CoChat
Sign Up
Cited by 187Extracellular vesicles in diseaseMesenchymal stem cell researchSarcoma Diagnosis and Treatment

Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

Open access
Baglio, S. Rubina, Lagerweij, Tonny, Pérez-Lanzón, Maria, Ho, Xuan Dung, Léveillé, Nicolas, Melo, Sonia A., Cleton-Jansen, Anne-Marie, Jordanova, Ekaterina S. +18 more·2017·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-16-2726

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

Abstract Purpose: Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. Experimental Design: By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)–educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography. Results: We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients. Conclusions: Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients. Clin Cancer Res; 23(14); 3721–33. ©2017 AACR.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1158/1078-0432.ccr-16-2726

Cites

6 of 6 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • 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 [119]

  • Anti-IL-6 receptor antibodies halted the pro-tumor effects of tumor extracellular vesicle-educated MSCs.

    “Importantly, anti-IL-6 receptor antibodies halted the pro-tumor effects of the tumor extracellular vesicle-educated MSCs [119].”

    From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [119]

  • 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 [60]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 51

  1. Messerschmitt PJ, Garcia RM, Abdul-Karim FW, Greenfield EM, Getty PJ. Osteosarcoma. J Am Acad Orthop Surg. 2009;17:515-27.
  2. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144:27-40.
  3. Rubio R, Abarrategi A, Garcia-Castro J, Martinez-Cruzado L, Suarez C, Tornin J, et al. Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells. Stem Cells. 2014;32:1136-48.
  4. Alfranca A, Martinez-Cruzado L, Tornin J, Abarrategi A, Amaral T, de Alava E, et al. Bone microenvironment signals in osteosarcoma development. Cell Mol Life Sci. 2015;72:3097-113.
  5. Ottaviani G, Jaffe N. The epidemiology of osteosarcoma. Cancer Treat Res. 2009;152:3-13.
  6. Longhi A, Pasini A, Cicognani A, Baronio F, Pellacani A, Baldini N, et al. Height as a risk factor for osteosarcoma. J Pediatr Hematol Oncol. 2005;27:314-8.
  7. Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557-63.
  8. Behnan J, Isakson P, Joel M, Cilio C, Langmoen IA, Vik-Mo EO, et al. Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression. Stem Cells. 2014;32:1110-23.
  9. Shinagawa K, Kitadai Y, Tanaka M, Sumida T, Onoyama M, Ohnishi M, et al. Stroma-directed imatinib therapy impairs the tumor-promoting effect of bone marrow-derived mesenchymal stem cells in an orthotopic transplantation model of colon cancer. Int J Cancer. 2012;132:813-23.
  10. Barcellos-de-Souza P, Gori V, Bambi F, Chiarugi P. Tumor microenvironment: bone marrow- mesenchymal stem cells as key players. Biochim Biophys Acta. 2013;1836:321-35.
  11. Luo J, Ok Lee S, Liang L, Huang C-K, Li L, Wen S, et al. Infiltrating bone marrow mesenchymal stem cells increase prostate cancer stem cell population and metastatic ability via secreting cytokines to suppress androgen receptor signaling. Oncogene. 2013;33:2768-78.
  12. Huang W-H, Chang M-C, Tsai K-S, Hung M-C, Chen H-L, Hung S-C. Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. Oncogene. 2013;32:4343-54.
  13. Jung Y, Kim JK, Shiozawa Y, Wang J, Mishra A, Joseph J, et al. Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun. Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.; 2013;4:1795.
  14. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319:1244-7.
  15. Skog J, Würdinger T, van Rijn S, Meijer DH, Gainche L, Sena-Esteves M, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat Cell Biol. 2008;10:1470-6.
  16. Peinado H, Alečković M, Lavotshkin S, Matei I, Costa-Silva B, Moreno-Bueno G, et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat Med. 2012;18:883-91.
  17. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In Vivo Imaging Reveals Extracellular Vesicle-Mediated Phenocopying of Metastatic Behavior. Cell. 2015;161:1046-57.
  18. Chalmin F, Ladoire S, Mignot G, Vincent J, Bruchard M, Remy-Martin J-P, et al. Membrane-associated Hsp72 from tumor-derived exosomes mediates STAT3-dependent immunosuppressive function of mouse and human myeloid-derived suppressor cells. J Clin Invest. 2010;120:457-71.
  19. Shao H, Chung J, Lee K, Balaj L, Min C, Carter BS, et al. Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat Commun. 2015;6:6999.
  20. Mohseny AB, Szuhai K, Romeo S, Buddingh EP, Briaire-de Bruijn I, de Jong D, et al. Osteosarcoma originates from mesenchymal stem cells in consequence of aneuploidization and genomic loss of Cdkn2. J Pathol. 2009;219:294-305.
