Autocrine insulin-like growth factor 1 and stem cell factor but not interleukin 6 support self-renewal of human myeloma cells

Abstract

In this study, we have identified the growth factors supporting myeloma self-renewal in eight myeloma cell lines. All cell lines able to form self-colonies displayed constitutive P-AKT and P-ERK1,2 but not P-STAT3 and did not express CD45, suggesting the presence of an insulin-like growth factor 1 (IGF1) loop. We showed that a blocking anti-insulin-like growth factor 1 receptor (IGF1R) monoclonal antibody (mAb) inhibited colony formation in correlation with IGF1R expression and decreased P-AKT. Imatinib or a blocking anti-stem cell factor (SCF) mAb also inhibited colony formation of two cell lines expressing C-KIT and SCF, and decreased P-AKT. Moreover, the PI3K/AKT pathway inhibitor wortmannin inhibited colony formation. Blocking interleukin (IL)6R did not inhibit colony formation in good agreement with a lack of constitutive P-STAT3. We showed that primary cells frequently co-expressed IGF1R/IGF1 but not C-KIT/SCF or IL6R/IL6, suggesting that in vivo autonomous growth could be possible via IGF1R. Despite their similar role in clonogenic growth and shared signaling pathway, IGF1R and C-KIT had opposite prognostic values, suggesting that they were surrogate markers. Indeed, we showed that both C-KIT and IGF1R prognostic values were not independent of MMSET expression. This study highlights the autocrine role of IGF1 in myeloma cells and reinforces the interest in targeting IGF1R in IGFR1+ CD45+/− patients, such as MMSET+ patients.

The insulin-like growth factor system in multiple myeloma: diagnostic and therapeutic potential

“…In addition, they found that the increased proliferation of human MM cell lines induced by IL-6 is dependent on the presence of an autocrine IGF-I loop [30]. Furthermore, autocrine IGF-I, but not IL-6, was recently described as being the main self-clonogenic growth factor for myeloma cell lines [99]. Finally, Huang et al .…”

Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

“…Specifically, RPMI8226-Luc and UBE6T-7 cells were injected separately in the right and left thighs, respectively (separate inoculation), or injected as a mixture in the right thigh (mixed injection) of NOD/SCID mice ( Figure 13A). The administration of cyclophosphamide (CY) alone, OSI-906 alone, and their combination significantly reduced the viability of MM cells, as determined by luciferase activity, in the separate inoc-A recent report by Chiron et al (34) implicating IGF-1 as an autocrine activator of MM urged us to investigate the role of IGF-1 for CAM-DR using gain-and loss-of-function approaches. We used recombinant IGF-1 (rIGF-1) to examine its effects on druginduced cytotoxicity under stroma-free conditions.…”

Impact of Interleukin-6 in Hematological Malignancies

“…It is not entirely clear at which stage in the development of the disease or exactly which cell populations within the malignant clone are dependent on IL-6 or need additional signals. A recent study suggests that autonomous growth, as assessed by spontaneous colony formation, is regulated by insulin-like growth factor (IGF)-1 and stem cell factor (SCF) rather than IL-6 [40]. IL-6 is also a potent osteoclast-activating factor, and contributes to the development of bone lesions.…”