Universität zu Köln

Bankov, Katrin, Doering, Claudia, Ustaszewski, Adam ORCID: 0000-0002-9542-0029, Giefing, Maciej ORCID: 0000-0002-4760-8246, Herling, Marco, Cencioni, Chiara ORCID: 0000-0001-6284-539X, Spallotta, Francesco, Gaetano, Carlo ORCID: 0000-0002-5238-1832, Kueppers, Ralf, Hansmann, Martin-Leo and Hartmann, Sylvia (2019). Fibroblasts in Nodular Sclerosing Classical Hodgkin Lymphoma Are Defined by a Specific Phenotype and Protect Tumor Cells from Brentuximab-Vedotin Induced Injury. Cancers, 11 (11). BASEL: MDPI. ISSN 2072-6694

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bankov, Katrin UNSPECIFIED UNSPECIFIED UNSPECIFIED Doering, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Ustaszewski, Adam UNSPECIFIED orcid.org/0000-0002-9542-0029 UNSPECIFIED Giefing, Maciej UNSPECIFIED orcid.org/0000-0002-4760-8246 UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED Cencioni, Chiara UNSPECIFIED orcid.org/0000-0001-6284-539X UNSPECIFIED Spallotta, Francesco UNSPECIFIED UNSPECIFIED UNSPECIFIED Gaetano, Carlo UNSPECIFIED orcid.org/0000-0002-5238-1832 UNSPECIFIED Kueppers, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansmann, Martin-Leo UNSPECIFIED UNSPECIFIED UNSPECIFIED Hartmann, Sylvia UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-128756
DOI:	10.3390/cancers11111687
Journal or Publication Title:	Cancers
Volume:	11
Number:	11
Date:	2019
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language REED-STERNBERG CELLS; REGULATORY FACTOR 4; STROMAL CELLS; MICROENVIRONMENTAL INTERACTIONS; GROWTH; EXPRESSION; INVOLVEMENT; CCL5/RANTES; RECEPTOR; LINES Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/12875