Osteoblastic niche supports the growth of quiescent multiple myeloma cells

Chen, Zheng; Orłowski, Robert Z.; Wang, Michael; Kwak, Larry W.; McCarty, Nami

doi:10.1182/blood-2013-07-517136

Cited by 68 publications

(78 citation statements)

References 8 publications

(4 reference statements)

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“…Whereas the presence of Wnt ligands in the BM niche is well established, expression of R-spondins in the BM microenvironment thus far has remained largely unexplored. Because autocrine R-spondins have been suggested to regulate differentiation of osteoblasts (38), which are important constituents of the MM niche (39,40), we hypothesized that osteoblasts could be a major source of R-spondins driving oncogenic Wnt signaling. Corroborating this hypothesis, we found expression of several R-spondins in (pre)osteoblasts and demonstrated that (pre)osteoblast-conditioned media robustly synergized with Wnt ligands in activating Wnt signaling.…”

Section: Discussionmentioning

confidence: 99%

“…However, the source of R-spondins remains to be defined. Prime candidates are osteoblasts, which have recently been suggested to use autocrine R-spondin for their differentiation (38) and, moreover, are key constituents of the MM niche (39,40). We therefore analyzed R-spondin mRNA expression in primary human osteoblasts (hOB) by qPCR.…”

Section: R-spondins Potentiate Wnt Signaling In MM In a Lgr4-dependentmentioning

confidence: 99%

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Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche. Here, we report a pivotal role for the R-spondin/leucine-rich repeat-containing G protein-coupled receptor 4 (LGR4) axis in driving aberrant Wnt/ β-catenin signaling in MM. We show that LGR4 is expressed by MM plasma cells, but not by normal plasma cells or B cells. This aberrant LGR4 expression is driven by IL-6/STAT3 signaling and allows MM cells to hijack R-spondins produced by (pre)osteoblasts in the BM niche, resulting in Wnt (co)receptor stabilization and a dramatically increased sensitivity to auto-and paracrine Wnts. Our study identifies aberrant R-spondin/LGR4 signaling with consequent deregulation of Wnt (co)receptor turnover as a driver of oncogenic Wnt/ β-catenin signaling in MM cells. These results advocate targeting of the LGR4/R-spondin interaction as a therapeutic strategy in MM.M ultiple myeloma (MM) in most patients is an incurable hematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow (BM). Despite the wide variety of underlying structural and numerical genomic abnormalities (1-3), virtually all MMs are highly dependent on a protective BM microenvironment, or "niche," for growth and survival (4). Understanding the complex reciprocal interaction between MM cells and the BM microenvironment is critical for the development of new targeted therapies.In MM, aberrant activation of the canonical Wnt pathway drives proliferation and is associated with disease progression, dissemination, and drug resistance (5-9). Because MMs with hallmarks of active Wnt signaling do not harbor mutations that typically underlie constitutive Wnt pathway activation, this oncogenic Wnt pathway activity was proposed to involve autocrine and/or paracrine Wnt ligands (6,8,10). Wnts are lipid-modified glycoproteins that function as typical niche factors because they are relatively unstable and insoluble due to their hydrophobic nature, which constrains long-range signaling (11). Binding of a Wnt ligand to its receptor Frizzled (Fzd) initiates a signaling cascade that ultimately results in stabilization and nuclear translocation of the Wnt effector β-catenin. In cooperation with TCF/LEF family transcription factors this orchestrates a transcriptional program (12, 13), comprising targets such as MYC and CCND1 (Cyclin D1) that play crucial roles in the pathogenesis of MM (14-16). Aberrant Wnt signaling in cancer typically results from mutations in APC, β-catenin (CTNNB1), or AXIN that drive constitutive, ligand-independent pathway ac...

