Doxorubicin resistance in a novel in vitro model of human pleomorphic liposarcoma associated with alternative lengthening of telomeres.

Abstract

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.

• Authors: Marcy A Mitchell, Jay E Johnson, Kara Pascarelli, Neil Beeharry, Maria Chiourea, Sarantis Gagos, Dina Lev, Margaret von Mehren, David Kipling, Dominique Broccoli
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 3 Pg. 682-92 (Mar 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20197395 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Doxorubicin

Topics

• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Chromosome Aberrations (chemically induced)
• Cytogenetic Analysis
• Doxorubicin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Gene Expression Profiling
• Genomic Instability (drug effects)
• HeLa Cells
• Humans
• Liposarcoma (drug therapy, genetics, pathology)
• Models, Theoretical
• Soft Tissue Neoplasms (drug therapy, genetics, pathology)
• Telomere (genetics, metabolism)