Identification and Characterization of Tumor-Initiating Cells in Human Osteocarcoma – A Model to Unravel the “Roots of Evil” in Bone Cancer
Osteosarcoma is the most common malignant bone tumor in children and young adults. Approximately less than one third of the patients survive in case of metastatic or recurrent disease.This cancer could be the result of aberrant bone formation due to specific mutations in tissue stem cells and/or dysregulation of the differentiation process. These mutated cells, which have been designated Tumor-Initiating Cells (TIC) or Cancer Stem Cells (CSCs), exhibit self-renewal, quiescence and drug resistance. Identification and characterization of this special tumor population may have a major impact on cancer patient management. Specific Aim#1 Determine in vitro “stemness” based on the ability of established osteosarcoma cell lines and primary tumors to generate sarcospheres after serial passages and correlation with activation of specific pathways related to self-renewal. Specific Aim#2 Functionally label tumor-initiating cells in human osteosarcoma based on quiescent and further characterization based on the expression of certain genes involve in osteogenesis. Specific Aim#3 Perform in vivo functional studies of tumorgenicity by orthotopic transplantation of TIC intratibially using immunodeficient mice. Our research study will help to identify the functional properties of TIC, which may have a correlation with clinical outcome, and to better understand the role of stem cells in osteosarcoma progression, especially metastasis. It may also provide a preclinical model for testing new therapeutic approaches. Finally, in the absence of validated surface markers, PKH26 labeling may offer an alternative method to isolate CSC although further validation of this method for osteosarcoma and other cancers is required.