Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma Journal Article
| Authors: | Singer, S.; Socci, N. D.; Ambrosini, G.; Sambol, E.; Decarolis, P.; Wu, Y.; O'Connor, R.; Maki, R.; Viale, A.; Sander, C.; Schwartz, G. K.; Antonescu, C. R. |
| Article Title: | Gene expression profiling of liposarcoma identifies distinct biological types/subtypes and potential therapeutic targets in well-differentiated and dedifferentiated liposarcoma |
| Abstract: | Classification of liposarcoma into three biological types encompassing five subtypes, (a) well-differentiated/dedifferentiated, (b) myxoid/round cell, and (c) pleomorphic, based on morphologic features and cytogenetic aberrations, is widely accepted. However, diagnostic discordance remains even among expert sarcoma pathologists. We sought to develop a more systematic approach to liposarcoma classification based on gene expression analysis and to identify subtype-specific differentially expressed genes that may be involved in liposarcoma genesis/progression and serve as potential therapeutic targets. A classifier based on gene expression profiling was able to distinguish between liposarcoma subtypes, lipoma, and normal fat samples. A 142-gene predictor of tissue class was derived to automatically determine the class of an independent validation set of lipomatous samples and shows the feasibility of liposarcoma classification based entirely on gene expression monitoring. Differentially expressed genes for each liposarcoma subtype compared with normal fat were used to identify histology-specific candidate genes with an in-depth analysis of signaling pathways important to liposarcoma pathogenesis and progression in the well-differentiated/ dedifferentiated subset. The activation of cell cycle and checkpoint pathways in well-differentiated/dedifferentiated liposarcoma provides several possible novel therapeutic strategies with MDM2 serving as a particularly promising target. We show that Nutlin-3a, an antagonist of MDM2, preferentially induces apoptosis and growth arrest in dedifferentiated liposarcoma cells compared with normal adipocytes. These results support the development of a clinical trial with MDM2 antagonists for liposarcoma subtypes which overexpress MDM2 and show the promise of using this expression dataset for new drug discovery in liposarcoma. ©2007 American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; protein expression; unclassified drug; human cell; histopathology; validation process; genetic analysis; cell proliferation; cell cycle; gene overexpression; unindexed drug; apoptosis; cluster analysis; gene expression profiling; models, biological; protein targeting; gene product; cell differentiation; gene expression regulation, neoplastic; reverse transcriptase polymerase chain reaction; oligonucleotide array sequence analysis; disease progression; binding protein; piperazines; cyclin b1; cyclin dependent kinase inhibitor 2a; replication factor c; cancer classification; dna topoisomerase (atp hydrolysing); thymidylate synthase; checkpoint kinase 1; cyclin dependent kinase inhibitor; forkhead transcription factor; protein p107; soft tissue neoplasms; cyclin e; somatomedin b; liposarcoma; imidazoles; cyclin dependent kinase 4; adipose tissue; protein mdm2; cyclin dependent kinase 1; ubiquitin conjugating enzyme; lipoma; ribonucleotide reductase; calreticulin; adipocyte; adipocytes; cyclin dependent kinase inhibitor 3; rac1 protein; nutlin 3a; cyclin b2; cyclin e2; fuse binding protein 1; ligase inhibitor; ribonucleotide reductase m2; transcription factor foxd1; trophinin |
| Journal Title: | Cancer Research |
| Volume: | 67 |
| Issue: | 14 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2007-07-15 |
| Start Page: | 6626 |
| End Page: | 6636 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-07-0584 |
| PUBMED: | 17638873 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 57" - "Export Date: 17 November 2011" - "CODEN: CNREA" - "Source: Scopus" |
