title: Characterization of the metastatic phenotype of a panel of established osteosarcoma cells.
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 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.
authors: Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Ling
authors: L
authors: Ren
authors: Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Arnulfo
authors: A
authors: Mendoza
authors: Genetic Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Jack
authors: J
authors: Zhu
authors: Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Joseph W
authors: JW
authors: Briggs
authors: Molecular Pathology Unit, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
authors: Charles
authors: C
authors: Halsey
authors: Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Ellen S
authors: ES
authors: Hong
authors: Comparative Molecular Cytogenetics Core Facility, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors: Sandra S
authors: SS
authors: Burkett
authors: School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors: James
authors: J
authors: Morrow
authors: Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Michael M
authors: MM
authors: Lizardo
authors: National Institute of Environmental Health, Research Triangle Park, North Carolina, USA.
authors: Tanasa
authors: T
authors: Osborne
authors: School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors: Samuel Q
authors: SQ
authors: Li
authors: Department of Orthopedic Surgery & Rehabilitation Medicine, University of Chicago, Medicine & Biological Sciences, Chicago, USA.
authors: Hue H
authors: HH
authors: Luu
authors: Genetic Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Paul
authors: P
authors: Meltzer
authors: Molecular Oncology Section - Metastasis Biology Group, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
authors: Chand
authors: C
authors: Khanna
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D009361:Neoplasm Invasiveness; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C491923:PHLDA1 protein, human; D014157:Transcription Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: DHT; breast cancer; estrogen receptor-α; integrin αvβ3; resveratrol