Abstract
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.
Highlights
Multiple myeloma (MM) is an incurable plasma cell malignancy, characterized by the massive accumulation of terminally differentiated monoclonal plasma cells in the bone marrow (BM)
We found no significant difference in total IGFI levels between MM patients (117.7 ng/ml; Confidence interval (CI) 104.9–130.5) (n = 17) and control individuals (137.2 ng/ml; CI 123.8–150.6) (n = 15) (Fig 1A)
IGF1 and IGF2 concentrations did not differ between the two compartments, suggesting that the total level of insulin-like growth factor (IGF) in the circulation can be used as a proxy for the levels in the BM (Fig 1D and 1H)
Summary
Multiple myeloma (MM) is an incurable plasma cell malignancy, characterized by the massive accumulation of terminally differentiated monoclonal plasma cells in the bone marrow (BM). MM cells are (in most cases) highly dependent on the BM microenvironment where growth and survival factors are secreted. The insulin-like growth factor (IGF) system has been demonstrated to play a prominent role within MM pathogenesis [1,2]. IGF1 has been shown to promote the growth, survival and migration of MM cells. PLOS ONE | DOI:10.1371/journal.pone.0154256 April 25, 2016
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