Cellular and Molecular Life Sciences

, Volume 72, Issue 16, pp 3097–3113 | Cite as

Bone microenvironment signals in osteosarcoma development

  • Arantzazu Alfranca
  • Lucia Martinez-Cruzado
  • Juan Tornin
  • Ander Abarrategi
  • Teresa Amaral
  • Enrique de Alava
  • Pablo Menendez
  • Javier Garcia-Castro
  • Rene RodriguezEmail author


The bone is a complex connective tissue composed of many different cell types such as osteoblasts, osteoclasts, chondrocytes, mesenchymal stem/progenitor cells, hematopoietic cells and endothelial cells, among others. The interaction between them is finely balanced through the processes of bone formation and bone remodeling, which regulates the production and biological activity of many soluble factors and extracellular matrix components needed to maintain the bone homeostasis in terms of cell proliferation, differentiation and apoptosis. Osteosarcoma (OS) emerges in this complex environment as a result of poorly defined oncogenic events arising in osteogenic lineage precursors. Increasing evidence supports that similar to normal development, the bone microenvironment (BME) underlies OS initiation and progression. Here, we recapitulate the physiological processes that regulate bone homeostasis and review the current knowledge about how OS cells and BME communicate and interact, describing how these interactions affect OS cell growth, metastasis, cancer stem cell fate and therapy outcome.


Bone sarcoma Growth plate Osteoblast Osteoclast Tumor stroma Microenvironment signaling Mesenchymal stem cell MicroRNA 



V-Akt murine thymoma viral oncogene homolog


Aldehyde dehydrogenase


Bone marrow


Bone morphogenic proteins


Chemokine (C–C Motif) ligands


Cancer stem cells


Chemokine (C–X–C Motif) ligands


Dickkopf proteins


Extracellular matrix


Endothelin 1


Extracellular membrane vesicles


Erythropoietin-producing hepatoma


Extracellular signal-related kinases


Fibroblast growth factors


Glioma-associated oncogene


Growth hormone


Growth plate


Hairy and enhancer of split


Hedgehog proteins


Hypoxia-inducible factors


Insulin-like growth factors


Indian hedgehog




Mitogen-activated protein kinases


Monocarboxylate transporter




Matrix metalloproteinases


Mesenchymal stem/progenitor cells


Mammalian target of rapamycin


Nuclear factor kB






Platelet-derived growth factor


Phosphatidylinositol-4,5-bisphosphate 3-kinase


Parathyroid hormone-related peptide


Receptor activator of nuclear factor kappa B


RANK ligand




Sex-determining region Y-box 2


Signal transducer and activator of transcription 3


Transforming growth factor α/β


Vascular endothelial growth factors


WNT inhibitory factor 1


Wingless-type MMTV integration site family


Yes-associated protein 1



We thank Dr. Ashley Hamilton (from The Francis Crick Institute, London, UK) for her comprehensive revision of the manuscript. This work was supported by the Plan Nacional de I+D+i 2008–2011 [ISCIII/FEDER (PI11/00377, Miguel Servet Program CP11/00024 & CP11/00206) and RTICC (RD12/0036/0015, RD12/0036/0027 & RD12/0036/0017)], the Plan Nacional de I+D+i 2013–2016 [MINECO/FEDER (SAF-2013-42946-R & SAF2013-43065)], Grupo Español de Investigación en Sarcomas (GEIS), Generalitat de Catalunya (Grupo SGR330), Health Canada and Obra Social La Caixa/Fundaciò Josep Carreras.


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Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Arantzazu Alfranca
    • 1
  • Lucia Martinez-Cruzado
    • 2
  • Juan Tornin
    • 2
  • Ander Abarrategi
    • 1
    • 3
  • Teresa Amaral
    • 4
    • 5
  • Enrique de Alava
    • 4
    • 5
  • Pablo Menendez
    • 6
    • 7
  • Javier Garcia-Castro
    • 1
  • Rene Rodriguez
    • 2
    Email author
  1. 1.Unidad de Biotecnología Celular, Área de Genética HumanaInstituto de Salud Carlos IIIMadridSpain
  2. 2.Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de AsturiasOviedoSpain
  3. 3.Haematopoietic Stem Cell LaboratoryThe Francis Crick InstituteLondonUK
  4. 4.Molecular Pathology Program, Institute of Biomedical Research of Salamanca-Centro de Investigación del CáncerCentro de Investigación del Cáncer (IBSAL-CIC)SalamancaSpain
  5. 5.Department of Pathology and Biobank, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS)CSIC-Universidad de SevillaSevilleSpain
  6. 6.Cell Therapy Program, School of Medicine, Josep Carreras Leukemia Research InstituteUniversity of BarcelonaBarcelonaSpain
  7. 7.Instituciò Catalana de Recerca I Estudis Avançats (ICREA)BarcelonaSpain

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