Dovitinib is currently under clinical investigation for hepatocellular carcinoma

by Selleckchem | Feb 19 2014

Telomerase-independent mechanisms of telomere maintenance, such as ALT, provide an alternative route whereby transformed cells may overcome the growth limitation Dovitinib imposed by critically short telomeres. In addition, tumors using ALT for telomere maintenance should be refractory to treatment targeting telomerase, a strategy currently being tested in clinical trials. Although a minority of human epithelial carcinomas have characteristics consistent with ALT utilization, ALT has been demonstrated with relatively high frequency in osteosarcomas, glioblastoma multiforme and other malignancies of mesenchymal origin. Indeed, ALT is utilized as frequently as telomerase in soft tissue sarcomas, including the most common subtype, liposarcoma. Efficacious treatment remains elusive for liposarcoma, however, perhaps a consequence of the high frequency of ALT utilization for telomere maintenance. The rarity of liposarcoma tumors has hampered the identification of mutations that contribute both to their development and to activation of the ALT mechanism. The ability to mechanistically explore these processes has likewise been limited by the corresponding rarity of cell lines. Here we describe the establishment of a new cell line derived from a pleomorphic liposarcoma. We believe that LS2 Bortezomib will serve as a potentially important model for ALT-positive liposarcomas, the prognosis of which is poorest for ALT positive when categorizing based on the telomere maintenance mechanism present in the sarcoma. The utility of LS2 is enhanced by our detailed genome-wide molecular characterization of both the cell line and its original tumor. The LS2 cell line retains the majority of DNA copy number changes present in the original tumor and has an expression profile consistent with pleomorphic liposarcomas. As a result, LS2 represents an important and novel experimental tool that might be used to test hypotheses aimed at understanding the development of liposarcomas. In addition, the importance of the chromosome 1q deletion, which is characteristic of ALT and is present in both the tumor and PP242 LS2 cell line, in regulation of ALT and sarcomagenesis can be tested in this model. Thus, LS2 will help us better understand not only the development of liposarcomas, but the pathways underlying the ALT mechanism, thereby revealing new targets for treatment of a number of clinically relevant malignancies that use recombination-based maintenance of telomeres. According to Antonescu two-thirds of soft tissue sarcomas lack a recurrent genetic signature and are characterized by complex karyotypes with numerous structural and numerical chromosome anomalies. Most of the adult spindle cell and pleomorphic sarcomas belong to this group. Despite such complexity, however, the karyotype of the LS2 cell line shares some recurrent rearrangements with the reported karyotypes of pleomorphic liposarcomas, including deletions in the long arm of chromosome 1, deletions of 2p and the monosomies-13,-14,-16 and-22. The role of these chromosomal changes in tumor phenotype can be determined using the LS2 cell line model system. Cytogenetic characterization of cell lines derived from well-differentiated, dedifferentiated and retroperitoneal liposarcomas have been described. Comparison to the original tumor is only available for the GOT3 cell line. Both the GOT3 and FU-DDLS-1 contain the Chr.12q amplicon, which is not present in the LS2 cell line. In contrast, neither cell line contains the Chr1q deletion characteristic of ALT-positive liposarcomas which is present in both LS2 and the tumor T27 from which it was derived. Chemotherapy regimens for treating liposarcoma have had limited efficacy. Thus, new targets are needed. The LS2 cell line will significantly add to the cell based models currently available for testing new compounds with potential therapeutic benefit for liposarcomas. The LS14 cell line, derived from a metastatic liposarcoma, is more resistant to doxorubicin than the SW872 cell line. We find SW872 to be the most sensitive of the three liposarcoma cell lines tested in the study described here. Importantly, this particular cell line, LS2, not only replicates the expected biologic findings, but also recapitulates the clinical experience with limited sensitivity to doxorubicin observed in the original tumor, T27. LS2 therefore represents a good model system in which to investigate the importance of candidate genes on activation of ALT for telomere maintenance and on ALT-associated tumor phenotypes, such as poor patient prognosis in liposarcomas.