Insulin‐like growth factor induces the survival and proliferation of myeloma cells through an interleukin‐6‐independent transduction pathway

Multiple myeloma (MM) is a B‐cell neoplasia that is associated with an increased level of bone resorption. One important mediator of bone remodelling, insulin‐like growth factor (IGF‐I), has been shown to stimulate the proliferation of human myeloma cells. However, the mechanisms of action of IGF‐I in these cells have not been determined. Using interleukin (IL)‐6‐dependent myeloma cell lines, we show IGF‐I to be as potent a survival and proliferation factor as IL‐6. We demonstrated that IGF‐I functions independently of the IL‐6 transducer gp130 and that these two cytokines have additive effects. Moreover, inhibition of the IGF‐I pathway did not modulate the proliferative effect of IL‐6. Accordingly, we found that IL‐6 and IGF‐I activated distinct downstream signalling molecules: IL‐6 activated STAT3 phosphorylation, whereas IGF‐I treatment resulted in the phosphorylation of IRS‐1. Interestingly, these signalling pathways appear to converge as both cytokines activated the ras/MAPK pathway. Thus, IGF‐I acts as a potent survival and proliferation factor for myeloma cells by stimulating an IL‐6‐independent signalling cascade. These data, together with the finding that, in vivo , IGF‐I is normally expressed in close proximity to myeloma cells within the bone matrix, strongly suggest a role for this cytokine in the pathophysiology of multiple myeloma.