Interleukin-6 in the bone marrow microenvironment promotes the growth and survival of neuroblastoma cells
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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. [Cancer Res 2009;69(1):329–37]
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Elevated IL-6 secretion by MSC has been detected after interaction with malignant cells in several epithelial, hematopoietic and mesenchymal cancers.
“Secretion of elevated levels of IL-6 by MSC has been detected upon interaction with malignant cells in several epithelial, hematopoietic and mesenchymal cancers (Table 2) [43, 69, 76, 77, 82, 115–119].”
From Mesenchymal stem cell secretome and regenerative therapy after cancer (2013) · cites this paper as [117]
The Results and Discussion (page not provided) report that bone-marrow mesenchymal stromal cells increased IL-6 production when exposed to neuroblastoma-cell products. The Discussion also describes a comparable response in myeloma, but the paper does not establish increased MSC secretion upon interaction with malignant cells across the full range of epithelial, hematopoietic and mesenchymal cancers named in the sentence. (LLM, conf=0.86)
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References 54 · Cited by 175
- Authors
- Ara, T., Song, L., Shimada, H., Keshelava, N., Russell, H. V., Metelitsa, L. S., Groshen, S. G., Seeger, R. C., & DeClerck, Y. A.
- Affiliations
- 1Division of Hematology-Oncology, Department of Pediatrics, and Departments of
- 2Pathology,
- Baylor College of Medicine (US)
- 3Preventive Medicine, and
- University of Southern California (US)
- ORCID
- Venue
- Cancer Research
- Published
- 2008-12-31
- Volume
- 69
- Issue
- 1
- Pages
- 329-337
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC2761219
- OpenAlex
- W2089788088
- Cited by
- 175
- References
- 54
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 7 · 2023: 5 · 2022: 9 · 2021: 12 · 2020: 9 · 2019: 7 · 2018: 6 · 2017: 15 · 2016: 10 · 2015: 13 · 2014: 13 · 2013: 10 · 2012: 13
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA 116548, P01CA081403, CA-81403, R01CA116548)
- Topics
- Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Keywords
- neuroblastoma, interleukin-6, bone marrow microenvironment, bone metastasis, mesenchymal stem cells, paracrine signaling, IL-6 receptor, cyclooxygenase-2, prostaglandin E2, etoposide resistance, apoptosis, tumor cell proliferation, STAT3, ERK1/2
- MeSH terms
- Animals, Bone Marrow Cells, Bone Neoplasms, Humans, Neuroblastoma, Recombinant Proteins, Interleukin-6, Mice, SCID, Mice, Inbred NOD, Stromal Cells, Apoptosis, Bone Marrow Neoplasms, Receptors, Interleukin-6, Cell Line, Tumor, Cell Growth Processes, STAT3 Transcription Factor, Mice
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