Insulin like growth factor binding protein 7 (IGFBP7) expression is linked to poor prognosis but may protect from bone disease in multiple myeloma

Abstract

BackgroundInsulin like growth factor binding protein 7 (IGFBP7) is a secreted protein binding insulin like growth factor 1 (IGF-1), insulin, vascular endothelial growth factor A (VEGFA), and activin A. It antagonizes bone morphogenetic proteins and is involved in the tumour propagation of solid as well as haematological malignancies. Its role in multiple myeloma (MM) is not defined so far. We therefore aim here to investigate its prognostic and pathophysiological role in MM.MethodsThe clinical significance of IGFBP7 gene expression was investigated by gene expression profiling in two independent cohorts (n = 948) of newly-diagnosed MM patients. Methylation of the IGFBP7 promoter was analysed by pyrosequencing and treatment of MM cell lines with 5-aza-2-deoxycytidine. The impact of IGFBP7 on MM cells was studied by CCK-8 assay, BrdU assay and flow cytometry, respectively. IGFBP7 expression in bone marrow stromal cells (BMSCs) was studied by quantitative RT-PCR. For osteoblast development, immortalized and primary human BMSCs were cultured in osteogenic differentiation medium for 7–14 days in the presence of recombinant human IGFBP7 and/or activin A.ResultsMedian IGFBP7 expression is significantly lower in CD138-purified plasma cells from individuals with MGUS and MM, compared to normal bone marrow plasma cells. IGFBP7 gene expression in MM cells is regulated by methylation, shown by pyrosequencing and exposure to demethylating agents (5-aza-2-deoxycytidine). High expression of IGFBP7 in MM cells is associated with adverse survival in two independent cohorts of 247 and 701 newly-diagnosed MM patients treated with high-dose therapy and autologous stem cell transplantation. IGFBP7 is associated with prognostically adverse chromosomal aberrations (t(4;14) and gain of 1q21), MMSET expression, and higher myeloma cell proliferation. In vitro, IGFBP7 overcomes activin A induced osteoblast suppression and promotes osteogenesis. MM cells downregulate IGFBP7 in stromal cells, possibly contributing to the osteoblast suppression found in MM. Conversely, higher IGFBP7 expression is associated with a lower probability of myeloma bone disease.ConclusionsOur data indicate that IGFBP7 expression is a marker for a specific methylation pattern in myeloma, linked to translocation t(4;14) associated MMSET expression, showing clinical features of adverse prognosis with absence of myeloma bone disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0105-1) contains supplementary material, which is available to authorized users.

IGFBP7 regulates the osteogenic differentiation of bone marrow‐derived mesenchymal stem cellsviaWnt/β‐catenin signaling pathway

“…Recently, evidence has revealed that IGFBP7 plays an important role in bone formation. IGFBP7 may exert protective effects against bone disease in multiple myeloma (14). IGFBP7 is methylated in subchondral bone (15, 16).…”

“…PTH, a stimulator of bone formation, increases IGFBP7 expression in osteoblasts (17). Moreover, IGFBP7 may protect against bone disease in multiple myeloma (14). IGFBP7 is related to subchondral bone sclerosis (15, 16) and neutralizes the inhibitory effects of activin A on osteoblast development (14).…”

“…Moreover, IGFBP7 may protect against bone disease in multiple myeloma (14). IGFBP7 is related to subchondral bone sclerosis (15, 16) and neutralizes the inhibitory effects of activin A on osteoblast development (14). Accumulating evidence has also demonstrated that activin A, a TGF‐β superfamily member, exerts an inhibitory effect on osteoblast maturation and mineralization (23, 24).…”

“…Wajapeyee et al (12, 13) found that oncogenic B‐Raf induced senescence and apoptosis through pathways mediated by secreted IGFBP7. In addition, Bolomsky et al (14) revealed that IGFBP7 may exert protective effects against bone disease in multiple myeloma. IGFBP7 was previously reported to be differentially methylated in subchondral bone (15, 16).…”

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

“…This could mean that the IGFBP complex remains intact in the circulation [153]. In addition, gene expression levels of the so-called IGFBP7 gene, also known as MAC25, Prostacyclin-Stimulating Factor, Tumor-Derived Adhesion Factor, or PGI2-Stimulating Factor, have been linked to poor prognosis [154]. IGFBP7 is not, however, a high affinity IGF binding protein and is not generally considered part of the extracellular IGF system [155].…”