mTORC1 Maintains the Tumorigenicity of SSEA-4+ High-Grade Osteosarcoma
نویسندگان
چکیده
Inactivation of p53 and/or Rb pathways restrains osteoblasts from cell-cycle exit and terminal differentiation, which underpins osteosarcoma formation coupled with dedifferentiation. Recently, the level of p-S6K was shown to independently predict the prognosis for osteosarcomas, while the reason behind this is not understood. Here we show that in certain high-grade osteosarcomas, immature SSEA-4(+) tumor cells represent a subset of tumor-initiating cells (TICs) whose pool size is maintained by mTORC1 activity. mTORC1 supports not only SSEA-4(+) cell self-renewal through S6K but also the regeneration of SSEA-4(+) TICs by SSEA-4(-) osteosarcoma cell dedifferentiation. Mechanistically, active mTORC1 is required to prevent a likely upregulation of the cell-cycle inhibitor p27 independently of p53 or Rb activation, which otherwise effectively drives the terminal differentiation of SSEA-4(-) osteosarcoma cells at the expense of dedifferentiation. Thus, mTORC1 is shown to critically regulate the retention of tumorigenicity versus differentiation in discrete differentiation phases in SSEA-4(+) TICs and their progeny.
منابع مشابه
Stage-specific embryonic antigen: determining expression in canine glioblastoma, melanoma, and mammary cancer cells
The expression of stage-specific embryonic antigens (SSEAs) was determined in several types of canine cancer cells. Flow cytometry showed SSEA-1 expression in glioblastoma, melanoma, and mammary cancer cells, although none expressed SSEA-3 or SSEA-4. Expression of SSEA-1 was not detected in lymphoma, osteosarcoma, or hemangiosarcoma cell lines. Relatively stable SSEA-1 expression was observed b...
متن کاملDetection of Survivin Gene Expression in Formalin-Fixed Paraffin-Embedded Tissues of Human Osteosarcoma: Its Potential Usefulness in Diagnosis and Prognosis of Bone Tumors
Osteosarcoma is a relatively uncommon malignancy however, it is the most common form of primary malignant bone tumors in human. Diagnosis and prognosis of patients with osteosarcoma is limited to clinico-radiopathological parameters, whereas molecular markers of tumor aggression have been poorly identified. Survivin, an inhibitor of apoptosis (IAP), is unique for its expression in human tumors ...
متن کاملUp-Regulation of Imp3 Confers In Vivo Tumorigenicity on Murine Osteosarcoma Cells
Osteosarcoma is a high-grade malignant bone tumor that manifests ingravescent clinical behavior. The intrinsic events that confer malignant properties on osteosarcoma cells have remained unclear, however. We previously established two lines of mouse osteosarcoma cells: AX cells, which are able to form tumors in syngeneic mice, and AXT cells, which were derived from such tumors and acquired an i...
متن کاملPrimary Osteosarcoma of the Sternum: A case Report and Review of the Literature
Osteosarcoma (osteogenic sarcoma: OS) is the most common primary malignant bone tumor of long bones, whereas primary osteosarcoma of chest wall, especially in sternum, is extremely rare. We report a 57-year-old man with an immobile slow growing mass located in the middle of the sternum. The patient had no significant pain or tenderness and the past medical history was not remarkable. CT-scan sh...
متن کاملSSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers.
Findings from studies on stem cells have been applied to cancer stem cell (CSC) research, but little is known about the relationship between ES cell-related cell surface markers and CSCs. In this study, we focused on stage-specific embryonic antigen 3 (SSEA-3), a marker of mesenchymal stem cells and Muse cells in colorectal cancer (CRC). Expression of SSEA-3 in human CRC cell lines and clinical...
متن کامل