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

作者：Rubio Ruth; Abarrategi Ander; Garcia Castro Javier; Martinez Cruzado Lucia; Suarez Carlos; Tornin Juan; Santos Laura; Astudillo Aurora; Colmenero Isabel; Mulero Francisca; Rosu Myles Michael; Menendez Pablo; Rodriguez Rene^*

来源：Stem Cells, 2014, 32(5): 1136-1148.

DOI：10.1002/stem.1647

• Bone
• Mesenchymal stem cells
• Bone morphogenetic protein-2
• Osteosarcoma
• WNT signaling
• Rb
• Tumoral microenvironment
• p53

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

• 出版日期2014-5