In general, a role of skeletal stem cells in cancer can be seen as running in parallel with their dual physiological functions — as progenitors of skeletal tissues and as providers and organizers of a microenvironment. The progenitor function comes into play in understanding the origin of primary bone tumors; the non-progenitor functions come into DAPT play in understanding how skeletal progenitors contribute to the establishment of hematopoietic and non-hematopoietic malignancies (bone metastasis). Skeletal stem cells may represent direct progenitors of sarcomas. In spite of the identification of specific molecular pathways underpinning

specific types of bone tumors, classical and predominant (and to some extent, partially obsolete) paradigms of histogenesis of bone tumors have largely remained indifferent to the notion that skeletal tissues emanate from a common progenitor. As a result, classification and textbooks of pathology still identify

primary bone tumors based on their predominant phenotype and/or clinical behavior. However, recent work has highlighted the significance of skeletal progenitor cells for understanding the biology of bone tumors. Transformation of murine bone marrow stromal cells in culture is a far more common event than currently appreciated Lumacaftor (perhaps accounting for some reports of extraordinary numbers of population doublings, mistaken as “self-renewal” in some reports). Screening of multiple murine “MSC” lines by in vivo transplantation assays (conducted to probe their osteogenic capacity) easily reveals their tumorigenic properties (our unpublished results) (Fig.1). The latter, in turn, are easily conceived of as the effect of the known chromosomal instability characteristic of murine cell cultures, at variance with humans. Spontaneous immortalization in cultures of human BMSCs, regardless of sporadic reports

[47], is admittedly an exceptional event, reflecting uncontrolled growth conditions. More importantly, while forced expression of hTERT in human skeletal stem cells can boost their osteogenic capacity [48] and [49], prolonged culturing mafosfamide of hTERT-immortalized human skeletal progenitors results in multiple genetic hits that may culminate with acquisition of full-blown tumorigenesis as assayed by in vivo transplantation [50]. By suggesting that inordinately high rates of proliferation over prolonged time can lead to transformation of skeletal progenitors, these data provide a direct view of sarcomagenesis as related to skeletal stem cells. More specifically, a pathogenetic link between Ewing’s sarcoma (a highly malignant bone tumor, EWS) and skeletal progenitors has been suggested recently.