Abnormal IGF-Binding Protein Profile in the Bone Marrow of Multiple Myeloma Patients.
Insulin-like growth factor (IGF) signalling plays a key role in homing, progression, and treatment resistance in multiple myeloma (MM). In the extracellular environment, the majority of IGF molecules are bound to one of six IGF-binding proteins (IGFBP1-6), leaving a minor fraction of total IGF free and accessible for receptor activation. In MM, high IGF-receptor type 1 expression levels correlate with a poor prognosis, but the status and role of IGF and IGFBPs in the pathobiology of MM is unknown. Here we measured total IGF1, IGF2, and intact IGFBP levels in blood and bone marrow samples from MM (n = 17), monoclonal gammopathy of undetermined significance (MGUS) (n = 37), and control individuals (n = 15), using ELISA (IGFs) and 125I-IGF1 Western Ligand Blotting (IGFBPs). MGUS and MM patients displayed a significant increase in intact IGFBP-2 (2.5-3.8 fold) and decrease in intact IGFBP-3 (0.6-0.5 fold) in the circulation compared to control individuals. Further, IGFBP-2 as well as total IGFBP levels were significantly lower in bone marrow compared to circulation in MM and MGUS only, whereas IGF1, IGF2, and IGFBP-3 were equally distributed between the two compartments. In conclusion, the profound change in IGFBP profile strongly suggests an increased IGF bioavailability in the bone marrow microenvironment in MGUS and MM, despite no change in growth factor concentration.
Department of Hematology, Aalborg Hospital, Aalborg University, Alborg, Denmark.|Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.|Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Liesbeth
L
Bieghs
Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
Malene
M
Brohus
Department of Haematology, Odense University Hospital, Odense, Denmark.
Ida B
IB
Kristensen
Department of Haematology, Odense University Hospital, Odense, Denmark.
Niels
N
Abildgaard
Department of Hematology, Aalborg Hospital, Aalborg University, Alborg, Denmark.
Martin
M
Bøgsted
Department of Hematology, Aalborg Hospital, Aalborg University, Alborg, Denmark.
Hans E
HE
Johnsen
Division of Endocrinology, Metabolism and Nutrition, Endocrine Research Unit, Mayo Clinic, Rochester, MN, United States of America.
Cheryl A
CA
Conover
Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
Elke
E
De Bruyne
Department of Hematology and Immunology-Myeloma Center Brussel, Vrije Universiteit Brussel, Brussels, Belgium.
Karin
K
Vanderkerken
Department of Chemistry and Bioscience, Aalborg University, Aalborg, Denmark.
Michael T
0000-0002-1423-2481
MT
Overgaard
Department of Biomedicine, Aarhus University, Aarhus, Denmark.
Mette
M
Nyegaard
D000368:Aged; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D009101:Multiple Myeloma / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011485:Protein Binding; D015398:Signal Transduction
C583557:IGF1 protein, human; C035170:IGF2 protein, human; C032231:IGFBP1 protein, human; C515497:IGFBP3 protein, human; D018970:Insulin-Like Growth Factor Binding Protein 1; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II