Bone environment is essential for osteosarcoma development from transformed mesenchymal stem cells

Stem Cells. 2014 May;32(5):1136-48. doi: 10.1002/stem.1647.


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.

Keywords: Bone; Bone morphogenetic protein-2; Mesenchymal stem cells; Osteosarcoma; Rb; Tumoral microenvironment; WNT signaling; p53.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Bone Morphogenetic Protein 2 / pharmacology
  • Bone Neoplasms / genetics
  • Bone Neoplasms / metabolism
  • Bone Neoplasms / pathology*
  • Bone and Bones / drug effects
  • Bone and Bones / metabolism
  • Bone and Bones / pathology*
  • Calcium Phosphates / chemistry
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cells, Cultured
  • Cellular Microenvironment*
  • Ceramics / chemistry
  • Durapatite / chemistry
  • Humans
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Mesenchymal Stem Cell Transplantation / methods
  • Mesenchymal Stem Cells / metabolism
  • Mesenchymal Stem Cells / pathology*
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Osteogenesis / drug effects
  • Osteogenesis / genetics
  • Osteosarcoma / genetics
  • Osteosarcoma / metabolism
  • Osteosarcoma / pathology*
  • Retinoblastoma Protein / deficiency
  • Retinoblastoma Protein / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tissue Scaffolds / chemistry
  • Tumor Suppressor Protein p53 / deficiency
  • Tumor Suppressor Protein p53 / genetics


  • Bone Morphogenetic Protein 2
  • Calcium Phosphates
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • Retinoblastoma Protein
  • Tumor Suppressor Protein p53
  • Durapatite
  • tricalcium phosphate