Cargando…

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo

In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain i...

Descripción completa

Detalles Bibliográficos
Autores principales: Clark, Kimberley C., Hewett, Duncan R., Panagopoulos, Vasilios, Plakhova, Natalya, Opperman, Khatora S., Bradey, Alanah L., Mrozik, Krzysztof M., Vandyke, Kate, Mukherjee, Siddhartha, Davies, Gareth C.G., Worthley, Daniel L., Zannettino, Andrew C.W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464474/
https://www.ncbi.nlm.nih.gov/pubmed/32756430
http://dx.doi.org/10.3390/cancers12082149
_version_ 1783577373903421440
author Clark, Kimberley C.
Hewett, Duncan R.
Panagopoulos, Vasilios
Plakhova, Natalya
Opperman, Khatora S.
Bradey, Alanah L.
Mrozik, Krzysztof M.
Vandyke, Kate
Mukherjee, Siddhartha
Davies, Gareth C.G.
Worthley, Daniel L.
Zannettino, Andrew C.W.
author_facet Clark, Kimberley C.
Hewett, Duncan R.
Panagopoulos, Vasilios
Plakhova, Natalya
Opperman, Khatora S.
Bradey, Alanah L.
Mrozik, Krzysztof M.
Vandyke, Kate
Mukherjee, Siddhartha
Davies, Gareth C.G.
Worthley, Daniel L.
Zannettino, Andrew C.W.
author_sort Clark, Kimberley C.
collection PubMed
description In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann–Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.
format Online
Article
Text
id pubmed-7464474
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-74644742020-09-04 Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo Clark, Kimberley C. Hewett, Duncan R. Panagopoulos, Vasilios Plakhova, Natalya Opperman, Khatora S. Bradey, Alanah L. Mrozik, Krzysztof M. Vandyke, Kate Mukherjee, Siddhartha Davies, Gareth C.G. Worthley, Daniel L. Zannettino, Andrew C.W. Cancers (Basel) Article In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann–Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM. MDPI 2020-08-03 /pmc/articles/PMC7464474/ /pubmed/32756430 http://dx.doi.org/10.3390/cancers12082149 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Clark, Kimberley C.
Hewett, Duncan R.
Panagopoulos, Vasilios
Plakhova, Natalya
Opperman, Khatora S.
Bradey, Alanah L.
Mrozik, Krzysztof M.
Vandyke, Kate
Mukherjee, Siddhartha
Davies, Gareth C.G.
Worthley, Daniel L.
Zannettino, Andrew C.W.
Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
title Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
title_full Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
title_fullStr Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
title_full_unstemmed Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
title_short Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo
title_sort targeted disruption of bone marrow stromal cell-derived gremlin1 limits multiple myeloma disease progression in vivo
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464474/
https://www.ncbi.nlm.nih.gov/pubmed/32756430
http://dx.doi.org/10.3390/cancers12082149
work_keys_str_mv AT clarkkimberleyc targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT hewettduncanr targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT panagopoulosvasilios targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT plakhovanatalya targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT oppermankhatoras targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT bradeyalanahl targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT mrozikkrzysztofm targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT vandykekate targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT mukherjeesiddhartha targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT daviesgarethcg targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT worthleydaniell targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo
AT zannettinoandrewcw targeteddisruptionofbonemarrowstromalcellderivedgremlin1limitsmultiplemyelomadiseaseprogressioninvivo