The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor.
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.
Sprynski
Anne Catherine
AC
Inserm U847, Montpellier, France.
Hose
Dirk
D
Caillot
Laurent
L
Réme
Thierry
T
Shaughnessy
John D
JD
Barlogie
Bart
B
Seckinger
Anja
A
Moreaux
Jérôme
J
Hundemer
Michael
M
Jourdan
Michel
M
Meissner
Tobias
T
Jauch
Anna
A
Mahtouk
Karène
K
Kassambara
Alboukadel
A
Bertsch
Uta
U
Rossi
Jean François
JF
Goldschmidt
Hartmut
H
Klein
Bernard
B
D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D016895:Culture Media, Serum-Free; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D066257:Heparin-binding EGF-like Growth Factor; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13 / Q000494:pharmacology
D016895:Culture Media, Serum-Free; C587883:HBEGF protein, human; C066855:HGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; C114631:TNFSF13 protein, human; D053300:Tumor Necrosis Factor Ligand Superfamily Member 13; D017228:Hepatocyte Growth Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D017493:Leukocyte Common Antigens