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

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