Hyaluronan, a major non-protein glycosaminoglycan component of the extracellular matrix in human bone marrow, mediates dexamethasone resistance in multiple myeloma.
Originating from a post-switch memory B cell or plasma cell compartment in peripheral lymphoid tissues, malignant multiple myeloma (MM) cells accumulate in the bone marrow of patients with MM. In this favourable microenvironment, their growth and survival are dependent upon both soluble factors and physical cell-to-cell and cell-to-extracellular-matrix contacts. In this study, hyaluronan (HA), a major non-protein glycosaminoglycan component of the extracellular matrix in mammalian bone marrow, acted as a survival factor against dexamethasone (Dex)-induced apoptosis in MM cell lines. These effects were mediated through an interleukin 6 (IL-6) autocrine pathway, involving signal transducers and activators of transcription-3 phosphorylation on IL-6-dependent XG-1 and XG-6 cell lines. HA promoted accumulation of IL-6 in the culture medium without affecting IL-6 gene expression, suggesting that HA protects, stabilizes and concentrates IL-6 close to its site of secretion, thus favouring its autocrine activity. In contrast, in the IL-6-independent RPMI8226 cell line, HA survival effect was mediated through a gp80-IL-6 receptor-independent pathway, resulting in the upregulation of Bcl-2 anti-apoptotic protein expression and nuclear factor-kappaB activation. Taken together, these data suggest that HA antagonizes Dex-induced apoptosis of MM cells by favouring the autocrine activity of different cytokines or growth factors. As HA is a major component of the bone marrow extracellular matrix, these findings support the idea that HA could play a major role in the survival of MM cells in vivo, and could explain why MM cells accumulate in the bone marrow of patients with MM and escape conventional chemotherapy.
Vincent
Thierry
T
INSERM Unité U475 and UMR-CNRS5094, Montpellier, and Laboratoire d'Hématologie, Hôpital St-Eloi, Montpellier, France.
Molina
Laurence
L
Espert
Lucile
L
Mechti
Nadir
N
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication; D001854:Bone Marrow Cells / Q000378:metabolism; D016207:Cytokines / Q000276:immunology*; D003907:Dexamethasone / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D006820:Hyaluronic Acid / Q000494:pharmacology*; D015850:Interleukin-6 / Q000276:immunology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D016207:Cytokines; D015850:Interleukin-6; D003907:Dexamethasone; D006820:Hyaluronic Acid