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Cited by 61Multiple Myeloma Research and TreatmentsGrowth Hormone and Insulin-like Growth FactorsTGF-β signaling in diseases

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

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Bieghs, Liesbeth, Johnsen, Hans E., Maes, Ken, Menu, Eline, Van Valckenborgh, Els, Overgaard, Michael T., Nyegaard, Mette, Conover, Cheryl A. +2 more·2016·Oncotarget
DOI 10.18632/oncotarget.8982PMC PMC5217049
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Abstract

// Liesbeth Bieghs 1,2,3 , Hans E. Johnsen 2,4,5 , Ken Maes 1 , Eline Menu 1 , Els Van Valckenborgh 1 , Michael T. Overgaard 6 , Mette Nyegaard 3 , Cheryl A. Conover 7 , Karin Vanderkerken 1,* and Elke De Bruyne 1,* 1 Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium 2 Department of Hematology, Aalborg Hospital, Aalborg University, Denmark 3 Department of Biomedicin, Aarhus University, Aarhus, Denmark 4 Clinical Cancer Research Center, Aalborg University Hospital, Denmark 5 Department of Clinical Medicine, Aalborg University, Denmark 6 Department of Chemistry and Biotechnology, Aalborg University, Denmark 7 Division of Endocrinology, Metabolism and Nutrition, Endocrine Research Unit, Mayo Clinic, Rochester, NY, USA * Equal senior authors Correspondence to: Elke De Bruyne, email: // Keywords : multiple myeloma, insulin-like growth factor, IGF-I targeting Received : January 04, 2016 Accepted : April 16, 2016 Published : April 25, 2016 Abstract Multiple myeloma (MM) is a highly heterogeneous plasma cell malignancy. The MM cells reside in the bone marrow (BM), where reciprocal interactions with the BM niche foster MM cell survival, proliferation, and drug resistance. As in most cancers, the insulin-like growth factor (IGF) system has been demonstrated to play a key role in the pathogenesis of MM. The IGF system consists of IGF ligands, IGF receptors, IGF binding proteins (IGFBPs), and IGFBP proteases and contributes not only to the survival, proliferation, and homing of MM cells, but also MM-associated angiogenesis and osteolysis. Furthermore, increased IGF-I receptor (IGF-IR) expression on MM cells correlates with a poor prognosis in MM patients. Despite the prominent role of the IGF system in MM, strategies targeting the IGF-IR using blocking antibodies or small molecule inhibitors have failed to translate into the clinic. However, increasing preclinical evidence indicates that IGF-I is also involved in the development of drug resistance against current standard-of-care agents against MM, including proteasome inhibitors, immunomodulatory agents, and corticoids. IGF-IR targeting has been able to overcome or revert this drug resistance in animal models, enhancing the efficacy of standard-of-care agents. This finding has generated renewed interest in the therapeutic potential of IGF-I targeting in MM. The present review provides an update of the impact of the different IGF system components in MM and discusses the diagnostic and therapeutic potentials.

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  • The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation.

    “The RAS/MAPK pathway plays a crucial role in MM by influencing cell proliferation, survival, and differentiation.”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [84]

    The IGF-R section (page unavailable) identifies RAS/RAF/MEK-ERK as a downstream pathway and says MEK-ERK mainly regulates the cell cycle and proliferation. It assigns the main anti-apoptotic effect to PI3K/Akt, not MEK-ERK, and does not link the RAS/MAPK pathway to MM-cell differentiation. The claim is therefore supported for proliferation but not for the full list of effects. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Activation of RAS/MAPK in MM is often driven by mutations and increased levels of cytokines in the tumor microenvironment, such as IL-6, IGF, and VEGF.

    “The activation of this pathway in MM is often driven by mutations and increased levels of cytokines present in the tumor microenvironment, such as IL-6, insulin-like growth factor (IGF), and vascular endothelial growth factor (VEGF) [84–86].”

    From Multiple myeloma: signaling pathways and targeted therapy (2024) · cites this paper as [84]

    The Introduction identifies KRAS, BRAF, and NRAS mutations in MM and lists IGF, IL-6, and VEGF among growth factors in its bone-marrow microenvironment. The IGF-R section says IGF signaling activates RAS/RAF/MEK-ERK. However, the paper does not establish that increased levels of all three listed factors often drive that pathway; its Angiogenesis section instead describes VEGF production downstream of IGF-driven MEK/ERK signaling. (LLM, conf=0.86)

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Cited by

Sorted by citations

Authors
Bieghs, L., Johnsen, H. E., Maes, K., Menu, E., Van Valckenborgh, E., Overgaard, M. T., Nyegaard, M., Conover, C. A., Vanderkerken, K., & De Bruyne, E.
Affiliations
  • Vrije Universiteit Brussel (BE)
  • Aalborg University Hospital (DK)
  • Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels, Belgium
  • Aarhus University (DK)
  • Mayo Clinic (US)
Corresponding author
Vanderkerken, Karin
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-04-25
Volume
7
Issue
30
Pages
48732-48752
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.8982
PMC
PMC5217049
OpenAlex
W2343003864
Cited by
61
References
3
Citations by year
2026: 5 · 2025: 8 · 2024: 9 · 2023: 9 · 2022: 1 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 4 · 2016: 1
FWCI
0.81
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • VBN Forskningsportal (Aalborg Universitet) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Multiple Myeloma Research Foundation
  • Aarhus Universitet
  • Kræftens Bekæmpelse
  • Fonds Wetenschappelijk Onderzoek
  • Vlaamse Liga Tegen Kanker
  • Vlaamse regering
  • Sixth Framework Programme
Topics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords
multiple myeloma, insulin-like growth factor system, IGF-1 receptor, insulin-like growth factor I, IGF binding proteins, drug resistance, proteasome inhibitors, immunomodulators, corticosteroids, bone marrow microenvironment, angiogenesis, osteolysis, prognostic factors, plasma cell malignancy, tumor microenvironment
MeSH terms
Animals, Antineoplastic Agents, Cell Survival, Clinical Trials as Topic, Humans, Insulin, Multiple Myeloma, Neoplasm Invasiveness, Neoplasms, Experimental, Neovascularization, Pathologic, Osteolysis, Endopeptidases, Phosphorylation, Prognosis, Protein Binding, Somatomedins, Biomarkers, Tumor, Signal Transduction, Receptors, Somatomedin, Insulin-Like Growth Factor Binding Proteins, Drug Resistance, Neoplasm, Cell Proliferation, Mice, Molecular Targeted Therapy

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