Fibroblasts in nodular sclerosing classical hodgkin lymphoma are defined by a specific phenotype and protect tumor cells from brentuximab-vedotin induced injury

Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterized by a proliferation of fibroblasts in the tumor microenviro
Classical Hodgkin lymphoma (cHL) is one of the most common malignant lymphomas in Western Europe. The nodular sclerosing subtype of cHL (NS cHL) is characterized by a proliferation of fibroblasts in the tumor microenvironment, leading to fibrotic bands surrounding the lymphoma infiltrate. Several studies have described a crosstalk between the tumour cells of cHL, the Hodgkin- and Reed-Sternberg (HRS) cells, and cancer-associated fibroblasts. However, to date a deep molecular characterization of these fibroblasts is lacking. Thus, the aim of the present study is a comprehensive characterization of these fibroblasts. Gene expression profiling and methylation profiles of fibroblasts isolated from primary lymph node suspensions revealed persistent differences between fibroblasts obtained from NS cHL and lymphadenitis. NS cHL derived fibroblasts exhibit a myofibroblastic phenotype characterized by myocardin (MYOCD) expression. Moreover, TIMP3, an inhibitor of matrix metalloproteinases, was strongly upregulated in NS cHL fibroblasts, likely contributing to the accumulation of collagen in sclerotic bands of NS cHL. As previously shown for other types of cancer-associated fibroblasts, treatment by luteolin could reverse this fibroblast phenotype and decrease TIMP3 secretion. NS cHL fibroblasts showed enhanced proliferation when they were exposed to soluble factors released from HRS cells. For HRS cells, soluble factors from fibroblasts were not sufficient to protect them from Brentuximab-Vedotin induced cell death. However, HRS cells adherent to fibroblasts were protected from Brentuximab-Vedotin induced injury. In summary, we confirm the importance of fibroblasts for HRS cell survival and identify TIMP3 which probably contributes as a major factor to the typical fibrosis observed in NS cHL.
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Metadaten
Author:Katrin Bankov, Claudia Döring, Adam Ustaszewski, Maciej Giefing, Marco Herling, Chiara Cencioni, Francesco Spallotta, Carlo Gaetano, Ralf Küppers, Martin-Leo Hansmann, Sylvia Hartmann
URN:urn:nbn:de:hebis:30:3-516406
DOI:http://dx.doi.org/10.3390/cancers11111687
ISSN:2072-6694
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=31671543
Parent Title (English):Cancers
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/10/30
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/01/08
Tag:classical Hodgkin lymphoma; fibroblasts; gene expression analysis; luteolin; methylation profiling; nodular sclerosis
Volume:11
Issue:11, Art. 1687
Pagenumber:17
First Page:1
Last Page:17
Note:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
HeBIS PPN:458522074
Institutes:Medizin
Frankfurt Institute for Advanced Studies (FIAS)
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Open-Access-Publikationsfonds:Medizin
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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