Abstract 2947: Establishment and characterization of a series of murine cancer homograft models derived from induced cancer stem cells (iCSCs)

Background: Both leukemia and solid tumors show considerable heterogeneity at histological and functional levels, as well as in their responses to therapies. For many years, genetic lesions during clonal evolution were considered to be responsible for such heterogeneity. However, recent studies suggest a new paradigm - that tumors show hierarchy in which cancer stem cells (CSCs) have the ability to self-renew and give rise to differentiated tumor cells, and are responsible for the overall organization of a tumor. CSCs have important roles in tumor development, relapse and metastasis due to their intrinsic self-renewal characteristics and tumorigenic properties. Identification and characterization of these crucial cells will allow earlier detection of malignancies and better prediction of tumor behavior, and ultimately lead to preventive and therapeutic clinical strategies against CSCs. Murine tumor models derived from CSCs provide a valuable tool for research of tumor cells derived from distinct cells of origin. Methods: We have generated a series of murine cancer homograft models by retroviral transduction of proto-oncogenes Myc (N-Myc or c-Myc) into hematopoietic stem cells, progenitor B cells or bone marrow stromal cells isolated from wild-type or Ink4a/Arf knockout (Ink4a/Arf KO) mice, and overexpression of H-RasV12 in normal neural stem cells isolated from Ink4a/Arf KO mice. Models were developed by transplanting tumor cells derived from distinct iCSCs into recipient animals. Results: Five murine cancer homograft models were successfully developed, including one precursor B acute lymphoblastic leukemia/lymphoma (pre-B ALL/LBL) model established through overexpression of N-Myc in hematopoietic stem cells isolated from wild-type C57BL/6 mice; two pre-B ALL/LBL models established through overexpression of c-Myc in progenitor B cells isolated from Ink4a/Arf KO C57BL/6 mice; one osteosarcoma established through overexpression of c-Myc in bone marrow stromal cells isolated from Ink4a/Arf KO C57BL/6 mice; and one glioblastoma model established through overexpression of H-RasV12 in normal neural stem cells isolated from Ink4a/Arf KO C57BL/6 mice. Characterization of in vivo growth, histopathology, immunohistochemistry, immune profiling and responses to immune, cytotoxic and targeted therapies were performed. The results indicated that tumors derived from distinct iCSCs shared phenotypic and functional characteristics with the corresponding human tumors. Concl