Abstract
Multiple Myeloma (MM) is a plasma cell malignancy primarily localized in the bone marrow. By multiprobe interphase FISH, tumors from almost all patients harbor chromosomal abnormalities. These abnormalities are not sufficient to promote survival and growth of multiple myeloma cells (MMC) ex vivo, i.e. without the tumor microenvironment. The tumor microenvironment expresses adhesion molecules and produces growth factors that are critical to trigger survival MMC. A plethora of growth factors have been identified as myeloma cell growth factors (MGF) but their individual role is not completely understood. MGF can be produced by the tumor environment or by MMC themselves. These MGF activate their specific receptors that in turn result in the activation of several signal transduction pathways which promote their survival and their growth. The numerous MGF make it difficult to understand their respective role in the natural history of the disease and whether they are necessary and sufficient or redundant. We studied the 5 most documented MGF and we found that IGF-1 is an important growth factor because an IGF-1R kinase inhibitor blocks growth in 7/8 HMCL and autocrine IGF-1 is essential to promote the growth activity of IL-6, HB-EGF or HGF. The IGF-1R gene is expressed in MMC isolated from 44% patients with MM and was identified as an adverse prognostic. The second major MGF, IL-6 promote the growth of 7/8 HMCLs. IL-6R was expressed in MMC of all patients and patients with high IL-6R expression also had a poor prognosis. We then studied insulin, a cytokine which has a high homology with IGF-1. We have shown that insulin is a MGF as potent as IGF-1. Insulin activity necessitates IGF-1R activation which is mediated by the presence of the IGF-1R/INSR heterodimer receptor (Hybrid-R) on MMC. Insulin can't activate homodimer IGF-1R at physiological concentrations therefore hybrid-R confers to insulin the capacity to activate IGF-1R and to be a MGF. An inhibitor targeting the IGF-1R and hybrid-R pathways either with or without a combination with an anti-IL-6 antibody could be promising for the treatment for MM patients expressing IGF-1R.