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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
Review

Abstract

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.

Keywords

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

Abbreviations

AKT

V-Akt murine thymoma viral oncogene homolog

ALDH

Aldehyde dehydrogenase

BM

Bone marrow

BMP

Bone morphogenic proteins

CCL

Chemokine (C–C Motif) ligands

CSC

Cancer stem cells

CXCL

Chemokine (C–X–C Motif) ligands

DKK

Dickkopf proteins

ECM

Extracellular matrix

EDN1

Endothelin 1

EMV

Extracellular membrane vesicles

EPH

Erythropoietin-producing hepatoma

ERK

Extracellular signal-related kinases

FGF

Fibroblast growth factors

GLI

Glioma-associated oncogene

GH

Growth hormone

GP

Growth plate

HES

Hairy and enhancer of split

HH

Hedgehog proteins

HIF

Hypoxia-inducible factors

IGF

Insulin-like growth factors

IHH

Indian hedgehog

IL

Interleukin

MAPK

Mitogen-activated protein kinases

MCT

Monocarboxylate transporter

miRs

MicroRNAs

MMP

Matrix metalloproteinases

MSC

Mesenchymal stem/progenitor cells

mTOR

Mammalian target of rapamycin

NFkB

Nuclear factor kB

OPG

Osteoprotegerin

OS

Osteosarcoma

PDGF

Platelet-derived growth factor

PI3K

Phosphatidylinositol-4,5-bisphosphate 3-kinase

PTHrP

Parathyroid hormone-related peptide

RANK

Receptor activator of nuclear factor kappa B

RANKL

RANK ligand

RB

Retinoblastoma

SOX2

Sex-determining region Y-box 2

STAT3

Signal transducer and activator of transcription 3

TGFα/β

Transforming growth factor α/β

VEGF

Vascular endothelial growth factors

WIF1

WNT inhibitory factor 1

WNT

Wingless-type MMTV integration site family

YAP1

Yes-associated protein 1

Notes

Acknowledgments

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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