期刊
STEM CELLS
卷 32, 期 5, 页码 1136-1148出版社
WILEY-BLACKWELL
DOI: 10.1002/stem.1647
关键词
Bone; Mesenchymal stem cells; Bone morphogenetic protein-2; Osteosarcoma; WNT signaling; Rb; Tumoral microenvironment; p53
资金
- Instituto de Salud Carlos III/Fondos FEDER [PI10/00449, PI11/00377FIS, CP11/00024, RD12/0019/0006, RD12/0036/0015, RD12/0036/0027]
- Junta de Andalucia/FEDER [P08-CTS-3678]
- MINECO [PLE-2009-0111]
- Spanish Association Against Cancer (Junta Provincial de Albacete) [CI110023]
- Grupo Espaol de Investigacion en Sarcomas
- Obra Social Cajastur-IUOPA
- EuroNanomed ERA-NET initiative (REBONE project) [PI10/02985FIS]
- Comunidad de Madrid (CellCAM) [P2010/BMD-2420]
- Health Canada [H4084-112281]
- ISCIII/FEDER
- Generalitat of Catalunya
- ICREA Funding Source: Custom
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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