  21. Baranski Z, Booij TH, Cleton-Jansen A-M, Price LS, van de Water B, Bovée JVMG, et al. Aven- mediated checkpoint kinase control regulates proliferation and resistance to chemotherapy in conventional osteosarcoma. J Pathol. 2015;236:348-59.
  22. Baglio SR, Rooijers K, Koppers-Lalic D, Verweij FJ, Pérez Lanzón M, Zini N, et al. Human bone marrow-and adipose-mesenchymal stem cells secrete exosomes enriched in distinctive miRNA and tRNA species. Stem Cell Res Ther. 2015;6:127.
  23. Grisendi G, Bussolari R, Cafarelli L, Petak I, Rasini V, Veronesi E, et al. Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy. Cancer Res. 2010;70:3718-29.
  24. van Eijndhoven MAJ, Zijlstra JM, Groenewegen NJ, Drees EEE, van Niele S, Baglio SR, et al. Plasma vesicle miRNAs for therapy response monitoring in Hodgkin lymphoma patients. JCI Insight. 2016;1:e89631.
  25. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.
  26. Pucci F, Garris C, Lai CP, Newton A, Pfirschke C, Engblom C, et al. SCS macrophages suppress melanoma by restricting tumor-derived vesicle-B cell interactions. Science (80-). 2016;352:242-6.
  27. Reagan MR, Kaplan DL. Concise Review: Mesenchymal Stem Cell Tumor-Homing: Detection Methods in Disease Model Systems. Stem Cells. Wiley Subscription Services, Inc., A Wiley Company; 2011;29:920-7.
  28. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13:392-402.
  29. Pricola KL, Kuhn NZ, Haleem-Smith H, Song Y, Tuan RS. Interleukin-6 maintains bone marrow- derived mesenchymal stem cell stemness by an ERK1/2-dependent mechanism. J Cell Biochem. 2009;108:577-88.
  30. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, et al. MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A. 2012;109:E2110-6.
  31. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. 2014;159:499-513.
  32. Cossetti C, Iraci N, Mercer TR, Leonardi T, Alpi E, Drago D, et al. Extracellular vesicles from neural stem cells transfer IFN-γ via Ifngr1 to activate Stat1 signaling in target cells. Mol Cell. 2014;56:193- 204.
  33. Zhang H-G, Liu C, Su K, Su K, Yu S, Zhang L, et al. A membrane form of TNF-alpha presented by exosomes delays T cell activation-induced cell death. J Immunol. 2006;176:7385-93.
  34. Seelenmeyer C, Stegmayer C, Nickel W. Unconventional secretion of fibroblast growth factor 2 and galectin-1 does not require shedding of plasma membrane-derived vesicles. FEBS Lett. 2008;582:1362-8.
  35. Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70:9621-30.
  36. Expression of transforming growth factor beta isoforms in osteosarcoma variants: association of TGF beta 1 with high-grade osteosarcomas. -PubMed -NCBI [Internet]. [cited 2015 Oct 5]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9771482
  37. Kloen P, Jennings CL, Gebhardt MC, Springfield DS, Mankin HJ. Expression of transforming growth factor-beta (TGF-beta) receptors, TGF-beta 1 and TGF-beta 2 production and autocrine growth control in osteosarcoma cells. Int J cancer. 1994;58:440-5.
  38. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736-46.
  39. Kuijjer ML, Hogendoorn PCW, Cleton-Jansen A-M. Genome-wide analyses on high-grade osteosarcoma: making sense of a genomically most unstable tumor. Int J cancer. 2013;133:2512- 21.
  40. Verrecchia F, Chu ML, Mauviel A. Identification of novel TGF-beta /Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem. 2001;276:17058-62.
  41. Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. Nature Research; 2015;17:816-26.
  42. Hoshino A, Costa-Silva B, Shen T-L, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329-35.
  43. Zhang L, Zhang S, Yao J, Lowery FJ, Zhang Q, Huang W-C, et al. Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature. 2015;527:100-4.
  44. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell. 2009;139:693-706.
  45. Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012;38:904-10.
  46. Xiao H, Chen L, Luo G, Son H, Prectoni JH, Zheng W. Effect of the cytokine levels in serum on osteosarcoma. Tumour Biol. 2014;35:1023-8.
  47. Rutkowski P, Kamińska J, Kowalska M, Ruka W, Steffen J. Cytokine and cytokine receptor serum levels in adult bone sarcoma patients: correlations with local tumor extent and prognosis. J Surg Oncol. 2003;84:151-9.
  48. Padua D, Massagué J. Roles of TGFbeta in metastasis. Cell Res. 2009;19:89-102.
  49. Webber JP, Spary LK, Sanders AJ, Chowdhury R, Jiang WG, Steadman R, et al. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene. 2015;34:290-302.
  50. Rossi J-F, Lu Z-Y, Jourdan M, Klein B. Interleukin-6 as a therapeutic target. Clin Cancer Res. 2015;21:1248-57.
  51. Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, et al. Targeting the TGFβ pathway for cancer therapy. Pharmacol Ther. 2015;147:22-31.

