Abstract 4183: Modeling soft tissue sarcomas by conditional inactivation of p53 and Rb tumor suppressor genes

Abstract Soft tissue sarcomas, particularly its most common type, undifferentiated pleomorphic sarcomas (also known as malignant fibrous histiocytomas), frequently carry mutations in p53 and Rb tumor suppressor genes. We have established the sarcoma mouse model using conditional inactivation of p53 and Rb by a single subcutaneous injection of adenovirus carrying Cre-recombinase into transgenic mice with floxed copies of p53 and Rb genes. The majority of sarcomas in this model are malignant fibrous histiocytomas, which is a neoplasm consisting of intermixed fibroblast- and histiocyte-like cells. By using irradiation chimeras that have been generated by transplanting bone marrow cells from mice carrying the Rosa26StopLacZ or the Z/EG reporter, as well as floxed p53 and Rb genes, to irradiated p53loxP/loxPRbloxP/loxP mice, we have determined that sarcomas in this model do not originate from hematopoietic cells but arise from the local resident cells. Although the majority of dermal cells infected with AdCMVCre-eGFP have shown expression of fibroblast marker procollagen type I or macrophage marker F4/80, we have observed that cells expressing stem cell markers Sca-1 and nestin also have been targeted by adenovirus. 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 proliferation, invasion, and soft agar assays, following conditional inactivation of p53 and Rb. Additionally, we have determined that sarcomas have increased expression of CXCR4, while its ligand SDF-1 is expressed by infiltrating macrophages. Treatment of sarcoma cells with SDF-1 leads to their increased invasion in Boyden chamber assay while CXCR4 knockdown with siRNA abrogates this effect. Taken together, our results indicate that local Sca-1low multipotent dermal stem/progenitor cells may be a preferential target for malignant transformation associated with p53 and Rb deficiency. Furthermore, accumulation of SDF-1 producing macrophages may stimulate sarcomagenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4183.