TY  - JOUR
A1  - Bankov, Katrin
A1  - Döring, Claudia
A1  - Ustaszewski, Adam
A1  - Giefing, Maciej
A1  - Herling, Marco
A1  - Cencioni, Chiara
A1  - Spallotta, Francesco
A1  - Gaetano, Carlo
A1  - Küppers, Ralf
A1  - Hansmann, Martin-Leo
A1  - Hartmann, Sylvia
T1  - Fibroblasts in nodular sclerosing classical hodgkin lymphoma are defined by a specific phenotype and protect tumor cells from brentuximab-vedotin induced injury
T2  - Cancers
N2  - 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.
KW  - classical Hodgkin lymphoma
KW  - nodular sclerosis
KW  - fibroblasts
KW  - gene expression analysis
KW  - methylation profiling
KW  - luteolin
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/51640
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-516406
SN  - 2072-6694
N1  - 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
VL  - 11
IS  - 11, Art. 1687
SP  - 1
EP  - 17
PB  - MDPI
CY  - Basel
ER  -