title: Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype.
abstract: The spread of lung cancer cells to distant sites represents a common event associated with poor prognosis. A fraction of tumor cells named cancer stem cells (CSCs) have the ability to overcome therapeutic stress and remain quiescent. However, whether these CSCs have also the capacity to initiate and sustain metastasis remains unclear. Here, we used tumor sphere cultures (TSC) isolated from mouse and human lung cancer models to enrich for CSCs, and assessed their metastatic potential as compared to non-CSCs. As expected, TSC overexpressed a variety of stem cell markers and displayed chemoresistance. The CSC phenotype of TSC was confirmed by their higher growth ability in soft agar and tumorigenic potential in vivo, despite their reduced in vitro cell growth kinetics. Surprisingly, the appearance of spontaneous lung metastases was strongly delayed in mice injected with TSC as compared to non-TSC cells. Similarly, this finding was confirmed in several other models of metastasis, an effect associated with a retarded colonization activity. Interestingly, such delay correlated with a quiescent phenotype whose underlined mechanisms included an increase in p27 protein and lower phospho-ERK1/2 levels. Thus, these data suggest that cells enriched for CSC properties display an impaired metastatic activity, a finding with potential clinical implications.
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Anne-Marie
authors: AM
authors: Bleau
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Carolina
authors: C
authors: Zandueta
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Miriam
authors: M
authors: Redrado
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Susana
authors: S
authors: Martínez-Canarias
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors: Leyre
authors: L
authors: Larzábal
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors: Luis M
authors: LM
authors: Montuenga
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors: Alfonso
authors: A
authors: Calvo
authors: Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.|IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
authors: Fernando
authors: F
authors: Lecanda
mesh_terms: D000362:Agar / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000166:cytology*; D010014:Osteolysis; D010641:Phenotype; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018874:Spheroids, Cellular / Q000166:cytology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000362:Agar; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: dormancy; osteolysis; p27; p38; stem cell