Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic “Stromal” Cells from Giant Cell Tumors of Bone

Venneker, Sanne; Eenige, Robin van; Kruisselbrink, Alwine B.; Palubeckaitė, Ieva; Taliento, Alice E.; Bruijn, Inge H. Briaire-de; Hogendoorn, Pancras C.W.; Sande, Michiel A. J. van de; Gelderblom, Hans; Mei, Hailiang; Bovée, Judith; Szuhai, Károly

doi:10.3390/cancers14194708

Cited by 8 publications

(2 citation statements)

References 38 publications

(49 reference statements)

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“…Given the relative novelty of this cell culture method, numerous applications still need to be explored. Epigenetics regulators, such as HDAC inhibitors, have been used to stimulate 3D in vitro models [ 28 , 29 ]. However, for the first time, we aimed to demonstrate that cells grown as spheroids can be treated with epigenetic drugs at a high concentration, i.e., 20 mM sodium butyrate, and still maintain their viability to investigate the response to the treatment and subsequent recovery.…”

Section: Discussionmentioning

confidence: 99%

Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model

Stransky

Cutler

Aguilan

et al. 2022

Epigenetics & Chromatin

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Background Three-dimensional (3D) cell culture has emerged as an alternative approach to 2D flat culture to model more accurately the phenotype of solid tissue in laboratories. Culturing cells in 3D more precisely recapitulates physiological conditions of tissues, as these cells reduce activities related to proliferation, focusing their energy consumption toward metabolism and homeostasis. Results Here, we demonstrate that 3D liver spheroids are a suitable system to model chromatin dynamics and response to epigenetics inhibitors. To delay necrotic tissue formation despite proliferation arrest, we utilize rotating bioreactors that apply active media diffusion and low shearing forces. We demonstrate that the proteome and the metabolome of our model resemble typical liver functions. We prove that spheroids respond to sodium butyrate (NaBut) treatment, an inhibitor of histone deacetylases (HDACi), by upregulating histone acetylation and transcriptional activation. As expected, NaBut treatment impaired specific cellular functions, including the energy metabolism. More importantly, we demonstrate that spheroids reestablish their original proteome and transcriptome, including pre-treatment levels of histone acetylation, metabolism, and protein expression once the standard culture condition is restored after treatment. Given the slow replication rate (> 40 days) of cells in 3D spheroids, our model enables to monitor the recovery of approximately the same cells that underwent treatment, demonstrating that NaBut does not have long-lasting effects on histone acetylation and gene expression. These results suggest that our model system can be used to quantify molecular memory on chromatin. Conclusion Together, we established an innovative cell culture system that can be used to model anomalously decondensing chromatin in physiological cell growth and rule out epigenetics inheritance if cells recover the original phenotype after treatment. The transient epigenetics effects demonstrated here highlight the relevance of using a 3D culture model system that could be very useful in studies requiring long-term drug treatment conditions that would not be possible using a 2D cell monolayer system.

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Section: Discussionmentioning

confidence: 99%

Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model

Stransky

Cutler

Aguilan

et al. 2022

Epigenetics & Chromatin

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“…To utilize and study the nature and several genes’ molecular mechanisms of action, their impact on the GCTB cells, and to devise treatment strategies, several GCTB cell lines have been established from patients. Patient-derived cell lines such as NCC-GCTB1-C1, NCC-GCTB2-C1, NCC-GCTB3-C1, NCC-GCTB4-C1, and NCC-GCTB5-C1 have been established from PDTXs, and the molecular genetic makeup of each has been studied extensively. − Several genes such as ALCAM + in stromal cells of the GCTB population, histone deacetylase inhibitors in stromal cells of the GCTB population, RANKL-based targeting − and PD-L1 and SIRP α in GCTB multinucleated cells, which are essential to studying the mechanism of eliminating the tumor or feedback immune mechanisms to kill the tumor, have been studied on 2D cell cultures of GCTB derived from PDTXs.…”

Section: In Vitro Culture Of Giant Cell Tumor Of Bone (Gctb)mentioning

confidence: 99%

Investigation of Giant Cell Tumor of Bone and Tissue Engineering Approaches for the Treatment of Giant Cell Tumor of Bone

Anandan,

Kumar,

Jeyakkani

et al. 2023

ACS Appl. Bio Mater.

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Primary bone tumors such as Ewing sarcoma, osteosarcoma, and chondrosarcoma, secondary bone tumors developed from progressive malignancies, and metastasized bone tumors are more prevalent and studied descriptively through biology and medical research. Less than 0.2% of cancer diagnoses are caused by rare bone-originating tumors, which despite being rare are particularly difficult due to their high death rates and substantial disease burden. A giant cell tumor of bone (GCTB) is an intramurally invasive but rare and benign type of bone tumor, which seldom metastasizes. The most often prescribed medication for GCTB is Denosumab, a RANKL (receptor activator of nuclear factor κB ligand) inhibitor. Because pharmaceutical drug companies rely on two-dimensional and animal models, current approaches for investigating the diverse nature of tumors are insufficient. Cell line based medication effectiveness and toxicity studies cannot predict tumor response to antitumor medicines. It has already been investigated in detail why molecular pathways do not reproduce in vitro, a phenomenon known as flat biology. Due to physiological differences between human beings and animals, animal models do not succeed in identifying side effects of the treatment, emulating metastatic growth, and establishing the link between cancer and the immune system. This review summarizes and discusses GCTB, the disease, its cellular composition, various bone tumor models, and their properties and utilization in research. As a result, this study delves deep into in vitro testing, which is vital for scientists and physicians in various fields, including pharmacology, preclinical investigations, tissue engineering, and regenerative medicine.

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Denosumab for giant cell tumors of bone from 2010 to 2022: a bibliometric analysis

Tan¹,

Zhang²,

Wei³

et al. 2023

Clin Exp Med

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Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic “Stromal” Cells from Giant Cell Tumors of Bone

Cited by 8 publications

References 38 publications

Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model

Investigation of reversible histone acetylation and dynamics in gene expression regulation using 3D liver spheroid model

Investigation of Giant Cell Tumor of Bone and Tissue Engineering Approaches for the Treatment of Giant Cell Tumor of Bone

Denosumab for giant cell tumors of bone from 2010 to 2022: a bibliometric analysis

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