Ion ofapoptosis and/or inhibition of tumour growth by deregulation of p16, p21, p53 and ERK

Ion ofapoptosis and/or inhibition of tumour growth by deregulation of p16, p21, p53 and ERK signaling [19,26,35-38]. However, results regarding the role of IGFBP7 in solid tumours are inconsistent and recent studies provide a more complex picture of IGFBP7 in different entities. In glioblastoma, IGFBP7 was shown to stimulate tumour cell proliferation and angiogenesis of brain endothelial cells [39,40]. Similarly, elevated IGFBP7 expression was detected in specific stages of colorectal cancer and silencing of IGFBP7 reduced proliferation as well as colonyBolomsky et al. Journal of Hematology Oncology (2015) 8:Page 10 offormation in colorectal cancer cell lines [41]. Expression of IGFBP7 was also detected in cancer-associated fibroblasts, endothelial cells, mesenchymal tumours and malignant epithelial cells with a mesenchymal phenotype. In the latter, loss of IGFBP7 significantly impaired the anchorage independent growth of tumour cells. Furthermore, IGFBP7 expression in cancer stromal cells supported the growth of colon cancer cells [41]. These findings establish a complex variety of functions for IGFBP7 depending on the malignancy investigated. In haematological malignancies, IGFBP7 was found to be associated with BAALC expression in T-ALL and to correlate with poor survival [26]. Similarly, in B-cell ALL IGFBP7 expression in BMSCs was found to be associated with asparaginase resistance and decreased leukemia-free survival [27]. In our study, high expression levels of IGFBP7 predicted poor outcome in two large and independent cohorts of MM patients. Whereas the mean values and standard deviations (5.564 ?3.213 vs. 3.155 ?1.966) as well as the percentage of patients expressing IGFBP7 as defined by the PANP algorithm (marginal and present, 44.9 vs. 12.9 ) significantly differed between the HM- and LR-cohort, the prognostic impact of IGFBP7 expression was comparable between both cohorts. Observed differences in frequency and height of expression are most likely due to different amplification protocols used (double vs. single amplification) [42-44]. IGFBP7 expression in MM cells was linked to prognostically adverse chromosomal aberrations such as translocation t(4;14) and amplification 1q21. The multiple myeloma SET domain (MMSET) protein, specifically overexpressed in t(4;14) myeloma, is a histone methyl transferase shown to modulate DNA methylation, thereby inducing the AZD3759 biological activity activation of specific target genes [45]. Interestingly, IGFBP7 expression was found to be regulated by MMSET in myeloma cells [45] which is in line with our observation of higher IGFBP7 transcript levels in t(4;14) cases. The association between MMSET expression and expression of IGFBP7 was confirmed by in-silico analysis of two open-source GEP datasets. This suggests that IGFBP7 represents a novel marker of high-risk myeloma, defined PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28298493 by an epigenetic signature and regulated by MMSET. The growth attenuating effects of IGFBP7 we observed in vitro were rather small and evident only at high IGFBP7 concentrations [46]. Moreover, we show that, in clinical myeloma samples, IGFBP7 expression is associated with higher myeloma cell proliferation, in turn associated with adverse prognosis. The phenotype of MMSET expressing myeloma seems to overrule the weak inhibitory activity of IGFBP7 on myeloma cell proliferation. Thus, rather than being mechanistically involved in the poor outcome, IGFBP7 might rather be seen as a marker associated with a high-risk disease phenotype.We show u.