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Section: Discussionmentioning

confidence: 99%

Section: R-spondins Potentiate Wnt Signaling In MM In a Lgr4-dependentmentioning

confidence: 99%

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Andel

Ren

Koopmans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…9 The potential quiescence of these MM subclones, coupled with their diversity, can contribute to enhanced tumorigenicity and an intrinsic resistance to therapy. 10 Therefore; the eradication of the majority bortezomib-sensitive subclones may ultimately promote the growth of pre-existing minority bortezomib-resistant sub-clones, limiting the efficacy of single-agent bortezomib. This finding is further supported by the clinical observation that approximately half of initially bortezomib-sensitive MM patients are no longer able to respond to bortezomib once relapsed.…”

Section: Introductionmentioning

confidence: 99%

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

et al. 2015

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Abbreviations: MM -multiple myeloma; PI -proteasome inhibitor; NF-kB -nuclear factor-kappa B; BMSC -bone marrow stromal cells; BTK -Bruton's tyrosine kinase.Multiple Myeloma (MM) is a haematologic malignancy characterized by the accumulation of clonal plasma cells in the bone marrow. Over the last 10-15 y the introduction of the proteasome-inhibitor bortezomib has improved MM prognosis, however relapse due to bortezomib-resistance is inevitable and the disease, at present, remains incurable. To model bortezomib-resistant MM we generated bortezomib-resistant MM cell lines (n D 4 ) and utilised primary malignant plasma cells from patients relapsing after bortezomib treatment (n D 6 ). We identified enhanced Bruton's tyrosine kinase (BTK) activity in bortezomib-resistant MM cells and found that inhibition of BTK, either pharmacologically with ibrutinib (0.5 mM) or via lenti-viral miRNA-targeted BTK interference, re-sensitized previously bortezomib-resistant MM cells to further bortezomib therapy at a physiologically relevant concentration (5 nM). Further analysis of pro-survival signaling revealed a role for the NF-kB p65 subunit in MM bortezomib-resistance, thus a combination of BTK and NF-kB p65 inhibition, either pharmacologically or via further lenti-viral miRNA NF-kB p65 interference, also restored sensitivity to bortezomib, significantly reducing cell viability (37.5 § 6 .9 %, ANOVA P 0 .001). Accordingly, we propose the clinical evaluation of a bortezomib/ibrutinib combination therapy, including in patients resistant to single-agent bortezomib.

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“…Accordingly, the role of angiogenesis in diffuse large B cell lymphoma measured by microvessel density has shown different results in regard to clinical outcome [32,33]. MM cells grow and expand almost exclusively in the bone marrow [34], and both osteoblastic and vascular niches can support the proliferation of MM cells [35]. This emphasizes Figure 2.…”

Section: Discussionmentioning

confidence: 97%

Content of Endothelial Progenitor Cells in Autologous Stem Cell Grafts Predict Survival after Transplantation for Multiple Myeloma

Blix

Kildal

Bertelsen

et al. 2015

Biology of Blood and Marrow Transplantation

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Multiple myeloma (MM) is considered an incurable B cell malignancy, although many patients can benefit from high-dose therapy with autologous stem cell transplantation (ASCT) as a first-line treatment. In non-Hodgkin lymphoma (NHL), ASCT is usually performed after relapse with curative intent. Disease progression is often associated with increased angiogenesis, in which endothelial progenitor cells (EPC) may have a central role. Here, we investigated the clinical impact of EPC levels in peripheral blood stem cell (PBSC) autografts for MM and NHL patients who received ASCT. EPC were identified by flow cytometry as aldehyde dehydrogenase(hi) CD34(+) vascular endothelial growth factor receptor 2(+) CD133(+) cells in both MM and NHL autografts. In MM, there was a positive correlation between EPC percentage and serum (s)-β2-microglobulin levels (r(2) = .371, P = .002). Unlike for NHL patients, MM patients with high numbers of infused EPC (EPC cells per kilogram) during ASCT had significant shorter progression-free survival (PFS) (P = .035), overall survival (P = .044) and time to next treatment (P = .009). In multivariate analysis, EPC cells per kilogram was a significant independent negative prognostic indicator of PFS (P = .03). In conclusion, the presence of high number of EPC in PBSC grafts is associated with adverse prognosis after ASCT in MM.

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Osteoblastic niche supports the growth of quiescent multiple myeloma cells

Abstract: • Osteoblastic niche supports quiescent multiple myeloma cells in vivo.• Multiple myeloma cells isolated from osteoblastic niche have enhanced tumorigenicity and stemlike properties.

Cited by 68 publications

References 8 publications

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins

Ibrutinib inhibits BTK-driven NF-κB p65 activity to overcome bortezomib-resistance in multiple myeloma

Content of Endothelial Progenitor Cells in Autologous Stem Cell Grafts Predict Survival after Transplantation for Multiple Myeloma

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