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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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 |
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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 |
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