STAT3 activation by IL-6 from mesenchymal stem cells promotes the proliferation and metastasis of osteosarcoma
Abstract
We previously demonstrated that human mesenchymal stem cells (MSCs) promote the growth of osteosarcoma in the bone microenvironment. The aim of the present study was to further determine the effect of IL-6/STAT3 signaling on the progression of osteosarcoma. First, conditioned medium from MSCs was used to stimulate the growth of osteosarcoma cells (Saos-2) in vitro. We found that STAT3 was activated and that the activation could be blocked by an IL-6-neutralizing antibody. The inhibition of STAT3 in Saos-2 cells by siRNA or AG490 decreased cell proliferation, migration and invasion, down-regulated the mRNA expression of Cyclin D, Bcl-xL and Survivin and enhanced the apoptotic response. Furthermore, a nude mouse osteosarcoma model was established by injecting luciferase-labeled Saos-2 cells into the tibia, and the effect of STAT3 on tumor growth was determined by treating the mice with AG490. In vivo bioluminescence images showed that tumor growth was dramatically reduced in the AG490 group. In addition, STAT3 inhibition decreased the lung metastasis rate and prolonged the survival of these mice. After treatment with AG490, the protein levels of IL-6, p-STAT3 and PCNA were decreased, and the level of apoptosis in the tumor was increased. Altogether, these data indicate that MSCs in the bone microenvironment might promote the progression of osteosarcoma and protect tumor cells from drug-induced apoptosis through IL-6/STAT3 signaling.
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Data from animal models indicates that mesenchymal stromal cells could increase chemoresistance.
“Data from animal models indicates that mesenchymal stromal cells could accelerate pulmonary metastases, promote proliferation of sarcoma cells and increase chemoresistance.”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [82]
Interleukin-6 secreted from mesenchymal stromal cells activates STAT-3 in adjacent osteosarcoma cells in a concentration-dependent manner, promotes their proliferation, protects them from chemotherapeutic drugs such as cisplatin and enhances their migration and invasion properties.
“IL-6 secreted from MSCs activates STAT-3 in adjacent osteosarcoma cells in a concentration-dependent manner, promotes their proliferation, protects them from chemotherapeutic drugs such as cisplatin and enhances their migration and invasion properties [82].”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [82]
Tumor extracellular vesicle-educated MSCs may promote osteosarcoma progression through IL-6 production and lung metastasis through STAT3 activation in tumor cells.
“Recent studies, using the xenograft mouse model of OS, demonstrated that tumor extracellular vesicle-educated MSCs may promote osteosarcoma progression through IL-6 production and lung metastasis through STAT3 activation in tumor cells [119,120].”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [120]
Osteosarcoma cells educate mesenchymal stem cells by secreting TGFβ-containing extracellular vesicles, triggering MSC IL-6 release and activating a STAT3-mediated tumour progression programme that drives formation of metastatic foci in the lung.
“Osteosarcoma cells educate these MSCs by secreting TGFβ-containing extracellular vesicles 60 , triggering MSC IL-6 release and activating a STAT3-mediated tumour progression programme that drives the formation of metastatic foci within the lung 61 .”
From Osteosarcoma (2022) · cites this paper as [61]
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- Authors
- Tu, B., Du, L., Fan, Q.-M., Tang, Z., & Tang, T.-T.
- Affiliations
- Shanghai Jiao Tong University (CN)
- ORCID
- Tu, Bing
- Venue
- Cancer Letters
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 325
- Issue
- 1
- Pages
- 80-88
- ISSN
- 0304-3835 (ISSN-L)
- OpenAlex
- W2115637208
- Cited by
- 196
- References
- 49
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 6 · 2023: 10 · 2022: 6 · 2021: 20 · 2020: 17 · 2019: 18 · 2018: 20 · 2017: 14 · 2016: 20 · 2015: 14 · 2014: 13 · 2013: 17 · 2012: 2
- FWCI
- 7.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Letters (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Shanghai Science and Technology Development Foundation
- National Natural Science Foundation of China
- Science and Technology Development Fund
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- osteosarcoma, mesenchymal stem cells, STAT3 activation, IL-6/STAT3 signaling, tumor microenvironment, tumor cell proliferation, lung metastasis, apoptosis, AG490, cyclin D, Bcl-xL, survivin, Saos-2 cells, conditioned medium
- MeSH terms
- Survivin, Animals, Bone Neoplasms, Cell Movement, Humans, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasm Invasiveness, Neoplasm Metastasis, Osteosarcoma, Transfection, Transplantation, Heterologous, Signal Transduction, Interleukin-6, Culture Media, Conditioned, Apoptosis, Disease Progression, Proliferating Cell Nuclear Antigen, Cell Line, Tumor, Cell Proliferation, STAT3 Transcription Factor, bcl-X Protein, Inhibitor of Apoptosis Proteins, Mice, Cyclin D, Mesenchymal Stem Cells
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