Serum insulinlike growth factor is not elevated in patients with multiple myeloma but is still a prognostic factor

Abstract

Insulinlike growth factor 1 (IGF-1) has growth-promoting effects on myeloma cells in vitro as well as in vivo. In this study, we measured the concentration of IGF-1 and its major binding protein, IGFbinding protein 3 (IGFBP-3), in serum from 127 patients with multiple myeloma. Serum had been drawn at the time of diagnosis, before treatment with highdose melphalan. IGFBP-3 in myeloma patients (1.6 ؎ 0.73 g/mL; mean ؎ SD) was significantly decreased compared to healthy age-and sex-matched controls (2.2 ؎ 0.42 g/mL). However, IGFBP-3 had no prognostic value in this study. The mean IGF-1 level did not differ between myeloma patients (17.8 ؎ 7.7 nM) and controls (17.3 ؎ 5.6 nM). Nevertheless, IGF-1 was a strong indicator of prognosis. After 80 months of follow-up, myeloma patients with low levels (< 13 nM) of serum IGF-1 had not reached median survival. In the patient group with IGF-1 levels above 13 nM, median survival was 62 months (P ‫؍‬ .006). These findings support the hypothesis of a role for IGF-1 in myeloma disease progression. IntroductionMultiple myeloma (MM) is a B-cell malignancy that is characterized by accumulation of clonal plasma cells in the bone marrow. The disease is associated with production of monoclonal immunoglobulins and painful bone destruction. In recent years, the role of cytokines in the development of MM has been the focus of many studies. Although interleukin 6 (IL-6) is the best documented growth factor in this malignancy, it is now clear that several cytokines induce MM cell proliferation and possibly promote disease development.Insulinlike growth factor (IGF) is mainly produced by hepatocytes in response to growth hormone stimulation but is also produced locally in many other tissues (eg, by chondroblasts, fibroblasts, and osteoclasts). 1 IGF-1 can be detected in high (nanomolar) concentrations in serum, where 90% is bound to IGF-binding protein 3 (IGFBP-3). This protein inhibits IGF-1 by rendering it inaccessible to the receptor. 1 Substantial evidence suggests a role for IGF-1 in the growth and survival of MM cells. In vitro, IGF-1 induces proliferation of several MM cell lines. 2-4 IGF-1 can also enhance the growth-promoting effect of IL-6 on MM cells. 2,3,5 MM cell lines express the IGF-1 receptor, and stimulation of the receptor activates a distinct signal transduction cascade. This results in proliferation of MM cells as well as protection against apoptosis. 6 A mouse model of myeloma indicates that IGF-1 in the bone marrow can act as a chemoattractant for myeloma cells in vivo. 7 This suggests that IGF-1 may contribute to the recruitment and homing of myeloma cells to the bone marrow compartment. Moreover, in mice with severe combined immunodeficiency inoculated with MM cells, administration of IGF-1 increases the growth rate of the tumor cells. 6 The probable functional interaction between IGF-1 and MM cells made us examine the levels of IGF-1 and IGFBP-3 in serum of patients with MM and to compare them to the concentration in healthy controls. We further wished to relate se...

IGF-1R is overexpressed in poor-prognostic subtypes of multiple myeloma

“…Our gene expression-based results are in agreement with previous studies measuring IGF-1R and IGF-1 protein levels by flow cytometry and ELISA respectively, 7,9 showing good concordance between gene expression and protein data. While Letters to the Editor the absolute difference in gene expression level of IGF-1R among patients with different TC classes and D13 status is small, this can be accounted for by the log-transformation and normalization of gene expression data.…”

“…Our results fail to confirm the prognostic importance of IGF-1R and IGF-1 suggested by other investigators. 7,9 This may be due to differences in the study population, the relatively shorter follow-up in our cohort or the sample size, and the limited number of events. However, it is important to note that powerful prognostic factors like t(4;14), t(14;16), D13 (Figure 2c and d) and plasma cell labeling index (data not shown) already demonstrate statistically significant prognostic impact in our cohort despite the relatively short follow-up, suggesting that IGF-1 and IGF-1R expression levels are unlikely to have important prognostic impact.…”

“…7 We found a similar level of IGF-1 expression between malignant and normal PCs (Figure 1d), confirming the results of a previous ELISA-based study of serum IGF-1 in MM. 9 This suggests that IGF-1, required by the myeloma cells, may be derived from bone marrow stromal cells. We found no difference in IGF-1 expression levels between the different TC groups and patients with or without D13 (data not shown).…”

Inhibition of hypoxia-inducible factor-1 function enhances the sensitivity of multiple myeloma cells to melphalan

“…This cytokine confers multiple drug resistance on myeloma cells (25,30). Importantly, clinical studies have revealed that increases in serum IGF-1 levels may be correlated with poor outcomes of multiple myeloma (37). IGF-1 is also known to activate HIF-1 in several cancer cell lines.…”

The skinny on obesity and plasma cell myeloma: a review of the literature

“…However, in the same study, higher IGF-I levels were associated with poorer myeloma survival. 78 Given the relationship between insulin and IGF, it is also important to point out a meta-analysis of studies looking at the association between type 2 diabetes mellitus and myeloma demonstrated nonsignificant increased odds of myeloma in patients with type 2 diabetes mellitus (odds-ratio = 1.22, 95% CI = 0.98-1.53). 79 Whether insulin and IGF are involved in the transition from MGUS to myeloma is a topic worthy of further exploration.…”