Novel dedifferentiated liposarcoma xenograft models reveal PTEN down-regulation as a malignant signature and response to PI3K pathway inhibition.

Abstract

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care.

• Authors: Kathleen B Smith, Linh M Tran, Brenna M Tam, Elizabeth M Shurell, Yunfeng Li, Daniel Braas, William D Tap, Heather R Christofk, Sarah M Dry, Fritz C Eilber, Hong Wu
• Journal: The American journal of pathology (Am J Pathol) Vol. 182 Issue 4 Pg. 1400-11 (Apr 2013) ISSN: 1525-2191 [Electronic] United States
• PMID: 23416162 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Cell Differentiation (drug effects, genetics)
• Cell Proliferation (drug effects)
• Down-Regulation (drug effects, genetics)
• Female
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lipid Metabolism (drug effects)
• Liposarcoma (drug therapy, enzymology, genetics, pathology)
• Male
• Mice
• Middle Aged
• Neoplasm Invasiveness
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Signal Transduction (drug effects, genetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Up-Regulation (drug effects, genetics)
• Xenograft Model Antitumor Assays