Osteosarcomas remain an enigmatic group of malignancies that share in common the presence of transformed cells producing osteoid matrix, even if these cells comprise a minority of the tumor volume. The differentiation state of osteosarcomas has therefore become a topic of interest and challenge to those who study this disease. In order to test how the cell of origin contributes to the final state of differentiation in the transformed cells, we compared the relative tumorigenicity of Cre-LoxP conditional disruption of the cell cycle checkpoint tumor-suppressor genes Trp53 and Rb1 using Prx1-Cre, Collagen-1α1-Cre and Osteocalcin-Cre to transform undifferentiated mesenchyme, preosteoblasts and mature osteoblasts, respectively. The Prx1 and Col1α1 lineages developed tumors with nearly complete penetrance, as anticipated. Osteosarcomas also developed in 44% of Oc-Cre;Rb1fl/fl;Trp53fl/fl mice. We confirmed using 5-ethynyl-2′-deoxyuridine click chemistry that the Oc-Cre lineage includes very few actively cycling cells. By assessing radiographic mineralization and histological osteoid production, the differentiation state of tumors did not correlate with the differentiation state of the lineage of origin. Some of the osteocalcin-lineage-derived osteosarcomas were among the least osteoblastic. Osteocalcin immunohistochemistry in tumors correlated well with the expression of DNA methyl transferases, suggesting that silencing of these epigenetic regulators may influence the final differentiation state of an osteosarcoma. Transformation of differentiated, minimally proliferative osteoblasts is possible but may require such an epigenetic reprogramming that the tumors no longer resemble their differentiated origins.
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We thank Thomas Clemens for the Oc-Cre mouse line, Malcolm Logan for Prx1-Cre and Benoit de Crombrugghe for Col1α1-Cre. This work was directly supported by National Cancer Institute (National Institutes of Health, NIH) K08CA138764. KBJ receives additional career development support from the Damon Runyon Cancer Research Foundation. This work was also partly supported by P30CA042014 from the National Cancer Institute.
The authors declare no conflict of interest.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Supplementary Information accompanies this paper on the Oncogene website
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Quist, T., Jin, H., Zhu, J. et al. The impact of osteoblastic differentiation on osteosarcomagenesis in the mouse. Oncogene 34, 4278–4284 (2015) doi:10.1038/onc.2014.354
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