title: The cancer stem-cell hypothesis: its emerging role in lung cancer biology and its relevance for future therapy.
abstract: The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review.
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St, James's Hospital, Dublin, Ireland. Electronic address: jdoflaherty@gmail.com.
authors.forename: John D
authors.initials: JD
authors.lastname: O'Flaherty
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St, James's Hospital, Dublin, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Barr
authors.affiliation: Centre for Cancer Research & Cell Biology, School of Medicine, Dentistry & Biomedical Science, Queen's University, Belfast, Ireland.
authors.forename: Dean
authors.initials: D
authors.lastname: Fennell
authors.affiliation: Faculty of Science and Technology, CELS Portfolio (Chemical, Earth & Life Sciences), Cell and Molecular Biosciences, Queensland University of Technology, Brisbane, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Richard
authors.affiliation: Department of Surgery, Trinity College, Dublin, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: Reynolds
authors.affiliation: Department of Histopathology, Trinity College, Dublin, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: O'Leary
authors.affiliation: Thoracic Oncology Research Group, Institute of Molecular Medicine, St, James's Hospital, Dublin, Ireland.
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents