separate from the melanin/melanosome compartment. Exosomes were prepared by ultracentrifugation or immunoisolation on anti-β2-microglobulin magnetic beads. TNF as well as TNF receptors 1 and 2 were present in the exosomes as determined by Western blot, flow cytometry, and deconvolution microscopy. The functional significance of melanoma-derived exosomes was established by their signaling competence with ability to generate significantly higher ROS levels in T cells compared with sham exosomes (P = 0.0006). In conclusion, we report here, for the first time, that TNF is found in tumor cell-derived exosomes and that these exosomes transmit redox signaling in trans to neighboring cells. The results are of importance for a better understanding of tumor escape mechanisms.

Place, publisher, year, edition, pages
2007. Vol. 43, no 1, 90-99 p.
Keyword [en]
TNF, Exosomes, Melanoma, Hydrogen peroxide, Redox signaling, Tumor escape mechanisms
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-13716DOI: 10.1016/j.freeradbiomed.2007.03.026ISI: 000247395000011OAI: oai:DiVA.org:liu-13716DiVA: diva2:21198
Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2017-09-22
In thesis
1. Immunological Studies in Malignant Melanoma: Importance of TNF and the Thioredoxin System
Open this publication in new window or tab >>Immunological Studies in Malignant Melanoma: Importance of TNF and the Thioredoxin System
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma is a tumor whose incidence is dramatically increasing in persons with light-coloured skin in all parts of the world. Due to its resistance against traditional chemo- and radiotherapy, melanoma has been a favourite target of alternative therapies, in particular those involving immunological mechanisms. Cytokines and particularly tumor necrosis factor (TNF) have been studied as possible antitumoral agents, but also as endogenous growth or differentiation factors. Previous studies showed that melanomas could express TNF in situ and that this expression correlated to decreased lymphocyte infiltration. On the other hand, redox reagents can modulate expression of cytokines, and the thioredoxin (Trx) system is particularly known to influence expression and secretion of TNF in vitro.

The overall aim of this research was to explore immunological aspects of melanoma, particularly the role of TNF both in vitro and in vivo, as well as its possible modulation by Trx.

In the in vitro studies first we developed a novel method for obtention of monoclonal antibodies against melanoma antigens, and generated and characterized specific monoclonal antibodies against both full-length and truncated Trx. We studied the cytokine expression of a panel of normal and transformed melanocytic cells by immunofluorescence, all of which presented TNF and Trx at levels comparable to monocytic cells, and TNF-receptors (TNFR) at low but detectable levels. Melanoma cells did not secrete TNF upon stimulation in spite of its presence in the Golgi apparatus. However, melanoma cells expressed the TNF-processing enzyme TACE and were capable of cleaving transfected GFP-tagged TNF. Imaging studies point to a possible cell-cell tranfer of endogenous TNF in melanoma cells.

On the other hand, TNF and Trx expression in melanoma cell lines correlated to resistance against exogenous TNF. We studied then the in situ expression of TNF and Trx by immunohistochemistry in a group of 44 cutaneous melanoma patients. Trx expression did not correlated to survival or other clinicalpathological parameters. TNF expression significantly correlated to better survival in tumors thicker than 0,8 mm, and constituted an independent prognostic factor.

These results point to a biological role of endogenous TNF in malignant melanoma, either by constituting an autocrine/paracrine differentiation factor or by modulating communication with other cell types, particularly of the host’s immune system.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2001. 79 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 703
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-5226 (URN)91-7373-142-0 (ISBN)
Public defence
2001-12-06, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:30 (English)
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Note
Article 4 changed significantly during the publication process.Available from: 2002-01-11 Created: 2002-01-11 Last updated: 2017-09-22Bibliographically approved

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Söderberg, AnitaBarral, Anna-MariaSöderström, MatsRosén, Anders

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