Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma
Menée sur 131 patients atteints d'un myélome multiple, cette étude évalue l'association entre la concentration plasmatique du facteur 15 de croissance et de différenciation et la survie des patients
Overexpression of growth differentiation factor 15 (GDF15) by bone marrow mesenchymal stem cells occurs widely in patients with multiple myeloma (MM), but the pathophysiological effects of GDF15 in this setting remain undefined. GDF15 has been described in numerous solid tumors but never in haematological malignancies. In this study, we report that GDF15 significantly increases survival of stroma-dependent MM cells including primary MM cells. In particular, GDF15 conferred resistance to melphalan, bortezomib, and to a lesser extent, lenalidomide in both stroma-dependent and stroma-independent MM cells. Akt-dependent signaling was critical to mediate the effects of GDF15, whereas Src and ERK1/2 signaling pathways were not involved. Given these results, we tested the clinical significance of plasma concentrations of GDF15 (pGDF15) in 131 MM patients 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, compared to patients with low pGDF15 levels. Our findings suggest that tumor microenvironment-derived GDF15 is a key survival and chemoprotective factor for MM cells which is pathophysiologically linked to both initial parameters of the disease as well as patient survival.
Cancer Research , résumé, 2012