Bioactivity and Prognostic Significance of Growth Differentiation Factor GDF15 Secreted by Bone Marrow Mesenchymal Stem Cells in Multiple Myeloma

Abstract

Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma, but the pathophysiologic effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in hematologic malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent multiple myeloma cells including primary multiple myeloma cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent multiple myeloma cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and extracellular signalregulated kinase 1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 patients with multiple myeloma and found that it correlated with disease prognosis. Specifically, patients with high levels of pGDF15 had lower probabilities of event-free and overall survival 30 months after diagnosis than patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for multiple myeloma cells, which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.

GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways

“…33 Recent studies suggest that GDF15 might be involved in the growth, survival, and invasiveness of various cancers. 19,20,34 In the present study, human PBMo-derived macrophages stimulated with TECM acquired M2-like characteristics and upregulated GDF15 in vitro. Several previous studies also showed that PBMo-derived macrophages acquired M2 characteristics such as CD163, CD204, IL-10, VEGFA, and MMPs by conditioned medium of tumor cell line (TCM).…”

“…Among the 12 genes related to tumor development (upregulated, seven genes including IL-6, IL-8, and CXCL1; downregulated, five genes; Table 1), we decided to focus on the GDF15 gene transcript (GDB accession no. NM_004864) that showed a log2 ratio of ∼ 4.0 in each cell line because TAM-derived GDF15, which is known to be a divergent member of human TGF-β superfamily associated with the growth and invasiveness of various cancers, 19,20 had not yet been reported in the microenvironment of ESCC.…”

“…19,20,34,48 Recent studies have also shown that the in vitro proliferation of ESCC cell lines was reduced by inhibition of PI3K or MEK1/2. 49,50 Here we demonstrated that GDF15 increased the growth of ESCC cell lines dose-dependently.…”

Early Epithelial Restitution by Nonsteroidal Anti-Inflammatory Drug–Activated Gene 1 Counteracts Intestinal Ulcerative Injuries

“…Although NAG-1 is involved in acute stress-induced apoptotic process (10), increasing recent evidences demonstrated that NAG-1 can trigger homeostatic cellular responses and play protective roles in both physiological and pathological states, including chronic inflammation and tumorigenesis (16)(17)(18)(19). In response to the cytotoxic NSAIDs, cells also can produce the survival signals.…”

“…Although most intestinal epithelial cells maintain a low level of NAG-1 expression, apoptotic mucosal surface epithelial cells can have relatively high levels of NAG-1 (15). Although NAG-1 is involved in acute stress-induced apoptotic process (10), increasing recent evidences demonstrated that NAG-1 can trigger homeostatic cellular responses and play protective roles in both physiological and pathological states, including chronic inflammation and tumorigenesis (16)(17)(18)(19). NAG-1, one of the major secreted proteins induced by p53, is thought to be important for promoting p53-mediated activity associated with cell cycle arrest and apoptosis (20).…”