Lung Cancer Stem Cell: Fancy Conceptual Model of Tumor Biology or Cornerstone of a Forthcoming Therapeutic Breakthrough? Tony Sourisseau, PhD, Khaled.

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Lung Cancer Stem Cell: Fancy Conceptual Model of Tumor Biology or Cornerstone of a Forthcoming Therapeutic Breakthrough? Tony Sourisseau, PhD, Khaled A. Hassan, MD, Ignacio Wistuba, MD, Frédérique Penault-Llorca, MD, PhD, Julien Adam, MD, Eric Deutsch, MD, PhD, Jean-Charles Soria, MD, PhD Journal of Thoracic Oncology Volume 9, Issue 1, Pages 7-17 (January 2014) DOI: 10.1097/JTO.0000000000000028 Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 1 Timeline of the key discoveries to the concept of CSC in lung cancer. CSC, cancer stem cell. Journal of Thoracic Oncology 2014 9, 7-17DOI: (10.1097/JTO.0000000000000028) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 2 Experimental strategies to the study of lung CSC resistance to anticancer therapy. The lung CSC can either be isolated from lung cancer–derived cell lines, from primary patient tumors, or from xenografted or GEMM tumors. The CSC population can be isolated by FACS- or magnetic beads–based technologies using cell membrane or functional markers of CSCs. The CSC identity of the putatively sorted population is then assessed in vitro by gene expression analysis, clonogenicity, or sphere-formation assay. In vivo, the CSC identity is generally assessed by subcutaneous xenotransplantation. The effect of chemotherapeutic agents on the CSC population can then be examined and compared with the non-CSC population. Alternatively, a therapeutic-resistant population can be isolated and the CSC traits of this population assessed in vitro or in vivo as previously mentioned. Finally, a population of CSCs can be isolated based on their specific ability to grow on low adherence substratum and form spheroid bodies. CSC, cancer stem cell; GEMM, genetically engineered mouse model; FACS, fluorescence-activated cell sorting. Journal of Thoracic Oncology 2014 9, 7-17DOI: (10.1097/JTO.0000000000000028) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 3 Challenges to clinical integration of lung CSC. A, A model integrating the different sources of tumor heterogeneity is presented and includes the genetically based clonal evolution (vertical doted arrow, clones are shown with different nuclei colors) and the nongenetic mechanisms of phenotypic heterogeneity (horizontal dotted arrow, the CSCs are represented as rounded cells). B, Chemotherapy primarily hits actively dividing cells and may therefore spare quiescent lung CSCs, subsequently leading to tumor relapse. C, Several pharmacological modulators of the Hedgehog, Notch, and Wnt signaling pathways can potentially deplete the lung CSC pool by enforcing their differentiation. According to recent observations, however, CSC may arise from the dedifferentiation of differentiated cells, potentially compromising the efficacy of differentiation therapies. D, Several mechanisms may contribute to the relapse ensuing targeted therapy such as the EGFR-TKI inhibition. First, genetic heterogeneity may generate resistant clones. Second, quiescent lung CSCs can resist therapy by alternative mechanisms and lead to disease relapse. From this model, tumor eradication may only be achieved by a combination therapy effecting differentiated and stem-like lung tumor cells. Combination therapies currently being evaluated in clinical trials are materialized by double arrows on the right-hand side. CSC, cancer stem cell; EGFR, endothelial growth factor receptor; TKI, tyrosine kinase inhibitor. Journal of Thoracic Oncology 2014 9, 7-17DOI: (10.1097/JTO.0000000000000028) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions

FIGURE 4 Future research strategies for the evaluation of the clinical potential of lung CSCs. The flowchart highlights the key steps for the demonstration of the lung CSC existence and its potential clinical significance. Examples of possible experimental approaches are listed. CSC, cancer stem cell. Journal of Thoracic Oncology 2014 9, 7-17DOI: (10.1097/JTO.0000000000000028) Copyright © 2014 International Association for the Study of Lung Cancer Terms and Conditions