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Modeling And Histogenesis Of Soft Tissue Sarcomas Associated With P53 And Rb Deficiency
Human soft tissue sarcomas (STS), particularly their most common type, undifferentiated pleomorphic sarcoma (UPS), also known as malignant fibrous histiocytoma (MFH), frequently carry mutations in P53 and RB tumor suppressor genes. We have established mouse model of STS by using Cre-loxP-mediated conditional inactivation of p53 and Rb tumor suppressor genes in the connective tissue cells of the dermis. Similar to human STS, the majority of sarcomas in this model are UPS and overexpress Cxcr4, which contributes to their invasive properties. By using irradiation chimeras that have been generated by transplanting bone marrow cells from mice carrying the Rosa26StoploxPLacZ or the Z/EG reporter, as well as floxed p53 and Rb genes, to irradiated p53loxP/loxPRbloxP/loxP mice, we have determined that sarcomas originate from the local resident cells. Notably, isolated mesenchymal multipotent cells characterized by strict plastic adherence and low levels of Sca-1 expression have shown enhanced potential for malignant transformation according to invasion, soft agar and tumorigenicity assay following conditional inactivation of p53 and Rb. Taken together, our results indicate that local Sca-1low dermal mesenchymal stem/progenitor cells may be a preferential target for malignant transformation associated with p53 and Rb deficiency. As the next step towards imaging of STS formation, we have evaluated applicability of highly fluorescent core-shell silica nanoparticles, known as C dots, for in vivo applications. We have demonstrated C dots are not toxic and can be used in a broad range of imaging applications including intravital visualization of capillaries and macrophages, sentinel lymph node mapping, and peptide-mediated multi-color cell labeling for real-time imaging of tumor metastasis and tracking of injected bone marrow cells in mice. These results demonstrate that fluorescent core-shell silica nanoparticles represent a powerful novel imaging tool within the field of nanomedicine and will be invaluable for future studies of STS pathogenesis.
dissertation or thesis