Cross Species Genomic Analysis Identifies a Mouse Model as Undifferentiated Pleomorphic Sarcoma/Malignant Fibrous Histiocytoma

Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e8075. DOI: 10.1371/journal.pone.0008075
Source: PubMed


Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras(G12D); Trp53(Flox/Flox) mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras(G12D); p53(Flox/Flox) mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.

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    • "It has been shown that tumor oxygenation predicts the likelihood of distant metastases in human sarcomas [5,43,44]. Gene expression data from human tumors and work with experimental mouse models highlight the importance of HIF pathway activation in sarcoma metastasis. In a genetically engineered, temporally and spatially restricted, mouse model of pleomorhpic undifferentiated sarcomas, the HIF-target FOXM1 is highly associated with lung metastasis [44]. "
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    ABSTRACT: Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression.
    Full-text · Article · Jun 2013 · Cancers
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    • "A cross species genomic analysis has led to the identification of a mouse model of undifferentiated pleomorphic sarcoma [45]. A gene-set from the LSL-KrasG12D; p53Flox/Flox murine model of soft tissue sarcoma was found to be highly enriched in undifferentiated pleomorphic sarcoma. "
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    ABSTRACT: Undifferentiated pleomorphic sarcoma (UPS) is an inclusive term used for sarcomas that defy formal sub-classification. The frequency with which this diagnosis is assigned has decreased in the last twenty years. This is because when implemented, careful histologic assessment, immunohistochemistry, and ultra-structural evaluation can often determine lineage of differentiation. Further attrition in the diagnostic frequency of UPS may arise by using array-comparative genomic hybridization. Gene expression arrays are also of potential use as they permit hierarchical gene clustering. Appraisal of the literature is difficult due to a historical perspective in which specific molecular diagnostic methods were previously unavailable. The American Joint Committee on Cancer (AJCC) classification has changed with different inclusion criteria. Taxonomy challenges also exist with the older term "malignant fibrous histiocytoma" being replaced by "UPS". In 2010 an analysis of multiple sarcoma expression databases using a 170-gene predictor, re-classified most MFH and "not-otherwise-specified" (NOS) tumors as liposarcomas, leiomyosarcomas or fibrosarcomas. Interestingly, some of the classifier genes are potential molecular therapeutic targets including Insulin-like growth factor 1 (IGF-1), Peroxisome proliferator-activated receptor γ (PPARγ), Nerve growth factor β (NGF β) and Fibroblast growth factor receptor (FGFR).
    Full-text · Article · Mar 2013 · Cancers
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    • "Investigations into the cellular origin of both undifferentiated pleomorphic sarcomas and embryonal rhabdomyosarcomas have identified the importance of the p53 and Rb pathways in the etiology of both malignancies [52]. In addition to the importance of these two tumor suppressor pathways, the Kras-signaling pathway has also been implicated in the development of undifferentiated pleomorphic sarcomas [53,54]. Mice harboring a latent copy of oncogenic KrasLSLG12D (silenced by a floxed “loxP-stop-loxP” (LSL) cassette) and two floxed p53 alleles (p53FlΔ2-10) that were simultaneously activated to express mutant KrasG12D and delete p53 following injection of adenoviral-Cre into the muscle, rapidly developed sarcomas with significant metastatic potential. "
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    ABSTRACT: Sarcomas are neoplastic malignancies that typically arise in tissues of mesenchymal origin. The identification of novel molecular mechanisms leading to sarcoma formation and the establishment of new therapies has been hampered by several critical factors. First, this type of cancer is rarely observed in the clinic with fewer than 15,000 newly cases diagnosed each year in the United States. Another complicating factor is that sarcomas are extremely heterogeneous as they arise in a multitude of tissues from many different cell lineages (e.g. bone (osteosarcoma), fat (liposarcoma), and muscle (myosarcoma)). The scarcity of clinical samples coupled with its inherent heterogeneity creates a challenging experimental environment for clinicians and scientists. Faced with these challenges, there has been extremely limited advancement in treatment options available to patients as compared to other cancers. In order to glean insight into the pathobiology of sarcomas, scientists are now using in vivo mouse models whose genomes have been specifically tailored to carry gene deletions, gene amplifications, and point mutations commonly observed in human sarcomas. The use of these model organisms has been successful in increasing our knowledge and understanding of how alterations in relevant oncogenic, tumor suppressive, and signaling pathways directly impact sarcomagenesis. It is the goal of many in the biological community that the use of these mouse models will serve as powerful in vivo tools to further our understanding of sarcomagenesis and potentially identify new therapeutic strategies.
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