Cited by

Sorted by citations

Authors
Baglio, S. R., Lagerweij, T., Pérez-Lanzón, M., Ho, X. D., Léveillé, N., Melo, S. A., Cleton-Jansen, A.-M., Jordanova, E. S., Roncuzzi, L., Greco, M., van Eijndhoven, M. A. J., Grisendi, G., Dominici, M., Bonafede, R., Lougheed, S. M., de Gruijl, T. D., Zini, N., Cervo, S., Steffan, A., Canzonieri, V., Martson, A., Maasalu, K., Köks, S., Wurdinger, T., Baldini, N., & Pegtel, D. M.
Affiliations
  • Cancer Center Amsterdam (NL)
  • 1Department of Pathology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
  • Hue University (VN)
  • Amsterdam UMC Location University of Amsterdam (NL)
  • 7Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S) and Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200 Porto, Portugal.
  • Leiden University Medical Center (NL)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • Istituto Ortopedico Rizzoli (IT)
  • University of Modena and Reggio Emilia (IT)
  • University of Verona (IT)
  • 13Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
  • Centro di Riferimento Oncologico (IT)
  • 4Department of Traumatology and Orthopedics, University of Tartu, Tartu, Estonia.
  • Tartu University Hospital (EE)
  • 3Department of Pathophysiology, University of Tartu, Tartu, Estonia.
  • 2Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
Corresponding author
  • Baldini, Nicola
  • Pegtel, D. Michiel
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2017-07-13
Volume
23
Issue
14
Pages
3721-3733
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-16-2726
OpenAlex
W2568514472
Cited by
187
References
6
Citations by year
2026: 8 · 2025: 11 · 2024: 13 · 2023: 23 · 2022: 28 · 2021: 37 · 2020: 28 · 2019: 16 · 2018: 15 · 2017: 8
FWCI
7.48
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (publishedVersion)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion, other-oa)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Murdoch University Research Portal (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (submittedVersion)
Funders
  • European Union's Horizon 2020 research and innovation programme (660200)
  • Dutch Cancer Society (VU2012-5510)
  • Italian Association for Cancer Research (15608)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
Keywords
osteosarcoma, mesenchymal stem cells, extracellular vesicles, TGF-beta, interleukin-6, STAT3 signaling, tumor microenvironment, paracrine signaling, lung metastasis, tocilizumab, circulating vesicles, tumor stroma
MeSH terms
Extracellular Vesicles, Animals, Disease Models, Animal, Female, Humans, Lung Neoplasms, Male, Osteosarcoma, Signal Transduction, Interleukin-6, Gene Expression Regulation, Neoplastic, Transforming Growth Factor beta, Cell Line, Tumor, Tissue Array Analysis, Cell Proliferation, STAT3 Transcription Factor, Mice, Mesenchymal Stem Cells, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review