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.
GENyO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Government, Granada, Spain.
Ruth
R
Rubio
Ander
A
Abarrategi
Javier
J
Garcia-Castro
Lucia
L
Martinez-Cruzado
Carlos
C
Suarez
Juan
J
Tornin
Laura
L
Santos
Aurora
A
Astudillo
Isabel
I
Colmenero
Francisca
F
Mulero
Michael
M
Rosu-Myles
Pablo
P
Menendez
Rene
R
Rodriguez
D000818:Animals; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2 / Q000494:pharmacology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002130:Calcium Phosphates / Q000737:chemistry; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D060833:Cellular Microenvironment; D002516:Ceramics / Q000737:chemistry; D017886:Durapatite / Q000737:chemistry; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology*; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054457:Tissue Scaffolds / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics
D055396:Bone Morphogenetic Protein 2; D002130:Calcium Phosphates; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D017886:Durapatite; C018392:tricalcium phosphate
Bone; Bone morphogenetic protein-2; Mesenchymal stem cells; Osteosarcoma; Rb; Tumoral microenvironment; WNT signaling; p53