title: Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells.
abstract: Neuroblastoma, the second most common solid tumor in children, frequently metastasizes to the bone marrow and the bone. Neuroblastoma cells present in the bone marrow stimulate the expression of interleukin-6 (IL-6) by bone marrow stromal cells (BMSC) to activate osteoclasts. Here we have examined whether stromal-derived IL-6 also has a paracrine effect on neuroblastoma cells. An analysis of the expression of IL-6 and its receptor, IL-6R, in 11 neuroblastoma cell lines indicated the expression of IL-6 in 4 cell lines and of IL-6R in 9 cell lines. Treatment of IL-6R-positive cells with recombinant human IL-6 resulted in signal transducer and activator of transcription-3 and extracellular signal-regulated kinase-1/2 activation. Culturing IL-6R-positive neuroblastoma cells in the presence of BMSC or recombinant human IL-6 increased proliferation and protected tumor cells from etoposide-induced apoptosis, whereas it had no effect on IL-6R-negative tumor cells. In vivo, neuroblastoma tumors grew faster in the presence of a paracrine source of IL-6. IL-6 induced the expression of cyclooxygenase-2 in neuroblastoma cells with concomitant release of prostaglandin-E2, which increased the expression of IL-6 by BMSC. Supporting a role for stromal-derived IL-6 in patients with neuroblastoma bone metastasis, we observed elevated levels of IL-6 in the serum and bone marrow of 16 patients with neuroblastoma bone metastasis and in BMSC derived from these patients. Altogether, the data indicate that stromal-derived IL-6 contributes to the formation of a bone marrow microenvironment favorable to the progression of metastatic neuroblastoma.
authors.affiliation: Division of Hematology-Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California.
authors.forename: Tasnim
authors.initials: T
authors.lastname: Ara
authors.forename: Liping
authors.initials: L
authors.lastname: Song
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Nino
authors.initials: N
authors.lastname: Keshelava
authors.forename: Heidi V
authors.initials: HV
authors.lastname: Russell
authors.forename: Leonid S
authors.initials: LS
authors.lastname: Metelitsa
authors.forename: Susan G
authors.initials: SG
authors.lastname: Groshen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Seeger
authors.forename: Yves A
authors.initials: YA
authors.lastname: DeClerck
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D019046:Bone Marrow Neoplasms / Q000401:mortality / Q000473:pathology / Q000556:secondary; D001859:Bone Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology*; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human