Next Article in Journal
The Perfect Combination: Enhancing Patient Response to PD-1-Based Therapies in Epithelial Ovarian Cancer
Next Article in Special Issue
The Acidic Microenvironment: Is It a Phenotype of All Cancers? A Focus on Multiple Myeloma and Some Analogies with Diabetes Mellitus
Previous Article in Journal
lncRNA and Mechanisms of Drug Resistance in Cancers of the Genitourinary System
Previous Article in Special Issue
Ex Vivo Models Simulating the Bone Marrow Environment and Predicting Response to Therapy in Multiple Myeloma
Article

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

1
Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia
2
Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
3
Department of Medicine, Columbia University Medical Center, New York City, NY 10032, USA
4
UCB (Union Chimique Belge) Pharma, Slough SL1 3WE, UK
5
Central Adelaide Local Health Network, Adelaide, SA 5000, Australia
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(8), 2149; https://doi.org/10.3390/cancers12082149
Received: 25 June 2020 / Revised: 24 July 2020 / Accepted: 29 July 2020 / Published: 3 August 2020
(This article belongs to the Special Issue Tumor Microenvironment and Exacerbation Mechanism in Multiple Myeloma)
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. View Full-Text
Keywords: multiple myeloma; Grem1; bone marrow stromal cells; Gremlin1 multiple myeloma; Grem1; bone marrow stromal cells; Gremlin1
Show Figures

Figure 1

MDPI and ACS Style

Clark, K.C.; Hewett, D.R.; Panagopoulos, V.; Plakhova, N.; Opperman, K.S.; Bradey, A.L.; Mrozik, K.M.; Vandyke, K.; Mukherjee, S.; Davies, G.C.G.; Worthley, D.L.; Zannettino, A.C.W. Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo. Cancers 2020, 12, 2149. https://doi.org/10.3390/cancers12082149

AMA Style

Clark KC, Hewett DR, Panagopoulos V, Plakhova N, Opperman KS, Bradey AL, Mrozik KM, Vandyke K, Mukherjee S, Davies GCG, Worthley DL, Zannettino ACW. Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo. Cancers. 2020; 12(8):2149. https://doi.org/10.3390/cancers12082149

Chicago/Turabian Style

Clark, Kimberley C., Duncan R. Hewett, Vasilios Panagopoulos, Natalya Plakhova, Khatora S. Opperman, Alanah L. Bradey, Krzysztof M. Mrozik, Kate Vandyke, Siddhartha Mukherjee, Gareth C.G. Davies, Daniel L. Worthley, and Andrew C.W. Zannettino 2020. "Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo" Cancers 12, no. 8: 2149. https://doi.org/10.3390/cancers12082149

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop