title: The metastatic microenvironment: lung-derived factors control the viability of neuroblastoma lung metastasis.
abstract: Recent data suggest that the mechanisms determining whether a tumor cell reaching a secondary organ will enter a dormant state, progress toward metastasis, or go through apoptosis are regulated by the microenvironment of the distant organ. In neuroblastoma, 60-70% of children with high-risk disease will ultimately experience relapse due to the presence of micrometastases. The main goal of this study is to evaluate the role of the lung microenvironment in determining the fate of neuroblastoma lung metastases and micrometastases. Utilizing an orthotopic mouse model for human neuroblastoma metastasis, we were able to generate two neuroblastoma cell populations-lung micrometastatic (MicroNB) cells and lung macrometastatic (MacroNB) cells. These two types of cells share the same genetic background, invade the same distant organ, but differ in their ability to create metastasis in the lungs. We hypothesize that factors present in the lung microenvironment inhibit the propagation of MicroNB cells preventing them from forming overt lung metastasis. This study indeed shows that lung-derived factors significantly reduce the viability of MicroNB cells by up regulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. Lung-derived factors affected various additional progression-linked cellular characteristics of neuroblastoma cells, such as the expression of stem-cell markers, morphology, and migratory capacity. An insight into the microenvironmental effects governing neuroblastoma recurrence and progression would be of pivotal importance as they could have a therapeutic potential for the treatment of neuroblastoma residual disease.
authors: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel 69978; Department of Biochemistry and Molecular Biology, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201.
authors: Shelly
authors: S
authors: Maman
authors: Liat
authors: L
authors: Edry-Botzer
authors: Orit
authors: O
authors: Sagi-Assif
authors: Tsipi
authors: T
authors: Meshel
authors: Weirong
authors: W
authors: Yuan
authors: Wuyuan
authors: W
authors: Lu
authors: Isaac P
authors: IP
authors: Witz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D014408:Biomarkers, Tumor / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D018450:Disease Progression; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000556:secondary; D010766:Phosphorylation / Q000235:genetics; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
keywords: disseminated tumor cells; dormant tumor cells; metastasis; microenvironment; micrometastasis; neuroblastoma