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, pre-osteoblasts, and mature osteoblasts, respectively. The Prx1 and Col1α1 lineages developed tumors with nearly complete penetrance, as anticipated. Osteosarcomas also developed in 44 percent of Oc-Cre;Rb1fl/fl;Trp53fl/fl mice. We confirmed using EdU click chemistry that the Oc-Cre lineage includes very few actively cycling cells. By assessing radiographic mineralization and histologic 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 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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