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Sphere-derived tumor cells exhibit impaired metastasis by a host-mediated quiescent phenotype

2015; Impact Journals LLC; Volume: 6; Issue: 29 Linguagem: Inglês

10.18632/oncotarget.4803

1949-2553

Anne‐Marie Bleau, Carolina Zandueta, Miriam Redrado, Susana Martínez-Canarias, Leyre Larzábal, Luis M. Montuenga, Alfonso Calvo, Fernando Lecanda,

Hedgehog Signaling Pathway Studies

// Anne-Marie Bleau 1 , Carolina Zandueta 1 , Miriam Redrado 1 , Susana Martínez-Canarias 1 , Leyre Larzábal 1 , Luis M. Montuenga 1, 2, 3 , Alfonso Calvo 1, 2, 3, * , Fernando Lecanda 1, 2, 3, * 1 Program in Solid Tumors and Biomarkers, Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain 2 Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain 3 IdiSNA, Navarra Institute for Health Research, Pamplona, Spain * These authors have contributed equally to this work Correspondence to: Fernando Lecanda, e-mail: flecanda@unav.es Keywords: stem cell, dormancy, p27, osteolysis, p38 Abbreviations: TSC, tumor sphere cultures; AC, adherent cultures; BLI, bioluminescence imaging; i.c., intracardiac; i.t., intratibial Received: November 04, 2014 Accepted: July 27, 2015 Published: August 07, 2015 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.