With the persistent elusiveness of a precursor lesion for osteosarcoma, even in very predictable genetic mouse models of the disease, we continue to learn most of what we know by candidate gene or candidate insult approaches, testing always for sufficiency in osteosarcomagenesis, but never necessity. We know that appropriately located chemical carcinogens or applied radiation rays or alpha-emitting radioisotopes have all proven sufficient to drive osteosarcomagenesis by driving mutagenesis and chromosomal instability, but genetically induced aneuploidy alone is not usually sufficient. We have learned that, when appropriately accounting for a mouse-specific Rb1 redundancy from p107, disruption of either the Rb1 pathway or p53 alone in the mouse generally is sufficient to drive osteosarcomagenesis. Their combination is alarmingly efficient, consistent with the observation from human osteosarcomas that both pathways are usually disrupted by some means in tumors. We have learned that these disruptions can initiate osteosarcomagenesis in undifferentiated mesenchymal progenitors or even committed cell types.
Other pathways, oncogenes, and tumor suppressors have been identified, some of which are clearly dependent on other disruptions or the application of other genetic insults to drive osteosarcomagenesis. No doubt, improved oncogenomic techniques will inspire yet new mouse models and the testing of the sufficiency of newly identified tumor suppressor disruptions and oncogene activations in the mouse. The new fields of host and niche biology as the environments in which cancers initiate and develop can also be expected to bring new knowledge to osteosarcomagenesis as well as further innovative experimentation in the mouse.
There remain challenges to the use of the mouse as a model organism for human osteosarcomagenesis. First, rodents more readily form osteosarcomas than do humans. Second, there are a number of specific pathways that are difficult to translate between the two. Other challenges, such as the lack of true lamellar bone in the mouse, highlight critical discrepancies in healthy bone biology between the species. Many scientists argue that genetically engineered or transplanted syngeneic osteosarcomas in rats, which have lamellar bone structure, or spontaneous osteosarcomas in canines may provide better preclinical models for drug testing and so forth. Nonetheless, the mouse as preclinical model may be less enlightening than the mouse as testing platform for the induction of osteosarcomas. The breadth and depth of genomic understanding of the mouse and facility with which it can be experimentally manipulated will not soon be replicated in any other mammalian species. While care must be taken in interpreting results in the mouse, attending to interspecies variations, that same attention can broaden our understanding of this complex disease even further. For example, specific biological eccentricities such as the pocket protein redundancy in mice have not prevented illumination of the human disease; they just require more careful attention to all the available literature. In similar fashion, perhaps further interrogation of Nf2 in murine osteosarcomagenesis may yet highlight pathways that are important, but unrecognized in the human diseasem.
Although mice and humans are decidedly different in many ways, most of the knowledge gained from mouse modeling has been validated in human clinical samples and cell lines. Clearly, the opportunity to prospectively test hypotheses in mouse-modeled osteosarcomagenesis is unique. There is doubtless much that remains to be learned from the mouse with regard to osteosarcoma initiation, progression, and metastasis.