TY - JOUR
T1 - Doxorubicin resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres
AU - Mitchell, Marcy A.
AU - Johnson, Jay E.
AU - Pascarelli, Kara
AU - Beeharry, Neil
AU - Chiourea, Maria
AU - Gagos, Sarantis
AU - Lev, Dina
AU - Von Mehren, Margaret
AU - Kipling, David
AU - Broccoli, Dominique
PY - 2010/3
Y1 - 2010/3
N2 - Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25% to 30% response rate in large multi-institutional trials. Although liposarcomas are the most common histologic form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that uses the alternative lengthening of telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA-damaging agents. We present detailed baseline molecular and genomic data, including genome-wide copy number and transcriptome profiles, for this model compared with its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also show the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provides a powerful new tool to develop treatments for this clinically poorly tractable tumor and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin.
AB - Soft tissue sarcomas are a diverse set of fatal human tumors where few agents have demonstrable clinical efficacy, with the standard therapeutic combination of doxorubicin and ifosfamide showing only a 25% to 30% response rate in large multi-institutional trials. Although liposarcomas are the most common histologic form of adult soft tissue sarcomas, research in this area is severely hampered by the lack of experimentally tractable in vitro model systems. To this end, here we describe a novel in vitro model for human pleomorphic liposarcoma. The cell line (LS2) is derived from a pleomorphic liposarcoma that uses the alternative lengthening of telomeres (ALT) mechanism of telomere maintenance, which may be important in modulating the response of this tumor type to DNA-damaging agents. We present detailed baseline molecular and genomic data, including genome-wide copy number and transcriptome profiles, for this model compared with its parental tumor and a panel of liposarcomas covering multiple histologies. The model has retained essentially all of the detectable alterations in copy number that are seen in the parental tumor, and shows molecular karyotypic and expression profiles consistent with pleomorphic liposarcomas. We also show the utility of this model, together with two additional human liposarcoma cell lines, to investigate the relationship between topoisomerase 2A expression and the sensitivity of ALT-positive liposarcomas to doxorubicin. This model, together with its associated baseline data, provides a powerful new tool to develop treatments for this clinically poorly tractable tumor and to investigate the contribution that ALT makes to modulating sensitivity to doxorubicin.
KW - Antineoplastic Agents/pharmacology
KW - Cell Line, Tumor
KW - Chromosome Aberrations/chemically induced
KW - Cytogenetic Analysis
KW - Doxorubicin/pharmacology
KW - Drug Resistance, Neoplasm/genetics
KW - Gene Expression Profiling
KW - Genomic Instability/drug effects
KW - HeLa Cells
KW - Humans
KW - Liposarcoma/drug therapy
KW - Models, Theoretical
KW - Soft Tissue Neoplasms/drug therapy
KW - Telomere/genetics
UR - http://www.scopus.com/inward/record.url?scp=77949662980&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-09-0705
DO - 10.1158/1535-7163.MCT-09-0705
M3 - Article
C2 - 20197395
SN - 1535-7163
VL - 9
SP - 682
EP - 692
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 3
ER -