The role of the insulin-like growth factor 1 receptor axis in multiple myeloma

Menu, Eline; Valckenborgh, Els Van; Camp, Benjamin Van; Vanderkerken, Karin

doi:10.1080/13813450902736583

Cited by 33 publications

(27 citation statements)

References 65 publications

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“…Our analyses confirmed that, compared with UC-MSCs, both nBM-and MM-BM-MSCs produce higher amounts of pro-MM cytokines, namely IL-6, IL-15, IGF-1, MIP-1a, OPG, and RANTES [34][35][36][37][38]. These results appear in line with most studies reporting that BM-MSCs from MM patients mediate the formation of an intense marrow gradient of soluble [39,40] or exosome-incorporated cytokines with a biological impact on the survival of myeloma plasma cells [6].…”

Section: Discussionsupporting

confidence: 72%

A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

Ciavarella

Caselli

Tamma

et al. 2015

Stem Cells and Development

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Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are under intensive investigation in preclinical models of cytotherapies against cancer, including multiple myeloma (MM). However, the therapeutic use of stromal progenitors holds critical safety concerns due to their potential MM-supporting activity in vivo. Here, we explored whether MSCs from sources other than BM, such as adipose tissue (AD-MSCs) and umbilical cord (UC-MSCs), affect MM cell growth in comparison to either normal (nBM-MSCs) or myelomatous marrow MSCs (MM-BM-MSCs). Results from both proliferation and clonogenic assays indicated that, in contrast to nBM-and MM-BM-MSCs, both AD and particularly UC-MSCs significantly inhibit MM cell clonogenicity and growth in vitro. Furthermore, when co-injected with UC-MSCs into mice, RPMI-8226 MM cells formed smaller subcutaneous tumor masses, while peritumoral injections of the same MSC subtype significantly delayed the tumor burden growing in subcutaneous plasmocytoma-bearing mice. Finally, both microarrays and ELISA revealed different expression of several genes and soluble factors in UC-MSCs as compared with other MSCs. Our data suggest that UC-MSCs have a distinct molecular profile that correlates with their intrinsic anti-MM activity and emphasize the UCs as ideal sources of MSCs for future cell-based therapies against MM.

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Section: Discussionsupporting

confidence: 72%

A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

Ciavarella

Caselli

Tamma

et al. 2015

Stem Cells and Development

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“…Therefore, Pim-2 overexpressed in MM cells in the MM bone marrow microenvironment appears to be an important therapeutic target. IGF-1 is another critical microenvironment-derived survival factor for MM cells, 14,15 and inhibition of the IGF-1/PI3K/Akt pathway by Akt or mammalian target of rapamycin inhibitors has drawn considerable attention as a new therapeutic modality against MM. 19,20 Because Pim-2 upregulation is largely independent of the PI3K/Akt pathway (Figure 3e), and because inhibition of Pim-2 and PI3K/Akt pathways cooperatively reduce MM cell survival (Figures 4b and e), Pim-2 should be targeted to improve anti-MM efficacy together with PI3K/Akt pathway inhibitors.…”

Section: Resultsmentioning

confidence: 99%

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

et al. 2011

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Bone marrow stromal cells (BMSCs) and osteoclasts (OCs) confer multiple myeloma (MM) cell survival through elaborating factors. We demonstrate herein that IL-6 and TNF family cytokines, TNFa, BAFF and APRIL, but not IGF-1 cooperatively enhance the expression of the serine/threonine kinase Pim-2 in MM cells. BMSCs and OCs upregulate Pim-2 expression in MM cells largely via the IL-6/STAT3 and NF-jB pathway, respectively. Pim-2 short interfering RNA reduces MM cell viability in cocultures with BMSCs or OCs. Thus, upregulation of Pim-2 appears to be a novel anti-apoptotic mechanism for MM cell survival. Interestingly, the mammalian target of rapamycin inhibitor rapamycin further suppresses the MM cell viability in combination with the Pim-2 silencing. The Pim inhibitor (Z)-5-(4-propoxybenzylidene) thiazolidine-2, 4-dione and the PI3K inhibitor LY294002 cooperatively enhance MM cell death. The Pim inhibitor suppresses 4E-BP1 phosphorylation along with the reduction of Mcl-1 and c-Myc. Pim-2 may therefore become a new target for MM treatment.

