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Bone microenvironment signals in osteosarcoma development

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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.

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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

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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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    1. Unidad de Biotecnología Celular, Área de Genética Humana, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain

      Arantzazu Alfranca, Ander Abarrategi & Javier Garcia-Castro

    2. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, 33006, Oviedo, Spain

      Lucia Martinez-Cruzado, Juan Tornin & Rene Rodriguez

    3. Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK

      Ander Abarrategi

    4. Molecular Pathology Program, Institute of Biomedical Research of Salamanca-Centro de Investigación del Cáncer, Centro de Investigación del Cáncer (IBSAL-CIC), Salamanca, Spain

      Teresa Amaral & Enrique de Alava

    5. Department of Pathology and Biobank, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBiS), CSIC-Universidad de Sevilla, Seville, Spain

      Teresa Amaral & Enrique de Alava

    6. Cell Therapy Program, School of Medicine, Josep Carreras Leukemia Research Institute, University of Barcelona, Barcelona, Spain

      Pablo Menendez

    7. Instituciò Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain

      Pablo Menendez

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    1. Arantzazu Alfranca
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    Correspondence to Rene Rodriguez.

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    A. Alfranca, L. Martinez-Cruzado and J. Tornin contributed equally to this article.

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    Alfranca, A., Martinez-Cruzado, L., Tornin, J. et al. Bone microenvironment signals in osteosarcoma development. Cell. Mol. Life Sci. 72, 3097–3113 (2015). https://doi.org/10.1007/s00018-015-1918-y

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