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

• Published in: Oncotarget Vol. 6; no. 30; pp. 29469 - 29481
• Main Authors: Ren, Ling, Mendoza, Arnulfo, Zhu, Jack, Briggs, Joseph W, Halsey, Charles, Hong, Ellen S, Burkett, Sandra S, Morrow, James, Lizardo, Michael M, Osborne, Tanasa, Li, Samuel Q, Luu, Hue H, Meltzer, Paul, Khanna, Chand
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 06.10.2015
• Subjects: Animals; Bone Neoplasms - genetics; Bone Neoplasms - metabolism; Bone Neoplasms - pathology; Cell Line, Tumor; Cell Movement; Disease Progression; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression Regulation, Neoplastic; Humans; JNK Mitogen-Activated Protein Kinases - metabolism; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - secondary; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Neoplasm Invasiveness; Osteosarcoma - genetics; Osteosarcoma - metabolism; Osteosarcoma - secondary; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; Research Paper; RNA Interference; Signal Transduction; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; Xenograft Model Antitumor Assays; DHT; breast cancer; integrin αvβ3; estrogen receptor-α; resveratrol
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.5177

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 metastatic 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.