Abstract
A plethora of myeloma growth factors (MGFs) has been identified, but their relative importance and cooperation have not been determined. We investigated 5 MGFs (interleukin-6 [IL-6], insulin-like growth factor type 1 [IGF-1], hepatocyte growth factor [HGF], HB-epidermal growth factor [HB-EGF], and a proliferation-inducing ligand [APRIL]) in serum-free cultures of human myeloma cell lines (HMCLs). In CD45(-) HMCLs, an autocrine IGF-1 loop promoted autonomous survival whereas CD45(+) HMCLs could not survive without addition of MGFs, mainly IGF-1 and IL-6. IGF-1 was the major one: its activity was abrogated by an IGF-1R inhibitor only, whereas IL-6, HGF, or HB-EGF activity was inhibited by both IGF-1R- and receptor-specific inhibition. APRIL activity was inhibited by its specific inhibitor only. Of the investigated MGFs and their receptors, only expressions of IGF-1R and IL-6R in multiple myeloma cells (MMCs) of patients delineate a group with adverse prognosis. This is mainly explained by a strong association of IGF-1R and IL-6R expression and t(4;14) translocation, but IGF-1R expression without t(4;14) can also have a poor prognosis. Thus, IGF-1-targeted therapy, eventually in combination with anti-IL-6 therapy, could be promising in a subset of patients with MMCs expressing IGF-1R.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Blotting, Western
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Cell Division / drug effects
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival / drug effects
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Chromosomes, Human, Pair 14 / genetics
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Chromosomes, Human, Pair 4 / genetics
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Culture Media, Serum-Free
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Heparin-binding EGF-like Growth Factor
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Hepatocyte Growth Factor / pharmacology
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Humans
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Immunoblotting
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Immunoenzyme Techniques
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In Situ Hybridization, Fluorescence
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Insulin-Like Growth Factor I / pharmacology*
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Intercellular Signaling Peptides and Proteins / pharmacology*
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Interleukin-6 / pharmacology
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Leukocyte Common Antigens / metabolism
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Multiple Myeloma / drug therapy
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology*
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Oligonucleotide Array Sequence Analysis
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Prognosis
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Receptors, Interleukin-6 / genetics
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Receptors, Interleukin-6 / metabolism
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Recombinant Proteins / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Translocation, Genetic
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Tumor Necrosis Factor Ligand Superfamily Member 13 / pharmacology
Substances
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Culture Media, Serum-Free
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HBEGF protein, human
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HGF protein, human
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Heparin-binding EGF-like Growth Factor
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Intercellular Signaling Peptides and Proteins
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Interleukin-6
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RNA, Messenger
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Receptors, Interleukin-6
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Recombinant Proteins
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TNFSF13 protein, human
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Tumor Necrosis Factor Ligand Superfamily Member 13
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Hepatocyte Growth Factor
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Insulin-Like Growth Factor I
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Receptor, IGF Type 1
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Leukocyte Common Antigens