Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells.
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.
Ara
Tasnim
T
Division of Hematology-Oncology, Department of Pediatrics, Keck School of Medicine, University of Southern California.
Song
Liping
L
Shimada
Hiroyuki
H
Keshelava
Nino
N
Russell
Heidi V
HV
Metelitsa
Leonid S
LS
Groshen
Susan G
SG
Seeger
Robert C
RC
DeClerck
Yves A
YA
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
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human