Oncotarget

Research Papers:

Characterization of the metastatic phenotype of a panel of established osteosarcoma cells

Ling Ren, Arnulfo Mendoza, Jack Zhu, Joseph W. Briggs, Charles Halsey, Ellen S. Hong, Sandra S. Burkett, James J. Morrow, Michael M. Lizardo, Tanasa Osborne, Samuel Q. Li, Hue H. Luu, Paul Meltzer and Chand Khanna _

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Oncotarget. 2015; 6:29469-29481. https://doi.org/10.18632/oncotarget.5177

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Abstract

Ling Ren1, Arnulfo Mendoza1, Jack Zhu2, Joseph W. Briggs1, Charles Halsey3, Ellen S. Hong1, Sandra S. Burkett4, James J. Morrow5, Michael M. Lizardo1, Tanasa Osborne6, Samuel Q. Li5, Hue H. Luu7, Paul Meltzer2 and Chand Khanna1

1 Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA

2 Genetic Branch, National Cancer Institute, Bethesda, Maryland, USA

3 Molecular Pathology Unit, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA

4 Comparative Molecular Cytogenetics Core Facility, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

5 School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA

6 National Institute of Environmental Health, Research Triangle Park, North Carolina, USA

7 Department of Orthopedic Surgery & Rehabilitation Medicine, University of Chicago, Medicine & Biological Sciences, Chicago, USA

Correspondence to:

Chand Khanna, email:

Keywords: osteosarcoma, PHLDA1/TDAG51, tumor metastasis

Received: June 08, 2015 Accepted: July 12, 2015 Published: August 13, 2015

Abstract

Osteosarcoma (OS) is the most common bone tumor in pediatric patients. Metastasis is a major cause of mortality and morbidity. The rarity of this disease coupled with the challenges of drug development for metastatic cancers have slowed the delivery of improvements in long-term outcomes for these patients. In this study, we collected 18 OS cell lines, confirmed their expression of bone markers and complex karyotypes, and characterized their in vivo tumorgenicity and metastatic potential. Since prior reports included conflicting descriptions of the metastatic and in vivo phenotypes of these models, there was a need for a comparative assessment of metastatic phenotypes using identical procedures in the hands of a single investigative group. We expect that this single characterization will accelerate the study of this metastatic cancer. Using these models we evaluated the expression of six previously reported metastasis-related OS genes. Ezrin was the only gene consistently differentially expressed in all the pairs of high/low metatstatic OS cells. We then used a subtractive gene expression approach of the high and low human metastatic cells to identify novel genes that may be involved in OS metastasis. PHLDA1 (pleckstrin homology-like domain, family A) was identified as one of the genes more highly expressed in the high metastatic compared to low metastatic cells. Knocking down PHLDA1 with siRNA or shRNA resulted in down regulation of the activities of MAPKs (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs). Reducing the expression of PHLDA1 also delayed OS metastasis progression in mouse xenograft models.


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