Bone Environment is Essential for Osteosarcoma Development from Transformed Mesenchymal Stem Cells

Authors

  • Ruth Rubio,

    1. GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Government, Granada, Spain
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  • Ander Abarrategi,

    1. Unidad de Biotecnología Celular, Área Biología Celular y del Desarrollo, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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  • Javier Garcia-Castro,

    1. Unidad de Biotecnología Celular, Área Biología Celular y del Desarrollo, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain
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  • Lucia Martinez-Cruzado,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Carlos Suarez,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Juan Tornin,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Laura Santos,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Aurora Astudillo,

    1. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
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  • Isabel Colmenero,

    1. Servicio de Anatomía Patológica, Hospital Universitario Niño Jesús, Madrid, Spain
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  • Francisca Mulero,

    1. Spanish National Cancer Research Center (CNIO), Molecular Imaging Core Unit, Madrid, Spain
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  • Michael Rosu-Myles,

    1. Health Canada Centre for Biologics Research, Biologics and Genetic Therapies Directorate, Health Canada, Ottawa, Ontario, Canada
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  • Pablo Menendez,

    1. GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Government, Granada, Spain
    2. Instituciò Catalana de Reserca i Estudis Avançacts (ICREA), Barcelona, Spain
    3. Josep Carreras Leukemia Research Institute and Cell Therapy Program, Facultat de Medicina, Barcelona University, Barcelona, Spain
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  • Rene Rodriguez

    Corresponding author
    1. GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Government, Granada, Spain
    2. Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
    • Correspondence: Rene Rodriguez Ph.D., Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Laboratorio 2 ORL–IUOPA, 33006 Oviedo, Spain. Telephone: +34-985-108000, ext. 38524; Fax: +34-985-108015; e-mail: renerg@ficyt.es; or Pablo Menendez, Ph.D., Josep Carreras Leukemia Research Institute, Facultat de Medicina, University of Barcelona, Carrer de Casanova, 143, 08036 Barcelona, Spain. Telephone: +34-935572810; Fax: +34-933231751; e-mail: pmenendez@carrerasresearch.org

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Abstract

The cellular microenvironment plays a relevant role in cancer development. We have reported that mesenchymal stromal/stem cells (MSCs) deficient for p53 alone or together with RB (p53−/−RB−/−) originate leiomyosarcoma after subcutaneous (s.c.) inoculation. Here, we show that intrabone or periosteal inoculation of p53−/− or p53−/−RB−/− bone marrow- or adipose tissue-derived MSCs originated metastatic osteoblastic osteosarcoma (OS). To assess the contribution of bone environment factors to OS development, we analyzed the effect of the osteoinductive factor bone morphogenetic protein-2 (BMP-2) and calcified substrates on p53−/−RB−/− MSCs. We show that BMP-2 upregulates the expression of osteogenic markers in a WNT signaling-dependent manner. In addition, the s.c. coinfusion of p53−/−RB−/− MSCs together with BMP-2 resulted in appearance of tumoral osteoid areas. Likewise, when p53−/−RB−/− MSCs were inoculated embedded in a calcified ceramic scaffold composed of hydroxyapatite and tricalciumphosphate (HA/TCP), tumoral bone formation was observed in the surroundings of the HA/TCP scaffold. Moreover, the addition of BMP-2 to the ceramic/MSC implants further increased the tumoral osteoid matrix. Together, these data indicate that bone microenvironment signals are essential to drive OS development. Stem Cells 2014;32:1136–1148

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