CXCR1/Akt signaling activation induced by mesenchymal stem cell-derived IL-8 promotes osteosarcoma cell anoikis resistance and pulmonary metastasis
Open accessAbstract
The loss of appropriate cell adhesion normally induces apoptosis via a process termed anoikis. The aim of this study was to investigate the effects of mesenchymal stem cells (MSCs) in the cancer microenvironment on the anoikis resistance and pulmonary metastasis of osteosarcoma (OS) cells, and to evaluate the critical role of the interleukin (IL)-8/C-X-C chemokine receptor (CXCR) 1/Akt-signaling pathway in these processes. Metastatic OS subtype cells, which did or did not interact with MSC-conditioned medium (MSC-CM) in vitro, were isolated from the pulmonary site and named Saos2-lung-M. Both MSC-CM and IL-8 treatment increased the anoikis resistance of Saos2 cells in vitro. Moreover, exogenous MSC-CM promoted the survival and metastasis of Saos2 cells in nude mice. Saos2-lung-M cells were more malignant and resistant to anoikis than parental cells. MSCs secreted IL-8, thereby protecting OS cells from anoikis. Blocking the IL-8/CXCR1/Akt pathway via CXCR1 knockdown inhibited the pulmonary metastasis of Saos2-lung-MSCs and prolonged the survival of tumor-bearing mice. In conclusion, MSCs enhanced OS cell resistance to anoikis and pulmonary metastasis via regulation of the IL-8/CXCR1/Akt pathway. These findings suggest that MSCs can "select for" OS cells with high metastatic potential in vivo, and highlight CXCR1 as a key target in the regulation of pulmonary metastasis of OS cells.
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Exogenous MSC-CM promote the survival and metastasis of Saos2 cells in nude mice.
“Also, MSC-CM treatment increases the anoikis resistance of Saos2 cells in vitro, whereas exogenous MSC-CM promote the survival and metastasis of Saos2 cells in nude mice [124].”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [124]
The Results section, “MSC-conditioned medium (CM) protected OS cells from anoikis in vitro and in vivo” (page unavailable), reports that MSC-CM-treated Saos2 cells survived longer in mice. The in-vivo metastasis experiment in “The distribution of MSCs in OS-bearing nude mice and MSC enhancement of OS growth and metastasis” (page unavailable) reports enhanced metastasis after injecting MSCs, rather than establishing that exogenous MSC-CM itself promoted metastasis. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMSC-CM treatment increases the anoikis resistance of Saos2 cells in vitro.
“Also, MSC-CM treatment increases the anoikis resistance of Saos2 cells in vitro, whereas exogenous MSC-CM promote the survival and metastasis of Saos2 cells in nude mice [124].”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [124]
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Joo, H. J., Chung, G. E., Han, S., Ka, H. I., Soh, S., & Yang, Y. D. (2022) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.113005 · Cited by 4 · see citing works
Zhang, J., Pan, R., & Tian, X. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1156663 · Cited by 3 · see citing works
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Sphingosine‐1‐Phosphate Promotes FOS Activation in Osteosarcoma Under Tumor Acidosis
Bozzini, N., Cortini, M., Righi, A., Grigoriadis, A. E., Dack, M. R. G., Elizabeta, I., Torricelli, F., Manicardi, V., Baldini, N., & Avnet, S. (2026) · Acta Physiologica · doi:10.1111/apha.70214 · Cited by 2 · see citing works
Cancer stem cells and clonal evolution in bone sarcomas
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Interaction of cancer cells with mesenchymal stem cells: implications in metastatic progression
Khurana, S., & Bhattacharyya, S. (2020) · Journal of the Indian Institute of Science · doi:10.1007/s41745-020-00182-5
McCusker, S. (2023) · Queensland University of Technology · doi:10.5204/thesis.eprints.240009
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Anoikis-related Genes Impact Prognosis and Tumor Immune Microenvironment in Bladder CancerPreprint
Zhang, T., Qu, S., & Wang, L. (2023) · Research Square · doi:10.21203/rs.3.rs-3448719/v1
Wen, H., Ni, X., Qian, S., Abdul, S., Lv, H., & Chen, Y. (2024) · Translational Cancer Research · doi:10.21037/tcr-23-1221
Anoikis-Related Genes Impact Prognosis and Tumor Microenvironment in Bladder Cancer
Zhang, T., Chen, S., Qu, S., & Wang, L. L. (2024) · Molecular Biotechnology · doi:10.1007/s12033-024-01255-x
Sarcoma metastasis: distinct biological principles beyond the carcinoma paradigm
Chevalier, N., Nathan, P. C., & Stamenkovic, I. (2026) · Cancer and Metastasis Reviews · doi:10.1007/s10555-026-10360-z
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- Authors
- Du, L., Han, X.-G., Tu, B., Wang, M.-Q., Qiao, H., Zhang, S.-H., Fan, Q.-M., & Tang, T.-T.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Venue
- Cell Death & Disease
- Published
- 2018-06-18
- Volume
- 9
- Issue
- 7
- Pages
- 714-714
- ISSN
- 2041-4889 (ISSN-L)
- PMC
- PMC6006172
- OpenAlex
- W2807923155
- Cited by
- 70
- References
- 41
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 11 · 2023: 11 · 2022: 9 · 2021: 13 · 2020: 8 · 2019: 7 · 2018: 5
- FWCI
- 4.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Cell Death and Disease (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Natural Science Foundation of China (81672205, 81502326)
- Topics
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Oncology › Chemokine receptors and signaling
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- osteosarcoma, mesenchymal stem cells, anoikis resistance, lung metastasis, interleukin-8, CXCR1, Akt signaling, tumor microenvironment, tumor cell survival, Saos-2 cells
- MeSH terms
- Animals, Bone Neoplasms, Cells, Cultured, Humans, Lung Neoplasms, Male, Mice, Inbred BALB C, Mice, Nude, Osteosarcoma, Signal Transduction, Gene Expression Regulation, Neoplastic, Interleukin-8, Culture Media, Conditioned, Disease Progression, Receptors, Interleukin-8A, Anoikis, Proto-Oncogene Proteins c-akt, Mice, Tumor Microenvironment, Mesenchymal Stem Cells
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