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“…2 One of the most important growth factors involved in MM progression is insulin-like growth factor-1 (IGF-1). [3][4][5] This cytokine induces proliferation of both interleukin-6 (IL-6)-independent and -dependent cell lines, acts synergistically with IL-6, and protects MM cells from dexamethasone-induced apoptosis. 3 Moreover, IGF-1 also stimulates homing and production of angiogenic factors.…”

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confidence: 99%

IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms

Bruyne

Bos

Schuit

et al. 2010

Blood

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IntroductionMultiple myeloma (MM) is a lethal plasma cell malignancy hallmarked by uncontrolled accumulation of monoclonal plasma cells in the bone marrow (BM). 1 There, the MM cells receive signals to survive and proliferate because of the existence of functional, mutual interactions through growth factors and adhesion molecules. 2 Importantly, these interactions also confer resistance to conventional therapies. 2 One of the most important growth factors involved in MM progression is insulin-like growth factor-1 (IGF-1). [3][4][5] This cytokine induces proliferation of both interleukin-6 (IL-6)-independent and -dependent cell lines, acts synergistically with IL-6, and protects MM cells from dexamethasone-induced apoptosis. 3 Moreover, IGF-1 also stimulates homing and production of angiogenic factors. 4,6,7 Binding to its receptor results in the activation of the Ras/Raf/MAPK (mitogen-activated protein kinase)/Erk (mainly triggering proliferation and secretion of vascular endothelial growth factor) and the PI-3K (phosphatidylinositol-3 kinase)/Akt pathways (involved mainly in antiapoptotic stimuli and mediating migration). 6,8 Both IGF-1 serum levels and IGF-1 receptor (IGF-1R) expression by the MM cells are important negative prognostic factors in MM. 9,10 The central role of IGF-1 in the MM pathophysiology is further supported by the encouraging preclinical results observed after targeting the IGF-1R with neutralizing antibodies or small molecule inhibitors. Previously, we demonstrated the efficacy of the IGF-1R tyrosine kinase inhibitor picropodophyllin to block the function of IGF-1R in vitro and in vivo and this both in murine and human MM cells. 11,12 The anti-MM activity of selective IGF-1R inhibitors was also confirmed with the use of the selective kinase inhibitor NVP-ADW742 in an orthotopic xenograft MM model. 4 Clinical trials examining the effect of both blocking antibodies and small molecule inhibitors are currently ongoing. 3 Bim (Bcl2like11) is a member of the BH3-only group of the Bcl-2 protein family and is a mediator of apoptosis. 13,14 Bim is a sensor of cell stress (withdrawal or inhibition of growth factor signaling or treatment with numerous cytotoxic agents) 13,15 and promotes apoptosis either indirectly by antagonizing the inhibitory function of the Bcl-2/Bcl-Xl members and thus liberating the innate cytotoxic Bax-like members or directly by activating the Bax-like members. 13 Three major isoforms of Bim are known: extra-long (BimEL), long (BimL), and short (BimS). All 3 isoforms induce apoptosis; the shortest being the most potent but the longest the most preponderant. 16 The proapoptotic activity of Bim seems to be controlled in various ways. In healthy cells, Bim is sequestered in its inactive form to the microtubular cytoskeleton or exists as inactive heterodimers (with antiapoptotic Bcl-2 family members) sequestered to the mitochondria. 17 In B and MM cells, Bim appears to be constitutively associated with Mcl-1. At induction of apoptosis, Bim is released from Mcl-1, thus activating ...

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The role of the insulin-like growth factor 1 receptor axis in multiple myeloma

Cited by 33 publications

References 65 publications

A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

A Peculiar Molecular Profile of Umbilical Cord-Mesenchymal Stromal Cells Drives Their Inhibitory Effects on Multiple Myeloma Cell Growth and Tumor Progression

The serine/threonine kinase Pim-2 is a novel anti-apoptotic mediator in myeloma cells

IGF-1 suppresses Bim expression in multiple myeloma via epigenetic and posttranslational mechanisms

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